One-year efficacy and safety study of a 1.62% testosterone gel in hypogonadal men: results of a 182-day open-label extension of a 6-month double-blind study.

INTRODUCTION: A new formulation of testosterone gel (1.62% testosterone gel) with increased viscosity and reduced volume of application has been shown to be safe and efficacious after 182 days of use in a phase 3, double-blind study in adult hypogonadal males. AIM: The objective of this study was to evaluate the efficacy and safety of the 1.62% testosterone gel after daily application to the skin in a 182-day (6-month) open-label extension of the initial 182-day double-blind study. METHODS: One hundred and sixty-three subjects, aged 26 to 77 years, continued on active (Continuing Active subjects) 1.62% testosterone gel for the remainder of the study (364 days total). In 28 subjects who had previously received placebo (Formerly Placebo subjects), the dose was titrated to normal levels of serum total testosterone (300-1,000 ng/dL). Dose adjustments for both groups were allowed at specific visits to maintain serum testosterone within a normal range. MAIN OUTCOME MEASURE: The main outcome measure was the percentage of subjects with serum total testosterone average concentrations (C(av) ) within the normal range at day 364. RESULTS: On day 364, 77.9% (95% confidence interval: 70.0, 84.6) of the Continuing Active subjects and 87.0% (66.4, 97.2) of the Formerly Placebo subjects had C(av) values within the eugonadal range. The 1.62% testosterone gel was safe and well tolerated in this study. CONCLUSION: Treatment with 1.62% testosterone gel for up to 1 year (182 days for the Formerly Placebo subjects, 364 days for the Continuing Active subjects) was safe and efficacious, resulting in >77% of treated subjects achieving normal serum testosterone levels at final visit.

Effect of application site, clothing barrier, and application site washing on testosterone transfer with a 1.62% testosterone gel.

OBJECTIVES: To evaluate the effect of application site location, clothing barrier, and application site washing on testosterone transfer from males dosed with 1.62% testosterone gel to female partners. RESEARCH DESIGN AND METHODS: Open-label, randomized, parallel group, crossover study performed in 24 healthy male/female couples. 2.5 or 5.0 g of gel was applied to upper arms and shoulders or abdomens of male subjects. Skin contact occurred 2 hours after gel application between male and female subjects to compare the effect of wearing or not wearing a t-shirt, washing or not washing before contact, and the effect of differing application sites. Treatments were separated by a 1-week washout period. On each dosing day, 15 minutes of supervised skin contact occurred between the dosed male and female partner. Contact was either abdomen to abdomen (male to female), or upper arms/shoulders (male) to upper arms/shoulders, wrists and hands (female), depending on the male application site. Serum samples were collected from females at baseline and after contact to assess secondary testosterone exposure. MAIN OUTCOME MEASURES: C(max) (maximum serum concentration), AUC(0-24) (area under serum concentration-time curve from 0-24 hours), and C(av) (time-averaged concentration over 24-hour post-contact period) were assessed. Subjects were monitored for adverse events. RESULTS: Testosterone exposure (C(av) and C(max)) in females increased by up to 27% (2.5 g) or up to 280% (5.0 g) from baseline after direct skin contact at 2 hours after gel application, although C(av) remained within the female eugonadal range. Transfer from the abdomen was prevented when a t-shirt was worn (2.5-g dose). When the application site was washed before contact, mean C(av) was comparable to baseline, and C(max) was slightly higher (14%). Transfer was higher after direct skin-to-skin contact when the application and contact sites were upper arms/shoulders versus the abdomen. Testosterone concentrations returned to baseline within 48 hours after last skin contact. CONCLUSIONS: There is a risk of testosterone transfer from males using 1.62% testosterone gel to others who come into direct skin contact with the application site. This can be prevented by covering the application site with a t-shirt (2.5-g dose), or washing the application site before contact. STUDY LIMITATIONS: Women for these studies were not selected by menopausal status. The study was conducted under circumstances that were intended to simulate exaggerated conditions of contact and may not represent average contact under normal conditions. CLINICAL TRIAL REGISTRATION NCT NUMBERS: Study was not registered (first subject enrolled 28 November 2007).

Serum testosterone levels in non-dosed females after secondary exposure to 1.62% testosterone gel: effects of clothing barrier on testosterone absorption.

