A Study in Patients with Erectile Dysfunction Comparing Different Formulations of Prostaglandin E1

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Vol. 154. 1744-1747. November 1995 Printed in U.S.A.

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A STUDY IN PATIENTS WITH ERECTILE DYSFUNCTION COMPARING DIFFERENT FORMULATIONS OF PROSTAGLANDIN E l D. VANDERSCHUEREN, R. M. HE-, E. J. KEOGH, R. W. CASEY, W.-H. WEISKE, F. G. OGRINC AND H. J. DE KONING GANS ON BEHALF OF THE ALPROSTADIL STUDY GROUP* From the Department of Endocrinology, Catholic University of Leuuen, Leuven, Belgium; Reproductive Medicine Research Institute of Sir Charles Gurdner Hospital, Nedlands, Australia; C.A.R.E. Centre, Mississauga, Ontario, Canada; Urology, Stuttgart, Germany, and Upjohn Company, Kalamazoo, Michigan

ABSTRACT

Purpose: Prostaglandin E l sterile powder and sterile solution are 2 new formulations of exogenous prostaglandin E l that are more convenient for auto-injection therapy for erectile dysfunction than the presently used pediatric sterile solution. Therefore, the pharmacodynamic profiles of intracavernous prostaglandin E l sterile powder and nonalcohol sterile solution were compared with the pediatric sterile solution in men with erectile dysfunction who were known to be stable responders to intracavernous prostaglandin El. Materials and Methods: Based on the dose used at home, patients were randomized to 1of 5 dose groups: 0 pg. (placebo), 2.5 pg., 5 pg., 10 pg. or 20 pg. Each patient received a single injection of the same dose of each of the 3 formulations. The primary pharmacodynamic end points were clinical evaluation of erectile response, Rigiscant real-time evaluation of erectile response and patient evaluation of erectile response. Results: No significant differences were identified among the formulations for any of these end points, either by comparison among all active doses or by comparison a t each prostaglandin E l dose level. There was also little or no intra-patient variation in dose response and the inter-dose variation in response between patients was not significant. Pharmacodynamic end points were well intercorrelated, although assessment of erectile response by the patients tended to be more positive than that by RigiScan or clinical evaluation. There were no major side effects. Penile pain on injection and/or during erection occurred in 9 to 17% of the patients according to the formulations. However, penile pain was also reported by 11% of the placebo-treated patients. Conclusions: The 3 formulations of prostaglandin E l showed equivalence and were safe for the treatment of erectile dysfunction with respect to side effects. KEY WORDS:alprostadil, prostaglandins E, impotence, penile erection, drug therapy Intracavernous injection of prostaglandin E l has been shown to be successful in the treatment of erectile dysfunction.' When injected at doses of 10 to 20 pg. prostaglandin E l produces complete and/or functional erections in 55 to 86%of the patients with erectile dysfunction of various origin.2-4 This result was also confirmed in recent articles in which overall response rates of 67%5 and 82%6 were reported. Prostaglandin E l is a naturally occurring constituent of many mammalian tissues and prostaglandin E l receptors have also been quantified in the cavernous tissue of men.7 Moreover, the receptor density and binding affinity correlate well with the clinical response to intracavernous prostaglandin E l injection, suggesting that this receptor binding may be an important initial step in the mechanism of action of prostaglandin E l on penile erection. Following intracavernous injection, prostaglandin E l is also rapidly metabolized in the cavernous tissue.8 Currently, in the treatment of erectile dysfunction prostaglandin E l is prepared as a magistral preparation by a 25fold dilution of a pediatric sterile solution containing 500 pg. prostaglandin E l in 1ml. of dehydrated alcohol. The dilution

