Roundtable Discussion - European Urology Supplements

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Dr. Giuliano: Dr. Brock, what was the incidence of myalgia in patients treated with tadalafil? Was elevated creatine kinase [CK] observed? If so, what were the.
European Urology Supplements

European Urology Supplements 1 (2002) 31±33

Roundtable Discussion FrancËois Giulianoa,*,1, Gerald Brockb,2, Geoffrey Hackettc,2, Wayne J.G. Hellstromd,2, Hartmut Porste,2, Bronwyn Stuckeyf,2 a

Centre Hospitalier Universitaire de BiceÃtre, AP-HP, 78 rue du GeÂneÂral Leclerc, 94270 Le Kremlin BiceÃtre, France University of Western Ontario, London, Ontario, Canada c Good Hope Hospital, Sutton Cold®eld, UK d Tulane University Medical School, New Orleans, LA, USA e Urological Practice, Hamburg, Germany f Keogh Institute for Medical Research, Nedlands, Australia b

Keywords: Erectile dysfunction; Phosphodiesterase type 5 inhibitors; Safety; Sildena®l; Tadala®l

Dr. Giuliano: Dr. Brock, what was the incidence of myalgia in patients treated with tadalafil? Was elevated creatine kinase [CK] observed? If so, what were the mechanisms? Dr. Brock: This issue was raised in earlier studies and has been addressed more recently. As Dr. Stuckey explained, in the integrated analyses of phase 3 clinical trial data, which evaluated more than 1000 patients, the incidence of back pain was 5% in patients who received placebo and 6% in patients who received tadalafil. The incidence of myalgia was 2% with placebo and 5% with tadalafil. We are not certain what the mechanism for these effects might be. Venous pooling may be involved. However, these adverse events probably represent a class effect of the phosphodiesterase type 5 [PDE5] inhibitors because similar effects have been observed with all of the different agents. The important message for us, as clinicians, is that a patient rarely stops taking a PDE5 inhibitor because of these side effects. In clinical trials, the incidence of premature study discontinuation because of these side effects was remarkably low. Dr. Giuliano: Dr. Porst, is it true that muscle pain or back pain may be related to PDE11 inhibition by PDE5 inhibitors? What was the incidence of back pain with higher doses of tadalafil? Were incidences of back pain *

Corresponding author. Tel. ‡33-1-4521-3698; Fax: ‡33-1-4521-2170. E-mail address: [email protected] (F. Giuliano). 1 Moderator. 2

Participants.

and myalgia higher with tadalafil than with sildenafil [citrate]? Dr. Porst: The side effects you mentioned cannot be ascribed specifically to PDE11 inhibition with tadalafil because we have seen back pain with higher doses, up to 200 mg, of sildenafil as well. When doses of any PDE5 inhibitor are increased, back pain is observed irrespective of whether the agent inhibits PDE11 and to what degree. Back pain may be a dose-related adverse effect with any PDE5 inhibitor. Dr. Giuliano: I have another question for Dr. Brock. Were the data you presented based upon a preselected patient population of sildenafil responders? Dr. Brock: Most of the patients who were recruited for clinical trials probably had previous exposure to sildenafil. If only those patients who had experienced effective treatment with sildenafil were included, and patients who did not respond to sildenafil were excluded, the results would have appeared better than in the general population. I think the data with tadalafil in clinical trials are representative of the true patient population that we actually see in the clinic. Dr. Giuliano: Dr. Stuckey, was this true of the phase 3 trials you discussed? Were sildenafil nonresponders excluded? Dr. Stuckey: As Dr. Brock explained, phase 3 studies included patients who were either sildenafil-naive or had taken sildenafil. The data I presented included sildenafil-naive patients as well as patients who had a range of experience on sildenafil.

1569-9056/02/$ ± see front matter # 2002 Published by Elsevier Science B.V. PII: S 1 5 6 9 - 9 0 5 6 ( 0 2 ) 0 0 1 1 6 - 1

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F. Giuliano et al. / European Urology Supplements 1 (2002) 31±33

Dr. Giuliano: What was the incidence of priapism in clinical trials with tadalafil? Dr. Brock: I am not aware of any reports of priapism in clinical trials with tadalafil. We are starting to encounter occasional case reports of priapism with sildenafil. However, considering that more than 45 million sildenafil prescriptions have been written for approximately 15 million patients since sildenafil's approval, priapism has been extremely rare. Of course, fewer patients have been exposed to tadalafil than sildenafil, but the incidence of priapism in patients receiving monotherapy with any PDE5 inhibitor appears to be very low. Dr. Giuliano: What was the role of psychotherapy or sexual therapy in clinical trials of tadalafil? Dr. Porst: Psychosexual counseling, or any other additional competitive treatment, was not allowed in these clinical trials. Patients receiving psychosexual counseling were excluded. Dr. Giuliano: Does the longer duration of tadalafil versus sildenafil in the serum result in a longer duration of adverse events, such as headache? Dr. Porst: It may seem reasonable that the longer the half-life, the longer the duration of adverse events, but the evidence has shown otherwise. In a daily-dosing trial conducted 3 years ago, when patients received doses of up to 100 mg of tadalafil, a dose that is about fivefold higher than what we now administer in clinical trials, many patients experienced headache in the first week. However, the incidence of this side effect decreased with continued treatment, even at these high doses. Clinical experience shows that similar effects are seen with vardena®l and sildena®l. In summary, the prolonged half-life of tadala®l appears to have no impact on the duration or onset of headache. Dr. Brock: I would agree with that completely and reiterate that patients very rarely dropped out of clinical trials because of adverse events. The reported headaches and other side effects were typically mild. Dr. Giuliano: Dr. Hackett, you mentioned that about 50% of men are averse to planning for sex, but exactly how was this question asked? Could it have been asked in a way that might result in misleading information? Dr. Hackett: We must maintain a healthy skepticism about the way questions are phrased in market research. For instance, recent market research data suggested that about 90% of patients are satisfied with an erectile dysfunction agent that has a duration of 4 or 5 hours. However, if these same men were asked whether being

