Testim 1 Gel: Review of Clinical Data

European Urology Supplements European Urology Supplements 4 (2005) 24 30 Testim 1 Gel: Review of Clinical Data Tom A. McNicholas* Department of Urology, Lister Hospital, Corey s Mill Lane, Stevenage, Hertfordshire SG1 4AB, UK Abstract Late-onset hypogonadism is a medical condition characterized by testosterone deficiency in ageing men, accompanied by clinical symptoms, that can negatively affect quality of life and multiple organ systems. The condition is generally managed using testosterone substitution. Many formulations of testosterone are available, including deep-muscle injections, buccal formulations, transdermal patches, and topical gels. Testim 1 Gel 1% testosterone gel (Auxilium Pharmaceuticals Norristown, Pennsylvania, USA, and Ipsen Paris, France) has been shown to restore serum testosterone concentrations to within the normal range in men with hypogonadism. Two randomized, controlled studies showed that Testim 1 Gel significantly improved sexual motivation, desire, performance, and function, as well as positive and negative mood scores and body composition after 90 days, compared with baseline. The magnitude of improvement seen with Testim 1 Gel was similar to that achieved with testosterone patches, but with fewer application-site reactions. Improvements in mood and sexual function were seen within the first 2 weeks of treatment. Long-term, open-label extension studies of Testim 1 Gel suggest that clinical benefits are maintained for up to 12 months without an additional increase in side-effects. Notably, Testim 1 Gel treatment for 12 months was associated with a gradual increase in bone mineral density, suggesting that Testim 1 Gel may help to prevent osteoporosis. The most common adverse events associated with Testim 1 Gel were application-site reactions, increased haematological parameters, and moderately increased prostate-specific antigen levels that remained within the normal range. Overall, the clinical evidence indicates that Testim 1 Gel is a safe and effective treatment option for use in the management of male hypogonadism. # 2005 Elsevier B.V. All rights reserved. Keywords: Hypogonadism; Late-onset hypogonadism; Testosterone; Testosterone gel; Testim Gel 1. Introduction * Tel. +44 1438 781095; Fax: +44 1438 781270. E-mail address: mcnic@globalnet.co.uk. Late-onset hypogonadism (LOH) is a clinical and biochemical condition associated with advancing age that is characterized by testosterone deficiency with or without reduced genomic sensitivity to testosterone [1]. If left unmanaged, LOH can negatively affect the function of multiple organ systems and impair quality of life in older men. LOH is managed primarily with testosterone substitution, the goals of which are: to restore testosterone levels to within the normal range; stimulate and maintain virilization (e.g. secondary sex characteristics, such as muscle mass, fat distribution, body hair); optimize bone density and prevent osteoporosis; potentially reduce cardiovascular risk; and restore sexual function, libido, and well-being [1]. Ideally, these goals should be met reliably, safely, and conveniently. Several formulations of testosterone are currently available for the treatment of hypogonadism, including intramuscular injections, buccal formulations, transdermal patches, and topical gels. Testim 1 Gel 1% testosterone gel (Auxilium Pharmaceuticals Norristown, Pennsylvania, USA, and Ipsen Paris, France) is a fast-drying topical gel that is available in Europe and the USA for the treatment of male hypogonadism. One 5 g tube of Testim 1 Gel contains 50 mg of testosterone. Application of 1 or 2 tubes daily to the shoulders or upper arms has been shown to restore average serum testosterone levels to within the normal range (10.4 34.7 nmol/l or 300 1000 ng/dl) in men with hypogonadism [2]. This paper reviews the clinical evidence available on the use of Testim 1 Gel in the management 1569-9056/$ see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.eursup.2005.05.005