of the pediatric sterile solution to doses suitable for the treatment of erectile dysfunction may be subject to error. Since penile pain a t injection andlor during erection is a commonly reported side effect of prostaglandin E1,Z.g it is possible that this side effect is related either to inappropriate dilution or to the alcohol component. Although priapism does not frequently occur after injection of prostaglandin El:. 10 it is possible that its occurrence may be related to the current formulation. Dilution of any product always has a risk of bacteriological contamination. For this reason the manufacturer's insert for the pediatric sterile solution clearly stipulates that any solution more than 24 hours old should be discarded. To overcome these problems the manufacturer has recently prepared 2 new formulations of prostaglandin E l for the treatment of erectile dysfunction. After reconstitution with 1 ml. sterile bacteriostatic water for injection, the freeze-dried sterile powder contains 20 pg./ml. prostaglandin El. The frozen prostaglandin E l sterile solution can be used by the patient directly after thawing. The major objective of our study was to investigate the pharmacodynamic equivalence of the 3 different prostaglandin E l formulations (pediatric Accepted for publication May 5, 1995. * Members: R. W. Casey, A. Czyzyk, R. De Bruyne, E. J. Keogh, P. sterile solution, sterile powder and nonalcohol sterile sohLavoisier, C. McMahon, A. Schmidt, L. Valiquette, D. Vanderschueren, tion) and to determine if the side effect profiles of the formuW.-H. Weiske, E. Wespes, 0. I. Linet, F. G. Ogrinc,R. M. Heyrman and lations were similar. H. J. de Koning Gans.

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Editor's Note: This article is the third of 5 published in this issue for which category 1 CME credits can be earned. lnstructions for obtaining credits are given with the questions on pages 1910 and 1911.

MATERIALS AND METHODS

Study design. This multi-national, multicenter, doubleblind, placebo-controlled, fixed dose, randomized crossover

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COMPARISON OF DIFFERENT FORMULATIONS OF PROSTAGLANDIN E l IN ERECTILE DYSFUNCTION

study design was prospectively approved by the ethical review committee of each participating center. After written informed consent was obtained, men with erectile dysfunction were included in the study and received 1 injection of the same dose (2.5 pg., 5 pg., 10 pg. or 20 pg.) of each prostaglandin E l formulation or 1 injection of placebo for each formulation, for a total of 3 injections for the entire study. m e r e was a washout period of at least 3 days between the administration of the 3 formulations studied. Before study entry all patients underwent a screening examination, consisting of a medical history, physical examination and routine safety laboratory evaluation, as well as measurement of relevant hormone levels and an electrocardiogram. Study population. Patients with erectile dysfunction, defined as the inability to achieve rigidity sufficient for vaginal penetration, of at least 4 months in duration were selected regardless of the type of dysfunction. To participate, patients had to be known stable responders to intracavernous prostaglandin E l . Patients were excluded if they had cavernous fibrosis, anatomical deformation of the penis, Peyronie's disease or a history of priapism, or if they were suffering from major diseases or took drugs that could substantially affect the evaluation of the erectile function. A total of 210 men 29 to 70 years old (mean age 53.1) was enrolled in the study. The duration of erectile dysfunction ranged from 0.5 to 41.0 years (mean 4.8). According to the clinical judgment of the investigator, the most prevalent cause of erectile dysfunction was psychogenic in 36% of the patients followed by vasculogenic in 21%, neurogenic in 7%, diabetes in 7% and mixed (vasculogenic-neurogenic) in 15%.An additional 15%of the population was classified as having other causes, including idiopathic, idiopathidage or post-pelvic traumafneurogenic etiologies. Of the 210 patients randomized 199 completed the study, that is they received 1 injection of each of the 3 formulations. The most frequent reason for discontinuation was patient loss to followup (1%).One patient in the 10 pg. group discontinued the study due to severe penile pain after injection, which was considered drug-related, and 2 discontinued the study due to systemic medical events, which were not judged to be related to study medication. Study medications. The study medication consisted of 3 different formulations of prostaglandin El: pediatric sterile solution, sterile powder and nonalcohol sterile solution. All formulations were intended to be used as a sterile solution for intracavernous administration. Patients received either single injections of each of the 3 placebo formulations or single injections of a fixed dose of either 2.5 pg., 5 pg., 10 pg. or 20 pg. of prostaglandin E l from each of the 3 active formulations. Randomization was done according to the dosage of