OBJECTIVE: To evaluate secondary exposure of testosterone transferred to females from a male partner, dosed with 1.62% testosterone gel after direct skin-to-skin contact with the application site, and to investigate the effect of wearing a t-shirt on testosterone transfer. RESEARCH DESIGN AND METHODS: Across three studies, a total of 72 healthy males applied 5.0 g 1.62% testosterone gel to their abdomen alone, upper arms/shoulders alone, or a combination of their upper arms/shoulders and abdomen (single dose or once daily for 7 days). Male-female contact occurred 2 or 12 hours after testosterone gel application, with males either wearing or not wearing a t-shirt. There were 15 minutes of supervised contact with the application site between the male and his female partner. Blood samples were collected over a 24 hour period in females for assessment of serum testosterone levels at baseline and after contact. MAIN OUTCOME MEASURES: Pharmacokinetic parameters included C(max) (maximum serum concentration), AUC(0-24) (area under the serum concentration-time curve from 0-24 hours), and C(av) (time-averaged concentration over the 24-hour period post-contact). Subjects were monitored for adverse events. CLINICAL TRIAL REGISTRATION NCT NUMBERS: Study 1 was not registered (first subject enrolled 8 March 2007); Study 2: 00998933; Study 3, 01130298. RESULTS: Testosterone levels (C(av) and C(max)) in females increased 86-185% from baseline after direct abdominal skin contact, although C(av) levels remained within female eugonadal range. Testosterone concentrations returned to baseline within 48 hours after last skin contact. A t-shirt barrier reduced testosterone transfer by approximately 40-48% when 5.0 g of testosterone gel was applied to the abdomen alone. A t-shirt barrier prevented transfer when 5.0 g of testosterone gel was applied to the upper arms and shoulders or to a combination of the upper arms and shoulders and the abdomen (C(max) and C(av) increased by approximately 5-11%). No major safety events were observed during the studies. CONCLUSIONS: There is a risk of testosterone transfer from males using 1.62% testosterone gel to others who come in contact with the application site for at least 12 hours after application. Secondary exposure can be mitigated by means of a t-shirt barrier. STUDY LIMITATIONS: Women for these studies were not selected by menopausal status. The study designs were intended to simulate exaggerated conditions of transfer.

Effects of skin washing on systemic absorption of testosterone in hypogonadal males after administration of 1.62% testosterone gel.

OBJECTIVE: The impact of washing on the pharmacokinetics, systemic absorption and residual testosterone on the skin after application of a 1.62% testosterone gel was investigated in an open-label, randomized, three-way crossover study in hypogonadal men. RESEARCH DESIGN AND METHODS: Twenty-four hypogonadal men (total testosterone <300 ng/dL) applied 5 g of 1.62% gel (81 mg testosterone) once daily to the shoulders/upper arms for 7 days during each of three consecutive treatment periods. On the 7th dosing day of each period, the skin was washed (soap/water) at one of the following times: 2, 6, or 10 hours post-dose. Pharmacokinetic serum samples were collected at baseline, and on days 6 (no washing) and 7 (with washing) of each treatment period. Skin stripping for determination of residual testosterone was also performed on days 6 and 7. A single location on the application site was stripped a total of 10 times. Testosterone was extracted from the tape strips using ethanol, and concentrations were determined using high performance liquid chromatography with diode array detection (HPLC-UV). MAIN OUTCOME MEASURES: Testosterone C(max), AUC(0-24), average concentration over the dosing interval (C(av)), and safety were assessed. RESULTS: Washing at 2 and 6 hours caused a 10-14% decrease in AUC(0-24) and C(av), but not C(max). Washing 10 hours after gel application had no effect on C(max), AUC(0-24), or C(av). Skin washing decreased the mean amount of testosterone remaining on the skin surface by at least 81%. CONCLUSIONS: Washing the site of gel application as soon as 2 hours after application had little impact on bioavailability and was effective in reducing residual testosterone on the skin. This finding may be important to prevent secondary transfer. STUDY LIMITATIONS: The experimental conditions using uniform timing and procedures for dose administration and washing may not fully reflect real world circumstances. CLINICAL TRIAL REGISTRATION NCT NUMBERS: Study was not registered (first subject enrolled 22 December 2006).

Pharmacokinetics and relative bioavailability of absorbed testosterone after administration of a 1.62% testosterone gel to different application sites in men with hypogonadism.

OBJECTIVE: To determine the pharmacokinetics, bioavailability, and safety of a new formulation (1.62%) of testosterone gel that produces eugonadal serum testosterone levels with use of a lower amount of gel than the currently available 1% gels. METHODS: In an open-label, randomized, 3-way crossover study, 36 male patients with hypogonadism applied 5 g of 1.62% testosterone gel (81 mg of testosterone) once daily to the abdomen, to the upper arms/shoulders, or alternating between both sites per an established schedule for 7 days. Serum levels of testosterone, dihydrotestosterone, and estradiol were measured and used to compare the pharmacokinetics and bioavailability of the 3 treatments. RESULTS: Each application method produced average serum testosterone concentrations within the eugonadal range (300 to 1,000 ng/dL), and steady-state testosterone concentrations were achieved after 2 days of gel application to either the abdomen or the upper arms/shoulders. When testosterone gel was applied to the abdomen, approximately 30% to 40% lower bioavailability (based on area under the serum concentration-time curve from 0 to 24 hours) was observed in comparison with application to the upper arms/shoulders. The 1.62% testosterone gel was found to be safe and well tolerated in men with hypogonadism. CONCLUSION: Although lower testosterone bioavailability was observed after abdominal application of 1.62% testosterone gel in comparison with application to the upper arms/shoulders, application to either site yielded eugonadal levels of serum testosterone.