of men with hypogonadism [2 6]. An overview of the clinical trials that will be discussed is given in Table 1 [2 6]. T.A. McNicholas / European Urology Supplements 4 (2005) 24 30 25 2. Pharmacokinetics Marbury et al. [2] compared the pharmacokinetic profile of Testim 1 Gel with that of another commercially available testosterone gel (AndroGel 1 /Testogel 1 Unimed Pharmaceuticals, Inc., and Solvay Pharmaceuticals, Inc., Marietta, Georgia, USA). A total of 29 men with hypogonadism aged >45 years were given a single administration of each gel (50 mg) 7 days apart [2]. Blood samples were taken regularly during the 24- hour period following application and again at 48 hours [2]. At baseline, 19 patients had a morning serum testosterone concentration <8.675 nmol/l and 10 had a concentration 8.675 10.4 nmol/l [2]. In general, mean concentrations of serum testosterone were higher following Testim 1 Gel administration, compared with AndroGel 1 /Testogel 1 (Fig. 1) [2]. Geometric mean estimates of the peak serum concentration (C max )and the 24-hour systemic availability (AUC 0 24 ) were also consistently higher following Testim 1 Gel administration (C max : 480 ng/ml vs. 368 ng/ml; AUC 0 24 : 5865 ngh/dl vs. 4499 ngh/dl) [2]. The ratio of the treatment comparison was 1.30 (90% CI 1.10 1.55) for C max and 1.30 (90% CI 1.08 1.57) for AUC 0 24,indicating that Testim 1 Gel and AndroGel 1 /Testogel 1 are Fig. 1. Total serum testosterone levels over 48 hours following a single dose of Testim 1 Gel 50 mg or AndroGel 1 /Testogel 1 50 mg (N =29)[2].(Reproduced with permission [2]. Copyright# 2003 John Wiley and Sons Ltd.). not bioequivalent [2]. Similar findings were found when serum concentrations of dihydrotestosterone (DHT) and free testosterone were compared following each treatment [2]. Testim 1 Gel may also have a favourable pharmacokinetic profile when compared with testosterone patches. Two randomized, controlled trials collected pharmacokinetic data after 90 days of treatment with Testim 1 Gel (50 mg or 100 mg daily) or a testosterone patch (Andropatch 1 [GlaxoSmithKline Brentford, UK] or Androderm 1 [Watson Pharmaceuticals Corona, California, USA], each 2 2.5 mg daily) [4,5]. In one trial, the mean increase in total testosterone concentration from baseline was significantly greater in patients using Testim 1 Gel 100 mg, compared with Table 1 Clinical trials evaluating Testim 1 Gel 1% testosterone gel [2 6] Study No. of patients Age in years. Mean SD (range) Total testosterone at baseline in nmol/l. Mean SD a Design End-points Marbury et al. [2] 29 61.2 8.9 (NR) b NR c Testim 1 Gel 50 mg vs. AndroGel 1 50 mg Pharmacokinetic profiles over 48 hours following a single administration Loizides et al. [3] 638 52.7 11.9 (18 86) d 7.08 2.46 Testim 1 Gel 50 mg or 100 mg Weekly assessment of sexual activity and mood over 1 month McNicholas et al. [4] 208 57.9 10.2 (31 80) 7.92 2.28 Testim 1 Gel 50 mg vs. Testim 1 Gel 100 mg vs. Andropatch 1 2 2.5 mg Steidle et al. [5] 406 58.0 10.3 8.1 2.3 Testim 1 Gel 50 mg vs. Testim 1 (20 80 included) e Gel 100 mg vs. Androderm 1 Dean et al. [6] 371 58.5 10.0 (21 81 included) NR = not reported. a All patients were required to have total testosterone 10.4 nmol/l at baseline. b All patients were aged >45 years. c Total testosterone was <8.675 nmol/l in 19 patients and 8.675 10.4 nmol/l in 10 patients at baseline. d 17.4% of patients were aged 65 years. e 26% of patients were aged 65 years. Pharmacokinetics, sexual activity, body composition, mood, and safety over 90 days Pharmacokinetics, sexual activity, body composition, mood, and safety over 90 days 2 2.5 mg vs. placebo 8.12 2.05 Testim 1 Gel 50 mg or 100 mg Pharmacokinetics, sexual activity, body composition, mood, and safety over 12 months

