A dose-response study of alprostadil sterile powder (S.Po.) (Caverject # ) for the treatment of erectile dysfunction in Korean and Indonesian men

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1 International Journal of Impotence Research (1997) 9, 47±51 ß 1997 Stockton Press All rights reserved /97 $12.00 A dose-response study of alprostadil sterile powder (S.Po.) (Caverject # ) for the treatment of erectile dysfunction in Korean and Indonesian men HK Choi 1, A Adimoelja 2, SC Kim 3, DM Soebadi 4, DH Seong 1 and RJ Garceau 5 1 Department of Urology, Yonsei University, College of Medicine, Seoul, Korea; 2 Unit Andrology Biomedicine, O&G Department, Dr. Soetomo Hospital/Airlangga University, Surabaya, Indonesia; 3 Department of Urology, Yongsan Hospital, Chung Ang University, College of Medicine, Seoul, Korea; 4 Department of Surgery/Urology, Dr. Soetomo Hospital/Airlangga University, Surabaya, Indonesia; and 5 Pharmacia and Upjohn, 7000 Portage Road, Kalamazoo, MI 49001, USA This open-label, dose-escalation study investigated the ef cacy and safety of alprostadil (PGE 1, prostaglandin E 1 ) Sterile Powder (S.Po.) (Caverject # ) for treatment of erectile dysfunction (ED) in 84 men with ED of various etiologies lasting 4 months. Doses started with 2.5 mg, then 5 mg, 10, 15, 20, 30, up to a 40 mg maximum. Eligible patients received single alprostadil injections in the physician's of ce until an erection occurred. Ten minutes after injection, the patient's erection was clinically evaluated. Optimal response was de ned as erection suf cient to permit vaginal penetration and lasting 30±60 min. The patient also reported his own evaluation of response and any side effects. Patients were 24±65 y old (mean: 43.7 y), had ED of psychogenic, vascular, or neurogenic origin lasting 4 months±30 y (mean: 3.75 y). Of 84 patients enrolled, 82 completed the study. In the 82 patients who completed the study 78 (92.9%) achieved an optimal response; 18/78 patients (23.1%) had an optimal response at 2.5 mg, 9/78 (11.5%) at 5 mg, 21/78 (26.9%) at 10 mg, 12/ 78 (15.4%) at 15 mg, and 11/78 (14.1%) at 20 mg. Only 5/78 (6.4%) at 30 mg and 2/78 (2.6%) at 40 mg achieved an optimal response. Mean optimal alprostadil dose was 11.9 mg, and the mean minimal effective dose was 9.9 mg. Mean onset of erection was 11.2 min; mean duration of erection was 50.5 min. Penile pain in ve patients (6%) was the only reported side effect. Keywords: erectile dysfunction; alprostadil; dose-response; impotence; Korea; Indonesia Introduction Correspondence: Dr RJ Garceau. Received 2 November 1995; revised 25 September 1996; accepted 27 November 1996 Between 15 million and 20 million men in the United States are estimated to suffer from erectile dysfunction (ED), de ned as the inability to achieve an erection suf cient to permit vaginal penetration. Since the introduction of intracavernous injection of vasoactive agents in 1982, 1 the diagnosis and treatment of male impotence have developed rapidly. Intracavernous injection therapy is usually recognized by Urologists as the gold standard of treatment for ED. 2 Since this therapy was rst reported with papaverine, 1 various other pharmacologic agents, such as phentolamine, 3 or a combination of papaverine/phentolamine have been used. The use of prostaglandin E 1 (PGE 1 ) for diagnosis and treatment of male impotence was rst reported by Ishi, et al in From 55% to 86% of men suffering from ED are reported to have complete functional erections after PGE 1 injections, depending on the study and possibly on the etiology of ED. 5±13 The usual effective dose varies from 10 to 20 mg, although some patients may require higher or lower doses. 5±16 The most frequently reported side effect of alprostadil injection is pain after injection, which occurs in 16.8% of patients. 8 In 1995 when the US FDA approved The Upjohn Company's alprostadil sterile powder (S.Po.) formulation (Caverject # ), for the treatment of ED. At the time of this study alprostadil was not yet approved for the treatment of male impotence in most Asian countries, including Korea and Indonesia. The US approved formulation of alprostadil currently used for clinical and investigative purposes is a freeze-dried sterile powder (20 mg/vial), a form which was designed to facilitate sterile injections, eliminate inadvertent overdoses, and improve the convenience of administration. While most studies to date have reported that doses between 10 mg and 20mg of alprostadil produce complete erections for the majority of patients, there is no standard, accepted dosage of alprostadil that achieves the maximal effective response with minimal or no adverse effects. In a recent study of