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jrostaglandin E l used at home. Patients using less than 10 ug. prostaglandin E l at home were randomized to receive placebo, or 2.5 pg. or 5 pg. prostaglandin E l , while those using 10 pg. or more at home were randomized to receive placebo, or 10 m. or 20 pg. prostaglandin E l . Study endpoints. To show that the 3 different formulations were comparable in efficacy, the pharmacodynamic end points chosen were clinical evaluation of erectile response by the investigator, RigiScan real-time monitoring of erectile response and patient assessment of erectile response. A clinical positive response was defined as an erection with sufficient rigidity and tumescence for vaginal penetration. An erectile response by RigiScan monitoring was defined as 70% or more radial rigidity of the penis for 10 minutes or longer.I1 Patient assessment of erectile response was rated on a scale from 0 (not effective) to 3 (very effective). Statistical analysis. The primary objective of all statistical analyses was to compare the 3 prostaglandin E l formulations. Although patients were assigned to 1 of the 4 doses of prostaglandin E l or placebo, the dose groups were considered strata or blocks in the analyses and were not intended for comparisons. The crossover design allowed for the assessment of first-order carryover effects from 1 crossover period to the next period, as well as the assessment of sequence effects. A preliminary analysis for continuous variables (duration of erection and maximum penile radial rigidity) was done using analysis of variance.12 For categorical variables (response to injection based on clinical evaluation, and response to injection based on RigiScan data), Friedman's test was used to assess the overall formulation effect within a dose. If this proved to be significant, pairwise comparisons of the formulations were performed using McNemar's test.13 For all pairwise comparisons, individual pairs of formulations were declared significantly different if the overall test of formulation effect was significant (p S0.05) and the pairwise comparison was also significant (p 50.05). RESULTS

Figure 1 shows the response (expressed as percentage of patients) to the intracavernous injection based on a clinical evaluation. Response was defined as full rigidity sufficient for vaginal penetration. There were no significant difFerences among the formulations within any dose group or for the combined active dose p u p (p >0.1). Furthermore, responses to the active doses of 5 m., 10 pg. and 20 pg. seemed equivalent for all 3 formulations. Also, when response was defined on the basis of Rigiscan data no significant differences were observed among the for-

Full Rigidity by Clinical A t w s m m t

RtGlSCAN :? 70% for 2 10 min.

'Oon 80 60 40 20 0

FIG. 1. Percentage of patients with positive response to intracave m u s injection based on clinical evaluation. Positive response was defined as erection judged by investigator to have sufficient rigidity and tumescence for vaginal penetration. m, new sterile solution. 0, sterile powder. 8 ,pediatric sterile solution. NX,, prostaglandin El.

FIG.2. Percentage of patients with positive response to intracavernous injection based on RigisCan data. Positive response W ~ Sdefined as erection with radial rigidity of 706 or more and lasting 10 sterile powder. H, minutes or longer. m, new sterile solution. 0, pediatric sterile solution. PGE,, prostaglandin E l .

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COMPARISON OF DIFFERENT FORMULATIONS OF PROSTAGLANDIN E l IN ERECTILE DYSFUNCTION Dumtion of erection (minutes) based on Rigiscan data