26 T.A. McNicholas / European Urology Supplements 4 (2005) 24 30 Table 2 Changes in minimum, maximum, and average serum total testosterone levels (nmol/l) from baseline after 90 days of treatment with Testim 1 Gel or Andropatch 1 (n = 208) [4] Parameter Gel Patch 50 mg 100 mg DC avg 6.54 12.41 a 3.82 DC min 2.98 b 7.14 a 0.35 DC max 11.50 19.68 b 8.23 a p < 0.001 vs. patch. b p < 0.05 vs. patch. those using patches (Table 2) [4]. Testim 1 Gel had similar dose-dependent effects on concentrations of DHT and free testosterone. Treatment with testosterone patches, however, produced relatively small changes in DHT concentrations (0.03 nmol/l for Andropatch 1, 0.91 nmol/l for Testim 1 Gel 50 mg, and 1.39 nmol/l for Testim 1 Gel 100 mg; p < 0.001 for each comparison) [4]. Similar results were found in the second trial: after 90 days of treatment, 75 80% of patients receiving Testim 1 Gel had a mean serum concentration above the lower limit of normal (10.4 nmol/l), compared with 57% of patients treated with Androderm 1 patch and 10% of patients receiving placebo [5]. Openlabel extension studies of Testim 1 Gel following these two 90-day randomized trials indicated that increased serum levels of testosterone, DHT, and free testosterone were maintained for up to 12 months [6]. Given these data, it appears that Testim 1 Gel (50 mg or 100 mg daily) can effectively restore serum testosterone levels to within the normal range in men with hypogonadism [2,4 6]. Testim 1 Gel is not bioequivalent to another testosterone gel [2], and may have a more favourable pharmacokinetic profile compared with testosterone patches [4,5]. 3. Time to onset of effects To determine the time to response in sexual activity, desire, and mood following the initiation of treatment with Testim 1 Gel, the Study of Testosterone Androgen Response Time (START) was conducted [3]. A total of 638 men with hypogonadism were given Testim 1 Gel at a daily dose of 50 or 100 mg for 30 days. Each patient kept a validated self-report diary to collect information on sexual function and mood [7,8]. Beginning 1 week prior to treatment initiation, the diary continued through the 30-day treatment period and average weekly scores were calculated. The mean age of the men was 52.7 years (range: 18 86 years) and 17.4% were aged 65 years. The mean morning serum testosterone concentration at baseline was 7.08 nmol/l. The percentage of patients who applied 1 tube of Testim 1 Gel daily was 89%. The remaining 11% started with 1 tube and increased to 2 tubes daily. By the end of the first week of treatment with Testim 1 Gel, scores for sexual desire, sexual motivation, spontaneous erections (day and night), sexual performance, sexual enjoyment, and satisfaction with duration of erection all increased significantly from baseline (Table 3) [3]. In general, maximum response was seen by the end of the second week and maintained throughout the study period [3].Significant improvements in the weekly frequency of intercourse were noted as early as week 2 [3]. Positive and negative mood scores also improved after treatment initiation, reached a maximum response within the first 2 weeks of treatment, and were maintained throughout the study [3]. Based on the results of the START study, it appears that improvement in sexual activity and mood can be seen within 2 weeks of initiating treatment with Testim 1 Gel [3]. The study investigators further suggested Table 3 Weekly scores of sexual function following initiation of Testim 1 Gel (N = 638) [3] Parameter Baseline Week 1 a Week 2 a Week 3 a Week 4 a Desire (0 = none, 7 = very high) 2.0 1.4 2.6 1.5 3.0 1.6 3.1 1.6 3.2 1.6 Motivation (number of days/week) 1.6 1.3 1.9 1.5 2.1 1.7 2.2 1.7 2.2 1.7 Performance (number of days/week) 0.9 1.1 1.1 1.2 1.3 1.3 1.3 1.3 1.3 1.2 Enjoyment (0 = none, 7 = very high) With partner 4.0 1.5 4.4 1.5 4.8 1.4 4.9 1.4 4.9 1.4 Without partner 3.3 1.4 3.6 1.4 b 4.0 1.5 4.0 1.5 4.1 1.5 Satisfaction with duration of erection (0 = not satisfied, 7 = very satisfied) 3.1 1.8 3.4 1.8 3.7 1.8 3.8 1.8 4.0 1.8 Spontaneous erections (number of days/week) 0.7 1.1 1.1 1.5 1.3 1.6 1.3 1.7 1.2 1.7 (Copyright# MedReviews, LLC. Reproduced with permission of MedReviews, LLC. Reviews in Urology is a copyrighted publication of MedReviews, LLC. All rights reserved.). Values are expressed as mean SD. a p < 0.0001 for all values versus baseline. b p < 0.01 versus baseline.