2 patients with vasculogenic impotence, 17 reported the successful use of an average dose of 5.58 mg of PGE 1 in 70 patients using it for selfinjection home therapy. The purpose of this open-label, dose-escalation study was to determine the minimal effective dose and the optimal effective dose in Korean and Indonesian men who had not previously received injection therapy for impotence. A secondary purpose was to evaluate the safety and side effects of intracavernous injection therapy with the PGE 1 sterile powder formulation of alprostadil. vaginal penetration and lasting from 30±60 min. If this response was achieved with the 2.5 mg dose, then for the purpose of classi cation that dose was de ned as both his minimal effective and optimal dose. If he failed to achieve an optimal response at the 40 mg dose, no additional higher doses were administered. Caverject TM was used in this study. When reconstituted with 1 ml of sterile water, this formulation contains 20 mg/ml of PGE, S. Po., 172 mg/ ml of lactose, and 47 mg/ml of sodium citrate with a 4±6 ph. Materials and methods Ef cacy assessment endpoints Patients A total of 84 men from 24 to 65 years of age (mean: 43.7 y) who had ED lasting from 4 months to 30 years (mean: 3.75 y) were enrolled in the study. The etiology of ED was psychogenic (42.9%), arteriogenic (10.7%), venogenic (7.1%), or neurogenic (3.6%), or a combination of more than one etiology (35.8%). All but one of the patients were Korean or Indonesian. After signing an informed consent form, all patients had physical (vital signs, penile exam, bulbocavernous re ex, cremasteric re ex, and sphnicter tone) and laboratory (CBC and differential, urine analysis, and VDRL) examinations. The medical history included the nature and duration of ED, as well as smoking habits. The probable cause(s) of ED was determined by each investigator according to customary of ce practice in the investigator of ces. Patients were excluded if they had a history of or propensity for priapism, or an underlying disease such as sickle cell anemia or trait, untreated endocrine disorders, cavernosal brosis or anatomical deformation of the penis, or Peyronie's disease. Patients were also excluded if they had a recent onset of acute illness (e.g., myocardial infarction, stroke, or arrhythmias), a history of sexually transmitted diseases within the prior 6 months, previously used intracavernosal injections, or were taking investigational or hormonal (e.g., testosterone) medications. Dosage regimen This dose-escalation study started with a 2.5 mg dose. 10 The starting dose was then titrated upward to 5, 10, 15, 20, 30, and 40 mg doses. Each patient then had this starting dose titrated upward with at least 24 hours between doses until he reached his optimal response, de ned as an erection suf cient to achieve Optimal dose response was the primary ef cacy measure, de ned as the patient's ability to achieve a full erection suf cient to permit vaginal penetration and lasting between 30 and 60 min. Secondary endpoints were the time-to-erection, duration of full erection, and the patient's evaluation of erectile response at the end of two hours. Patients were followed by the same trained observer for the entire injection period at 10-minute intervals starting after an injection. Erections were evaluated on a 3-point scale as ``absent,'' ``partial,'' or ``full.'' Patients were followed until they had achieved complete detumescence. Non-responders were followed for at least 60 min after injection. Non-responders and partial responders could receive the next higher dose up to the maximum 40 mg dose. Safety measurements Patients were evaluated for the occurrence of any medical events, and vital signs were recorded as injection baseline and thereafter at 5, 15, 60, and 120 (if a response was noted) minutes after injection. The patient's overall evaluation of the effectiveness and side effects of the injection were also recorded at the end of the study period. If the patient reported any pain, he was asked to assess it as mild, moderate, or severe. He was also asked about the potential impact of the pain on the feasibility of intercourse. Statistical analysis Descriptive statistics were used for the primary analyses. For optimal and lowest used doses, the patient distribution was categorized by dose, and the mean was calculated with a 95% con dence interval. All patients who received at least one dose