DISCUSSION

Our study clearly demonstrated that the pharmacological response to the different formulations of prostaglandin E l Dose (& New Sterile Sterile powder Pediatric Sterile was similar when comparing different doses or when comSolution Solution paring all active doses together. Therefore, we may assume 0.5 -f: 0.5 1.6 2 1.4 0.0 ? 0.0 Placebo that the different formulations are bioequivalent. This as27.4 ? 7.7 32.8 2 8.2 2.5 29.8 2 8.7 sumption should be correct because prostaglandin El was 64.8 ? 11.8 63.5 2 11.7 5 51.9 ? 9.6 injected via the intracavernous route. This can be considered 34.6 ? 9.2 35.0 2 9.4 10 29.1 z 8.2 49.9 ? 9.7 51.1 2 11.1 20 52.3 ? 10.9 as a true 1-compartment m0de1.I~Indeed, when injected inDuration of erection expressed as mean plus or minus standard e m r in tracavernously, its effect is confined to the cavernous tissue minutes based on RigiScan data. Duration was defined as minutes from the in which it is rapidly metabolized resulting in nonmeasurstart of erection (time when radial rigidity first reached 70% or more at the tip or base of the penis, given that it remained at that level for 10 consecutive able systemic concentrations after intracavernous injection.8 minutes) to the end of erection (time when radial rigidity decreased to less It is also known that prostaglandin El is rapidly metabolized than 10% at the tip and base of the penis,given that it remained at that level when injected systemically, mainly due to a significant firstfor 10 wnsecutive minutes). pass effect on the pulmonary c i r c ~ l a t i o n . ~ ~ The localized effect and metabolization of prostaglandin E l in cavernous tissue without systemic interference may also PATIENT ASSESSWENT OF EACH FORMULATlON explain why we found little or no intra-patient variation. Indeed, pharmacological responses were similar at visits 1to 3. In clinical terms, this finding would mean that, once a patient is established on a dose he will probably continue to have a similar response to the dose of prostaglandin El without loss of sensitivity to this product. We were also surprised to find that our patients who were stable responders at home on a dose of less than 10 pg. showed no significant differences in response between doses of 2.5 and 5 pg. Also, the patients who were stable responders a t home a t doses of 10 pg. or more showed no significant 10 20 differences in response between doses of 10 c ~ g .and 20 pg. In clinical practice, this would mean that one can probably FIG.3. Mean response in each dose up to intracavernous injec- maintain the patient on a lower dose of prostaglandin El at tion based on patient assessment rateKn scale of 0 (not effective)to home. A n improved hemodynamic response after long-term 3 (very effective). For clarity, bars representing standard error were intracavernous injection for erectile dysfunction has already omitted. W, new sterile solution. 0, sterile powder. W, pediatric been observed previously.16 Patients who use 20 pg. may, sterile solution. PGE,, prostaglandin El. therefore, have a similar response to a 10 pg. dose and those who use 5 pg. may have a similar response to a 2.5 pg. dose. Recently, a single-blind, placebo-controlled study showed mulations for the combined active dose group or for the active that 80% of the patients responded to prostaglandin El at doses of 5 pg., 10 pg. and 20 pg. within formulations (fig. 2). doses of less than 20 %.I7 In another double-blind study a Response was defined as the presence of 70% rigidity for at plateau effect was reached at 5 to 10 pg.18 Most studies, least 10 minutes. The overall response (percent) by RigiScan however, use a starting prostaglandin E l dose of 20 pg.lS on all active doses tended to be somewhat lower than the Once established on a starting dose, it then is possible that patients w i l l also have a similar response to a dose lower response (percent) by clinician evaluation. than the starting dose. Therefore, it may also be wise to start Finally, the patient assessment of each formulation is patients a t a dose of 10 pg. instead of 20 pg. It is also shown in figure 3. Again, no differences were observed among important to note that even a low dose of 2.5 pg. gives a the formulations for any dose level or for all active doses sigdicantly different response compared with placebo, combined. Also, the subjective evaluation of the response by which lends scientific strength to the clinical experience that the patient seemed no different between the active doses of 5 some patients with erectile dysfunction can be maintained on pg. to 20 pg. The duration of erectile response as evaluated low doses, such as 2.5 pg. prostaglandin El. by RigiScan data was not significantly different among the The 2 new formulations of prostaglandin El also offer an groups (see table). advantage in that they are ready to use for the patient, are Overall, there was agreement- defined as the sum of the not subject to dilution or an error of dilution, and do not number of injections that resulted in a response by all meth- present the problems of bacteriological stability of a solution, ods plus the number of injections that resulted in no response since they may be used immediately. The major side effect, by all methods divided by the total number of injections also reported previ0usly,2~9was penile pain, which occurred among all 3 methods of evaluation- for 313 of the 488 after using all 3 different formulations. Therefore, we may prostaglandin El injections (64%)for which evaluations were assume that penile pain is related to the prostaglandin El available. The majority of disagreement was due to the 72 itself and not to the formulation or its Drenaration. Interestinjections (15%) that were rated as a resDonse by clinical and ingly, however, penile pain was also repoked in 11% of the patient evaluations but not by the Rigkcan data. Also, 60 placebo treated patients. Therefore, penile pain may also be injections (12%) were rated as a response by patient evalua- explained by other factors, such as injection technique or tion but not by clinical evaluation or RigiScan data. patient fear of the injection. However, this last explanation is There were no reports of major side effects of priapism or unlikely because all patients were known stable responders blood pressure changes in this study. The most frequent to intracavernous prostaglandin El and were familiar with medical event for each prostaglandin El formulation was the method of administration. penile pain, which occurred in 9% of the patients given the Priapism was not reported in any of the 210 patients who pediatric sterile solution, 14% given the sterile powder and received more than 600 injections in this study, which is in 17% given the nonalcohol sterile solution. However, penile agreement with the low incidence of priapism secondary pain also occurred in 11% of the placebo treated patients. intracavernous prostaglandin El that has been reported in Prostaglandin El