T.A. McNicholas / European Urology Supplements 4 (2005) 24 30 27 that if clinicians do not see improvements within this time period, it may be necessary to check serum testosterone concentrations to determine whether dose adjustments are required [3]. 4. Short-term efficacy Two randomized, controlled trials (also discussed above in terms of their pharmacokinetic results) have evaluated the efficacy of Testim 1 Gel when given for 90 days (Table 4) [4,5]. Both trials compared the effects of Testim 1 Gel 50 mg or Testim 1 Gel 100 mg daily with those of testosterone patches (Androderm 1 or Andropatch 1, each 2 2.5 mg daily) [4,5], and one of the trials included a placebo arm [5]. At day 30, 60, and 90, both trials measured mood and sexual function using a validated questionnaire [7,8] and body composition according to dual-energy X-ray absorptiometry (DEXA) [4,5]. 4.1. The European trial (McNicholas et al. [4]) A total of 208 men with hypogonadism were enrolled in a trial conducted in 29 centres in Denmark, Germany, the Netherlands, Sweden, and the UK [4]. The mean age was 57 years (range: 31 80 years) and the mean serum concentration of testosterone at baseline was 7.92 nmol/l [4]. In all 3 treatment groups (Testim 1 Gel 50 mg, Testim 1 Gel 100 mg, Andropatch 1 ), scores for sexual function, including motivation, desire, and performance, improved after 90 days from baseline [4]. In both Testim 1 Gel groups, the incidence of spontaneous erections increased significantly at all time points from baseline, whereas there were no significant changes in the testosterone patch group (Table 4) [4]. Positive mood scores improved significantly from baseline at all time points in patients treated with Testim 1 Gel 50 mg or 100 mg, with the exception of scores on day 60 in the Testim 1 Gel 50 mg group [4]. In the testosterone patch group, positive mood scores were not significantly different from baseline at any time point, and differences among treatment groups were not statistically significant [4]. With regard to negative mood scores, however, patients who received Testim 1 Gel had significantly better scores after 90 days than those who received testosterone patches (p < 0.05) [4]. Negative mood scores improved significantly from baseline at all time points in patients treated with Testim 1 Gel 50 mg or 100 mg, with the exception of scores on day 30 in the Testim 1 Gel 100 mg group [4]. In patients who received testosterone patches, negative mood scores were not significantly different from baseline at any time point [4]. Lean body mass increased significantly from baseline in all 3 treatment groups [4]. The percent fat was reduced by 0.12% from baseline in the group receiving Testim 1 Gel 100 mg (p < 0.01) [4]. Because of the relatively short duration of the study, no significant changes in bone mineral density (BMD) were observed in any treatment group [4]. 4.2. The US trial (Steidle et al. [5]) Steidle et al. [5] reported the results of a randomized, placebo-controlled trial of 406 men with hypogonadism conducted at 43 centres in the USA. Men Table 4 Mean change from baseline to 90 days in scores for sexual function and body composition in 2 randomized, controlled trials [4,5] Parameter McNicholas et al. [4] (N = 208) Steidle et al. [5] (N = 406) Gel 50 mg Gel 100 mg Patch Gel 50 mg Gel 100 mg Patch Placebo Sexual function scores Desire (daily mean) 0.8 1.0 a 0.7 1.4 a 0.5 1.2 b 0.5 1.2 c 1.0 1.4 a,d 0.6 1.2 a 0.5 1.0 a Motivation (weekly mean) 0.4 1.2 b 0.4 1.3 b 0.5 1.4 b 0.2 1.5 0.6 1.4 a,e 0.4 1.1 b 0.1 1.2 Performance (weekly mean) 0.3 1.0 b 0.4 0.9 a 0.3 1.0 b 0.3 1.1 0.5 1.2 a,e 0.3 0.7 b 0.2 0.9 b Spontaneous erections (weekly mean) 0.6 1.4 b 0.5 1.4 b 0.3 1.2 0.3 1.3 0.7 1.4 a,f 0.3 1.1 0.0 1.0 Body composition Lean body mass, kg 0.9 1.8 b 1.5 1.7 a 1.0 1.9 b 1.5 4.5 1.7 2.6 e,g 0.9 1.8 0.6 1.8 Fat mass, kg 0.1 1.8 0.2 1.5 0.1 2.0 0.8 2.4 d 0.8 2.0 d 0.4 1.8 d 0.1 1.5 Percent fat, % 0.4 2.0 0.7 1.3 b 0.3 1.9 1.1 3.2 e 1.2 1.9 d,g 0.5 1.6 0.2 1.4 Values are expressed as mean SD. p < 0.001 vs. baseline. p < 0.05 vs. baseline. p < 0.01 vs. baseline. p < 0.01 vs. placebo. p < 0.05 vs. placebo. p < 0.001 vs. placebo. g p < 0.05 vs. patch.