3 of alprostadil were included in all ef cacy and safety analyses. 49 Results Primary ef cacy measurements Of 84 enrolled patients, 82 completed the study. The two patients who dropped out of the study were not included in the nal analyses; one was lost to follow-up and the other requested implantation surgery. Of the 82 who completed the study, 78 (92.9%) achieved an optimal response (Table 1; Figure 1). More than half of patients (48, 61.5%) achieved an optimal response between 2.5 and 10 mg, and more than three quarters (60/78, 76.9%) reached an optimal response by the 15 mg dose. Eighteen patients (23.1%) had an optimal response at 2.5 mg, 9 (11.5%) at 5 mg, 21 (26.9%) at 10 mg, 12 (15.4%) at 15 mg, and 11 patients (14.1%) at 20 mg. Only 2.6% of (2) patients achieved an optimal response at 40 mg, and only 6.4% at 30 mg (Figure 1). The mean optimal alprostadil dose was 11.9 mg ( 8.9 mg), and the median dose was 10 mg. Duration was recorded for all full erections at the optimal dose as well as for time to complete detumescence. Mean duration of optimal duration erection was 50.5 min (30±150 min). The mean time Figure 1 Split bar graph showing the percentage of patients with an optimal response at each different dose level and the cumulative percentage of responders across dose levels. to erection for optimal responders (latency) was 11.2 min. The mean total time to complete detumescence was 84.9 min (40±160 min). There was no statistically signi cant correlation between etiology and optimal dose response (Table 2). Although ED of psychogenic origin was the most common kind, accounting for 36 of 84 patients (42.9%), optimal dose responses in this group were spread across all dose levels up to 30 mg; only one patient had an optimal dose response at 40 mg. The Table 1 Pre-treatment characteristics and optimal dose response statistics for Oriental/Asian men with erectile dysfunction Pre-treatment characteristics (N ˆ 84, 100%) No. patients Mean (s.d.) Minimum Maximum Age (y) (10.4) Race 83 (98.8) Oriental/Asian 1 (1.2) Other Height (cm) (9.4) Weight (kg) (7.8) Duration of ED (y) (4.8) Origin of ED (N ˆ 84, 100%) Venogenic 6 (7.1) Arteriogenic 9 (10.7) Psychogenic 36 (42.9) Neurogenic 3 (3.6) Mixed** 30 (35.8) Optimal dose response statistics (N ˆ 78, 92.9%)* Mean (s.d.) Median Minimum Maximum Mean optimal dose (mg) 11.9 (8.9) Mean duration of erection (min) 50.5 (24.6) Mean latency (min) 11.2 (4.1) Mean time to complete detumescence (min) 84.9 (26.8) * N ˆ total number of patients who reached optimal dose response during of ce injection.** venogenic arteriogenic or psychogenic; arteriogenic psychogenic; neurogenic arteriogenic or psychogenic

4 50 Table 2 Correlation between number (%) of optimal dose responders at each dose and etiology of erectile dysfuntion Etiology N* Alprostadil dosage levels Total number of optimal 2.5 mg 5 mg 10 mg 15 mg 20 mg 30 mg 40 mg responders (%) Venogenic 6 4 (66.7) 0 (0.0) 1 (16.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 5 (83.3) Arteriogenic 9 2 (22.2) 1 (11.1) 1 (11.1) 2 (22.2) 1 (11.1) 0 (0.0) 1 (11.1) 8 (88.9) Psychogenic 36 4 (11.1) 6 (16.7) 9 (25.0) 4 (11.1) 9 (25.0) 3 (8.3) 1 (2.8) 36 (100) Neurogenic 3 2 (66.7) 0 (0.0) 0 (0.0) 1 (33.3) 0 (0.0) 0 (0.0) 0 (0.0) 3 (100) Mixed** 30 6 (20.0) 2 (6.7) 10 (33.3) 5 (16.7) 1 (3.3) 2 (6.7) 0 (0.0) 26 (86.7) * N ˆ total number of patients whose ED was diagnosed by etiology. ** venogenic arteriogenic or psychogenic; arteriogenic psychogenic; neurogenic arteriogenic or psychogenic other groupings (arteriogenic, venogenic and neurogenic) had too few patients to see any dose correlation. For the 30 patients with ED of more than one etiology, 18 patients (60%) achieved an optimal dose response between 2.5 mg and 10 mg. Physician assessment of a full erection was greater than patient assessment at all dose levels (Table 3). When the physician assessment included time of a full erection for 30±60 min (optimal erection) this then corresponded to patient assessment. The evaluation of any erection by the patient versus the physician again shows the physician much more likely to assess the patient as having a response than the patient himself. Eighty-two of 84 patients (97.6%) were able to achieve a full erection. Seventy-eight of 84 patients (92.9%) who achieved an erection were also able to achieve an optimal response with alprostadil. Safety results Penile pain in ve patients (6%) was the only reported side effect. No episode of pain was considered serious, and all patients recovered with no residual effects. No patients discontinued because of pain. Not all injections were associated with pain, nor was pain dose-related. No patient experienced an erection lasting longer than 3 hours. One patient had an erection lasting 134 min at 2.5 mg. There were no reports of penile hematoma, penile abnormalities, or abnormal clinical or laboratory results. Discussion Erectile dysfunction is becoming recognized as a common disorder in Paci c Rim countries like Korea and Indonesia. Reliable estimates on the incidence of ED are not available, but its frequency is probably similar to that reported in the United States. Results from this study indicate that doses of alprostadil S.Po. between 2.5 mg and 