COMPARISON OF DIFFERENT FORMULATIONS OF PROSTAGLANDIN E l IN ERECTILE DYSFUNCTION

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dysfunction in 61 patients. Urologe, 27: 22, 1988. the This low incidence of priapism seems cer5. Linet, 0. I. and Neff, L. L.: Intracavernous prostaglandin E l in tainly a n advantage of this drug compared to other vasoacerectile dysfunction. Clin. Invest., 7 2 139, 1994. tive drugs, such as papaverine or phentolamine.20.21 How6. Chen, J., Godschalk,M., Katz, P. G. and Mulligan, T.: The lowest ever, this extremely low frequency of priapism is not effective dose of prostaglandin E l as treatment for erectile surprising due to the fact t h a t patients were selected as dysfunction. J. Urol., 163:80, 1995. known stable responders to prostaglandin E l without a his7. Aboseif, S., Riemer, R. K, Stackl, W., Lue, T. and Tanagho, E.: tory of priapism. Quantificationof prostaglandin E l receptors in cavernous tisFinally, in our study different methods of evaluation of sue of men, monkeys and dogs. Urol. Int., 50: 148, 1993. erectile response to intracavernous injection were used. The 8. van Ahlen, H., Peskar, B. A., Sticht, G. and Hertfelder, H.J.: overall positive erectile response, as rated by the clinician, Pharmacokinetics of vasoactive substances administered into tended to be higher t h a n the response rate by the RigiScan the human corpus cavernosum. J. Urol., 161: 1227, 1994. device, which may indicate t h a t real-time RigiScan monitor9. Waldhauser, M. and Schramek, P.: Efficiency and side effects of prostaglandin E l in the treatment of erectile dysfunction. ing underestimates the rigidity as assessed by the clinician. J. Urol., 140: 525, 1988. However, the overall correlation of assessment by the clinician and RigiScan d a t a was good. Therefore, although not 10. Schramek, P., Dorninger, R., Waldhauser, M., Konency, P. and Porpaczy, P.: Prostaglandin E l in erectile dysfunction. Effialways helpful in the clinical evaluation of a n individual cacy and incidence of priapism. Brit. J. Urol., 65: 68, 1990. patient, real-time monitoring by the RigiScan device may aid the evaluation of clinical trials for erectile dysfunction. It has 11. Kessler, W. 0.: Nocturnal penile tumescence. Urol. Clin. N. Amer., 15:81, 1988. also been reported recently that the RigiScan device under- 12. Milliken, G. A. and Johnson, D. E.: Analysisof crossoverdesigns. estimates the circumference, particularly at lower levels of In: Analysis of Messy Data: Designed Experiments. New York rigidity compared to a mercury-in-rubber strain gauge.22 Van Nostrand Reinhold Co. vol. 1, pp. 433-451, 1984. Moreover, the 2 devices consistently recorded different de- 13. Lehmann,E. L.: Statistical methods based on ranks. In: Nongrees of rigidity. Most importantly, however, RigiScan and parametrics. San Francisco: Holden-Day Inc., pp. 262-270, clinical evaluation correlated well with the subjective evalu1975. ation of our patients, although the patient evaluation used in 14. Benet, L. Z., Mitchell, J. R. and Scheiner, L. B.: Pharmacokinetics: the dynamics of drug absorption, distribution, and elimiour study was most likely to identify a response. RigiScan nation. In:The Pharmacological Basis of Therapeutics. Edited criteria were least likely to identify a response and the clinby A. Goodman Gilman, T. W. Rall,A. S. Nies and P. Taylor. ical evaluation results were between those methods. This New York Pergamon Press, chapt. 