28 T.A. McNicholas / European Urology Supplements 4 (2005) 24 30 aged 20 80 years were included, and 26% were aged 65 years [5]. The mean serum concentration of testosterone at baseline was 8.1 nmol/l [5]. Patients were given Testim 1 Gel 50 mg or 100 mg, Androderm 1, or placebo [5]. After 90 days, patients who received Testim 1 Gel 100 mg showed significant improvement in sexual motivation (p < 0.05), desire (p < 0.01), performance (p < 0.05), and the number of spontaneous erections (p < 0.001), compared with placebo [5]. Other measures of sexual function, such as enjoyment with or without a partner, satisfaction of erection duration, and percentage of full erection, revealed no significant differences between treatment groups [5]. Positive and negative mood scores improved from baseline in all treatment groups, and no statistical differences between treatment groups were found [5]. Lean body mass increased significantly in patients who received Testim 1 Gel 100 mg, compared with those who received testosterone patch or placebo (p < 0.05 for each comparison) [5]. Testim 1 Gel 50 mg and 100 mg significantly reduced fat mass and percent fat, compared with placebo (p < 0.05 and p < 0.01, respectively), whereas the testosterone patch did not [5]. The strikingly similar results reported in these 2 randomized, controlled trials confirm that, in men with hypogonadism, Testim 1 Gel can restore serum testosterone levels to within the normal range, leading to measurable improvements in sexual function, mood, and body composition [4,5]. The magnitude of benefit is similar to, or for some parameters, even better than that achieved with testosterone patches [4,5]. 5. Long-term efficacy The combined results of 2 studies which evaluated the long-term efficacy and safety of treatment with Testim 1 Gel were reported [6]. Patients who participated in both 90-day, randomized trials discussed above [4,5] were invited to enrol in an open-label, multicentre extension study, in which all patients received Testim 1 Gel (50 mg or 100 mg daily) for up to 12 months [6]. Of the combined 371 patients enrolled, 257 received Testim 1 Gel for >9 months [6]. Although all patients were hypogonadal when they entered the short-term studies [4,5], 90% had a baseline testosterone level within the normal range when they entered the long-term extension study [6]. Scores for sexual motivation, desire, and performance were significantly higher at all time points during the extension study, when compared with baseline scores (p < 0.001 for each comparison) [6]. Satisfaction with Fig. 2. Positive and negative mood scores (on a 0 7 Likert-type categorical scale) during 12 months of treatment with Testim 1 Gel 50 mg or 100 mg, showing both dosage groups combined (N = 371) [6]. (Copyright# MedReviews, LLC. Reproduced with permission of MedReviews, LLC. Reviews in Urology is a copyrighted publication of MedReviews, LLC. All rights reserved.). the duration of erection, percentage of full erection, and the incidence of spontaneous erections also improved significantly. Improvements in positive and negative mood scores were seen as early as month 1 and were maintained throughout the study period (Fig. 2) [6]. Significant improvements in lean body mass, fat mass, and percent fat were seen at months 6 and 12 [6]. Total body mass, however, did not change significantly from baseline, according to DEXA scans [6]. BMD of the lumbar spine increased significantly from baseline (p < 0.001) [6]. The mean percent change from baseline in BMD was 1.33% at month 6 and 2.58% at month 12 (Fig. 3) [6]. Data from the long-term extension study support the conclusion that the improvements seen with Testim 1 Gel in the short-term randomized trials, including improvements in sexual function, mood, and body composition, were maintained for up to an additional Fig. 3. Mean percentage change in bone mineral density of the lumbar spine from baseline during 12 months of treatment with Testim 1 Gel 50 mg or 100 mg, showing both dosage groups combined (N = 371) [6]. (Copyright# MedReviews, LLC. Reproduced with permission of MedReviews, LLC. Reviews in Urology is a copyrighted publication of MedReviews, LLC. All rights reserved.).