able to have sex up to 24 or 36 hours after taking a pill would be a favorable feature of such a drug, the majority would also likely answer yes. The 50% value for the proportion of men averse to planning sex might be an underestimate. Dr. Giuliano: How long must a patient wait to take nitrates after taking sildenafil? Dr. Brock: The nitrate issue is important because myocardial infarctions have been observed in men who took sildenafil with nitrates or nitric-oxide donors. Because sildenafil can potentiate the hypotensive effects of nitrates, concomitant use of these medications is clearly contraindicated [1]. In my view, PDE5 inhibitors as a class will not be approved for use with nitroglycerin or nitrates of any kind. Data on tadala®l from a placebo-controlled, three-way crossover study presented at the 2002 American College of Cardiology meeting [2] showed that there was no signi®cant difference in mean hypotensive responses between patients who took nitroglycerin or long-acting nitrates together with either tadala®l or placebo. However, the frequency of blood pressure ``outliers'' in nitrate patients was higher with tadala®l compared with placebo. In a subset of patients, the blood pressure-lowering effects of nitrates were ampli®ed by tadala®l. Therefore, on an individual basis, one cannot predict how any particular nitrate patient will respond to PDE5 inhibitors. Certain patients will have hypotensive responses. This is why I believe that coadministration of nitrates will be contraindicated for the entire class of PDE5 inhibitors in Europe and North America as regulatory review processes move forward. Dr. Giuliano: Do panel members recommend daily dosing of tadalafil? Dr. Porst: The daily dosing concept is promising. It may be possible with lower doses of tadalafil than we have been administering in clinical trials. Dr. Giuliano: Is there any difference in efficacy between tadalafil and sildenafil? Dr. Porst: When we compare data on all three PDE5 inhibitors, we see more or less the same efficacy: intercourse in 70±80% of attempts and about 80± 85% improvement based on the global assessment question. My feeling is that patients will wish to try all the PDE5 inhibitors once they receive regulatory approval. About 70±80% of my patients have tried a second drug for a given indication after it became available: for example, apomorphine as well as sildena®l.

F. Giuliano et al. / European Urology Supplements 1 (2002) 31±33

When all three PDE5 inhibitorsÐsildena®l, vardena®l and tadala®lÐbecome commercially available, the majority of patients will try all three and then, along with their partners, make their own choices. Unlike the case with therapy for benign prostatic hyperplasia or hypertension, the choice of a particular PDE5 inhibitor will be chie¯y the patient's and his spouse's or partner's, not the prescribing physician's. Dr. Brock: I do not completely concur with Dr. Porst. At the end of the day, the physician will still write the prescription for one PDE5 inhibitor or another, and a number of factors will influence this choice. Some of these factors will include the rapidity of the drug's onset, its duration of proerectile effects, whether it is compatible with food or alcohol consumption and the clinical ``track record'' for the drug's safety and tolerability. We do not yet have the information to determine which will be the agent of first choice, but I do agree that a number of patients will want to try multiple agents. Dr. Giuliano: Our final question is for Dr. Hellstrom, who was the coordinator of a clinical trial evaluating the effects of tadalafil on semen characteristics. In this

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study, did patients who received tadalafil have normal sperm counts? Was the fertilization potential of sperm affected? Dr. Hellstrom: We performed two studies involving more than 200 men with normal sperm by World Health Organization criteria at baseline. We excluded about 75% of elderly men who had subnormal sperm concentrations, motility or morphology. After dividing the remaining population into quartiles to analyze men with low-to-normal versus highto-normal sperm counts, we found no differences in either the tadala®l or placebo group. The percentage of sperm with normal motility and the percentage with normal morphology were also not signi®cantly different in the two groups. Patients in these studies received 10 or 20 mg of tadala®l per day for 6 consecutive months, which enabled us to assess the effects of tadala®l over two complete human spermatogenesis cycles. Tadala®l also had no signi®cant effect on serum levels of testosterone, luteinizing hormone or follicle-stimulating hormone. Effects on fertility were not assessed. However, in animal studies with rats and mice, there was no change in fertility with tadala®l.

References [1] Cheitlin MD, Hutter Jr AM, Brindis RG, Ganz P, Kaul S, Russell Jr RO, Zusman RM. ACC/AHA expert consensus document. Use of sildena®l (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association. J Am Coll Cardiol 1999;33:273±82.

[2] Kloner R, Emmick J, Bedding A, Humen D. Pharmacodynamic interactions between tadala®l and nitrates. J Am Coll Cardiol 2002;39(Suppl A):291A [abstract 1051±30].