1, pp. 3-32, 1990. finding confirms t h a t t h e RigiScan criteria used tend to be 15. Simmet, T. and Peskar, B. A: Prostaglandin E l and arterial more strict for identifying a response or that the RigiScan occlusive disease: pharmacological considerations. Eur. J. data underestimate t h e response. The agreement among the Clin. Invest., 18 549, 1988. methods would have been greater if a response by RigiScan 16. Marshall, G., Breza, J. and Lue, T. F.: Improved hemodynamic monitoring had been based on a more moderate level of radial response a h r long-term intracavernous injection for imporigidity (for example 60% rather than 70%) as the threshold tence. Urology, 43:844, 1994. or a shorter interval required above the threshold (for exam- 17. von Heyden, B., Donatucci, C. F., Marshall, G. A, Broehard, G. B. and Lue, T. F.: A prostaglandin E l dose-response study ple 6 consecutive minutes rather than 10). in man. J. Urol., 1M): 1825, 1993. In conclusion, our study shows t h a t the 3 prostaglandin E l formulations were pharmacodynamically equivalent, none 18. Godschalk, M. F., Chen, J., Katz, P. G. and Mulligan, T.: Treatment of erectile failure with prostaglandin El: a double-blind, resulted in major side effects and the incidence of minor side placebocontrolled, dose-response study. J. Urol., 151: 1530, effects, such as penile pain, was not different among the 1994. formulations. 19. Bodner, D. R., Lindan, R., Leffler, E., Kursh, E. D. and Resnick, M. I.: The application of intracavernous injection of vasoactive REFERENCES medications for erection in men with spinal cord injury. J. Urol., 138: 310, 1987. 1. Virag, R. and Adaikan, P. G.: Effects of prostaglandin E l on penile erection and erectile failure. Letter to the Editor. J. 20. Mahmoud, K Z., el Dakhli, M. R., Fahmi, I. M. and Abdel-Aziz, A. B. A.: Comparative value of prostaglandin E l and papavUrol., 137: 1010, 1987. erine in treatment of erectile failure: double-blind crossover 2. Stackl, W., Hasun, R. and Marberger, M.: Intracavernous injecstudy among Egyptian patients. J. Urol., 147: 623,1992. tion of prostaglandin E l in impotent man. J. Urol., 140: 66, 21. Earle, C. M., Keogh. E. J., Wisniewski, Z. S., Tulloch, A. G. S., 1988. Lord, D. J., Watters, G. R.and Glatthaar, C.: F’rostaglandin E l 3. Ishii, N., Watanabe, H., Irisawa, C., Kikuchi, Y.,Kubta, Y., therapy for impotence, comparison with papaverine. J. Urol., Kawamura, S.,Suziki, K, Chiba, R., Tokiwa, M. and Shirai, 143: 57,1990. M.: Intracavernous injection of prostaglandin E l for the treat22. Munoz, M. M., Bancroft, J. and Marshall, I.: The performance of ment of erectile impotence. J. Urol., 141: 323, 1989. the Rigiscan in the measurement of penile tumescence and 4 . Porst, H.: Comparative usefulness of prostaglandin El, papavrigidity. Int. J. Impoten. Res., 5: 69, 1993. erine, and papverindphentolamine for the diagnosis of erectile