T.A. McNicholas / European Urology Supplements 4 (2005) 24 30 29 year of treatment [4 6]. Notably, the improvements in BMD suggest that continued treatment with Testim 1 Gel may provide ongoing bone repletion, which may prevent osteoporosis. 6. Tolerability In general, Testim 1 Gel is well tolerated and associated with few serious adverse events. In the two 90- day randomized studies, the total incidence of adverse events was similarly low in both Testim 1 Gel groups and substantially lower than that seen with testosterone patches [4,5]. This was due primarily to a lower rate of application-site reactions with the gel than with the patch [4,5]. The most common adverse events associated with Testim 1 Gel treatment are increases in haemoglobin and haematocrit levels, application-site reactions, and increases in prostate-specific antigen (PSA) levels [6]. Other less frequently reported side-effects include benign prostatic hyperplasia (BPH), increased blood pressure, acne, gynaecomastia, headache, hot flushes, insomnia, increased lacrimation, mood swings, smell and taste disorders, spontaneous erections, and reduced libido [5,6]. In the long-term extension study of Testim 1 Gel, 40 patients (10.8%) withdrew due to adverse events [6]. The most common reasons cited for study withdrawal were increases in PSA (2.4%), increases in haematology parameters (2.4%), and application-site reactions (1.1%) [6]. 6.1. Application-site reactions Local application-site reactions occurred in 4.0% and rash occurred in 1.9% of patients treated with Testim 1 Gel in the 12-month extension studies [6].In the two 90- day randomized trials comparing Testim 1 Gel and testosterone patches, the incidence and severity of application-site reactions were consistently higher in patients receiving testosterone patches, compared with those receiving Testim 1 Gel [4,5]. In both studies, approximately 15% of patients receiving testosterone patches withdrew from the study due to adverse events, mostly application-site reactions [4,5]. In the European trial, skin irritation occurred in 53% of patients using the testosterone patch for 90 days, compared with 4.2% and 0% of patients receiving Testim 1 Gel 100 mg and 50 mg, respectively [4]. Doubling the dose of Testim 1 Gel did not appear to increase the incidence or severity of skin reactions [4]. In the US study, the incidence of skin irritation among patients who received Testim 1 Gel was similar to the incidence in patients who received a placebo gel [5]. 6.2. Lipid profiles Small reductions in total cholesterol, HDL cholesterol, and LDL cholesterol have been reported with Testim 1 Gel treatment [4,5]. However, significant changes in the ratio of total:hdl cholesterol and of LDL:HDL cholesterol after 90 days of treatment, compared with baseline values, were not observed [4,5]. 6.3. Haematocrit and haemoglobin Increased testosterone levels are associated with increases in haematocrit and haemoglobin levels [5,9,10]. Therefore, as expected, treatment with Testim 1 Gel for 90 days was associated with an increase in haematocrit and haemoglobin levels, compared with baseline and placebo [4,5]. Testosterone patches also increased haematocrit and haemoglobin levels but to a lesser extent, reflecting the lower levels of serum testosterone achieved with patches [4,5]. In the US study, haematocrit and haemoglobin levels increased by 2.3 3.4% and 0.9 0.96 g/dl, respectively, after 90 days of treatment with Testim 1 Gel 50 mg, and 2.8 3.5% and 0.94 1.06 g/dl, respectively, with Testim 1 Gel 100 mg [5]. These increases were greater than those seen with patches (1.1 2.6% and 0.48 0.74 g/dl) or placebo ( 0.1 2.8% and 0.12 0.71 g/dl) [5].Inthe long-term extension study of Testim 1 Gel, mean values for haematocrit and haemoglobin increased but remained within the normal range throughout the 12- month study period [6]. Although a moderate increase in haematological parameters may be beneficial in some men with anaemia, lethargy, and fatigue, an increase in haematocrit to levels greater than 55% could produce symptoms of polycythaemia. Periodic monitoring of haematocrit and haemoglobin levels during treatment with Testim 1 Gel is therefore recommended. 6.4. Prostate health Testim 1 Gel is associated with moderate increases in PSA levels in some men. In the European trial, the percentage of patients who had a PSA value of >4.0 ng/ ml at least once during the study was 3%, 4%, and 3% in patients treated with Testim 1 Gel 50 mg, 100 mg, and testosterone patch, respectively [4]. The mean change in PSA values from baseline was <1.0 ng/ml in all treatment groups [4]. In the US trial, the percentage of patients who had a PSA value of >4.0 ng/ml at least once was 1.8%, 2.9%, 6.6%, and 3.2% in patients receiving Testim 1 Gel 50 mg, 100 mg, testosterone patch, and placebo, respectively [5]. The mean change in PSA values from baseline was 0.3, 0.1, 0.2, and 0.1 ng/ml, respectively [5]. In the long-term extension study of Testim 1 Gel, the mean increase in PSA