10 mg may produce an optimal response in more than half of men suffering from ED, regardless of etiology. Starting with a 2.5 mg dose may minimize the risk of prolonged erection or priapism in all patients 17 as well as help to determine the lowest optimal dose for individual patients. In this study the mean optimal dose of alprostadil was 11.9 mg, and the mean minimal dose was 9.9 mg. The dose which appears to optimal agreement between subjects' assessment and Investigators includes having a time of 30±60 min of a full erection as assessed by the physician. Unlike other studies that have reported a correlation between origin of ED and dose response ef cacy, 18 this study did not nd any signi cant correlations between these factors. When analyzing by country there were no notable differences between Korean and Indonesian men in their minimally effective or optimal dose responses. The incidence of penile pain as a side effect of intracavernosal injection was lower (6%) in this study than has been reported in other studies (16.8%). 8 This difference may be related to the low starting dose and the fact that over half the patients achieved an optimal response to alprostadil injection by the 10 mg dose level or may be related to Table 3 Investigator versus subject assessments DosageÐmg 2.5 mg 5 mg 10 mg 15 mg 20 mg 30 mg 40 mg Full erectionðinvestigator Full erectionðsubject Optimal erection Any erectionðinvestigator Any erectionðsubject Total number subjects receiving injection

5 local customs. Indonesian people favor injections as a method of receiving medications. This may result in the feeling that some injection pain is normal and therefore not to be reported. Absence of other side effects (e.g., hematoma, etc.) may re ect both the low starting dose, and the technique of these Investigators. Conclusion Alprostadil sterile powder is safe and effective for the treatment of ED in Korean and Indonesian men suffering from impotence of various origins. A starting dose of 2.5 mg may produce satisfactory results for most patients with a reduced risk of side effects. References 1 Virag R. Intracavernous injection of papaverine for erectile failure. Letter to the editor. Lancet 1982; 2: Lue TF, Goldstein I. Introduction. In: Goldstein I, Lue TF, eds. The role of alprostadil in the diagnosis and treatment of erectile dysfunction. Proceedings of a symposium: Aug 3±4, Brook Lodge, Kalamazoo, Michigan. Princeton, NJ: Excerpta Medica, 1993:1±2. 3 Zorgniotti AW, Le eur RS. Auto-injection of the corpus cavernosum with a vasoactive drug combination for vasculogenic impotence. J Urol 1985; 133: 39±41. 4 Ishi N, Watanabe H, Irisawa C, Kikuchi Y, Kawanura S, Suzuki K, et al. Studies on male sexual impotence report 18: Therapeutic trial with prostaglandin E 1 for organic impotence. J Jap Soc Urol 1986; 77: 954± Adaikan PG, Ng SC, Chan C, Ratnam SS. Why intracavernous PGE1 for diagnosis and treatment of impotence? Int J Impotence Res 1990; 2(suppl 2): 325± Hwang TI-S, Yang C-R, Wang S-J, Chang C-L, Tzai T-S, Change C-H, Wu H-C. Impotence evaluated by the use of prostaglandin E 1. J Urol 1991; 146: 786± Junemann K-P, Alken P. Pharmacotherapy of erectile dysfunction: a review. Int J Impotence Res 1989; 1: 71±93. 8 Linet OI, Neff LL. Intracavernous prostaglandin E 1 in erectile dysfunction. Clin Investig 1994; 72: 139± Lewis RW. The pharmacologic erection. Prob Urol 1991; 5: 541±558. J Urol 1989; 141: 549± Lee LM, Stevenson WD, Szasa G. Prostaglandin E 1 versus phentolamine/papaverine for the treatment of erectile impotence: A double-blind comparison. J Urol 1989; 141: 549± Sarosdy MF, Hudnall CH, Erickson DR, Hardin TC, Novicki DE. A prospective double-blind trial of intracorporeal papaverine versus prostaglandin E1 in the treatment of impotence. J Urol 1989; 141: 551± Schramek P, Waldhuaser M. Dose-dependent effect and sideeffect of prostaglandin E 1 in erectile dysfunction. Br J Clin Pharmac 1989; 28: 567± Ravnik-Oblak M, Oblak C, Vodusek DB, Kristl V, Ziherl S. Intracavernous injection of prostaglandin E 1 in impotent diabetic men. Diabetes 1991; 40(suppl 1): 533a. 14 Gerber GS, Levine LA. Pharmacological erection program using prostaglandin E 1. J Urol 1991; 146: 786± Porst H. Prostaglandin E 1 bei erektiler Dysfunktion. Urologe 1989; 28: 94± Earle CM, Keogh EJ, Ker JK, Cherry DJ, Tulloch AGS, Lord JD. The role of intracavernous vasoactive agents to overcome impotence due to spinal cord injury. Paraplegia 1992; 30: 273± Von Heyden B, Donatucci CF, Kaula N, Lue TF. Intracavernous pharmacotherapy for impotence: Selection of appropriate agent and dose. J Urol 1993; 149: 1288± Gana TF, Quinzanos LF, Castell R, Dator JDP, Gatchalian ER, Lim GU. A dose-response study of alprostadil (PGE 1 ) in patients with erectile dysfunction. Submitted to J Urol