30 T.A. McNicholas / European Urology Supplements 4 (2005) 24 30 level from baseline was small but statistically significant at 3, 6, and 9 months (0.39 ng/ml, 0.37 ng/ml, and 0.45 ng/ml, respectively; p < 0.001 for each comparison) [6]. Mild BPH occurred in 3 patients in the US trial (2 of whom had received Testim 1 Gel and 1 had received placebo), and 2 patients in the testosterone patch group were diagnosed with prostate cancer [5]. In both 90- day trials, International Prostate Symptom Scores (IPSS) and results of digital rectal examinations (DRE) did not indicate any clinically relevant treatment-related effects or differences [4,5]. This was also seen in the long-term extension study of Testim 1 Gel, in which 3 patients (0.8%) were diagnosed with prostate cancer during the 12-month study period [6]. Given the incidence of prostate cancer in a general population of older men (<1%) [11], these occurrences were not unexpected. Nevertheless, patients undergoing testosterone substitution with Testim 1 Gel should be monitored regularly for changes in prostate health until data from longer-term studies on the effects of testosterone substitution on prostate health become available. 7. Conclusions For men with hypogonadism, Testim 1 Gel can effectively and consistently restore serum testosterone levels to within the normal range and may have a more favourable pharmacokinetic profile than another testosterone gel and testosterone patches [2,4,5]. Improvements in mood, sexual motivation, desire, and performance are seen within the first 2 weeks of initiating treatment, indicating that Testim 1 Gel can provide rapid improvements of some of the immediate symptoms of hypogonadism [3]. Data from randomized, controlled studies indicate that Testim 1 Gel is at least as effective as testosterone patches in improving mood, sexual function, and body composition, with the advantage of fewer application-site reactions [4,5]. Lastly, long-term data show that the benefits gained with Testim 1 Gel treatment are maintained for up to 12 months without a substantial increase in adverse events [6]. In patients who receive Testim 1 Gel, periodic monitoring of blood and prostate health by measuring haemoglobin, haematocrit, and PSA levels is necessary. References [1] Morales A, Lunenfeld B, for the International Society for the Study of the Aging Male. Investigation, treatment and monitoring of late-onset hypogonadism in males. Official recommendations of ISSAM. Aging Male 2002;5:74 86. [2] Marbury T, Hamill E, Bachand R, Sebree T, Smith T. Evaluation of the pharmacokinetic profiles of the new testosterone topical gel formulation, Testim TM, compared to AndroGel 1. Biopharm Drug Dispos 2003;24:115 20. [3] Loizides E, Swierzewski MJ, O Neill C, Griesser J, Smith T. Early response time in sexual activity and mood to testosterone gel replacement in hypogonadal males from the Testim 1 START study. Rev Urol 2004;6(Suppl 6):S16 21. [4] McNicholas TA, Dean JD, Mulder H, Carnegie C, Jones NA. A novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function. BJU Int 2003;91:69 74. [5] Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand R, for the North American AA250 T Gel Study Group. AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J Clin Endocrinol Metab 2003;88: 2673 81. [6] Dean JD, Carnegie C, Rodzvilla J, Smith T. Long-term effects of Testim 1 1% testosterone gel in hypogonadal men. Rev Urol 2004;6(Suppl 6):S22 9. [7] Lee KK, Berman N, Alexander GM, Hull L, Swerdloff RS, Wang C. A simple self-report diary for assessing psychosexual function in hypogonadal men. J Androl 2003;24:688 98. [8] Arver S, Dobs AS, Meikle AW, Caramelli KE, Rajaram L, Sanders SW, et al. Long-term efficacy and safety of a permeation-enhanced testosterone transdermal system in hypogonadal men. Clin Endocrinol (Oxf) 1997;47:727 37. [9] Wang C, Swedloff R, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, et al., for the Testosterone Gel Study Group. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab 2000;85:2839 53. [10] Tenover JL. Testosterone and the aging male. J Androl 1997;18: 103 6. [11] Stanford JL, Stephenson RA, Coyle LM, Cerhan J, Correa R, Eley JW, et al. Prostate Cancer Trends, 1973 1995. SEER Program, National Cancer Institute. NIH Pub. No. 99-4543. Bethesda, MD, USA. 1999.