Efficacy and safety study of 1.62% testosterone gel for the treatment of hypogonadal men.

INTRODUCTION: Male hypogonadism is a significant and growing problem that can be successfully treated with testosterone replacement therapy. A new formulation of testosterone gel (1.62%) was developed with increased viscosity, reduced volume of application, and increased skin permeation compared with other currently available testosterone gels. AIM: To evaluate the efficacy and safety of titrated doses of 1.62% testosterone gel after daily application to the skin of hypogonadal men for 182 days. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study in hypogonadal men (234 active; 40 placebo), 18 to 80 years of age with average serum total testosterone concentrations <300 ng/dL and prostate-specific antigen <2.5 ng/mL. Topical testosterone gel (1.62%), 1.25 g, 2.5 g, 3.75 g, and 5.0 g, or placebo gel was applied once daily to either upper arms/shoulders or abdomen. Dose adjustments were made on days 14, 28, and 42. Main Outcome Measures. The percentage of subjects with serum total testosterone average concentrations (C(av) ) within the normal range of 300-1,000 ng/dL on study days 14, 56, 112, and 182. RESULTS: Following titration, significantly (P < 0.0001) more subjects receiving active treatment had testosterone C(av) values (range 81.6% to 82.5%) within the eugonadal range compared with placebo (range 28.6% to 37.0%) on all study days. The 1.62% gel was safe and well tolerated. CONCLUSIONS: In this study, treatment with 1.62% testosterone gel was safe and efficacious, resulting in an acceptable percentage of hypogonadal males achieving eugonadal serum testosterone levels.

Testosterone concentrations in diabetic and nondiabetic obese men.

OBJECTIVE: To determine the prevalence of subnormal testosterone concentrations in patients with obesity and with type 2 diabetes in a primary care clinic population. RESEARCH DESIGN AND METHODS: Free testosterone concentrations of 1,849 men (1,451 nondiabetic and 398 diabetic) in the Hypogonadism In Males (HIM) study were analyzed. The HIM study was a U.S.-based cross-sectional study designed to define the prevalence of hypogonadism in men aged >45 years. Free testosterone was measured by equilibrium dialysis. RESULTS: The prevalence of subnormal free testosterone concentrations in lean, overweight, and obese nondiabetic men was 26% (n = 275), 29% (n = 687), and 40% (n = 489), respectively (P < 0.001 for trend), and 44% (n = 36), 44% (n = 135), and 50% (n = 227), respectively, in diabetic men (P = 0.46 for trend within group and P < 0.05 compared with nondiabetic men). The mean free testosterone concentration of diabetic men was significantly lower than that of nondiabetic men. Free testosterone concentrations were negatively and significantly (P < 0.001) related to age (r = -0.37), BMI (r = -0.18), and sex hormone-binding globulin (r = -0.11) in multiple regression analysis. The average decline of free testosterone concentrations was 7.8 pg/ml per decade in nondiabetic men and 8.4 pg/ml per decade in diabetic men. CONCLUSIONS: Forty percent of obese nondiabetic men and 50% of obese diabetic men aged >or=45 years have subnormal free testosterone concentrations. In view of its high prevalence, obesity is probably the condition most frequently associated with subnormal free testosterone concentrations in males. The concomitant presence of diabetes is associated with an additional increase in the prevalence of subnormal free testosterone concentrations.

Efficacy and safety of single- and multiple-dose ketotifen fumarate 0.025% ophthalmic solution in a pediatric population.

Allergic conjunctivitis can seriously disrupt children's daily activities. This study assessed the efficacy (onset and duration of action) and safety of ketotifen fumarate 0.025% ophthalmic solution compared with vehicle placebo in pediatric subjects after single and multiple dosing. This was a double-masked, multicenter, fellow-eye, placebo-controlled, conjunctival allergen challenge trial. Eligible subjects (8-16-yr-olds) who produced a qualifying reaction to allergen were randomized to a single dose (one drop) of ketotifen fumarate in one eye and vehicle placebo in the fellow eye, followed by an allergen challenge at 15 min and 8 h post-dose. Subjects who had a qualifying reaction to allergen in the placebo-treated eye and a qualifying response to ketotifen in the active-treated eye following the single dose were re-randomized to a multiple-dose treatment period. They were instructed to instill one drop of ketotifen fumarate in one eye and placebo in the other eye twice daily for 4 wk. An allergen challenge was conducted 8 h after the last dose. The primary efficacy assessment was ocular itching, judged by the subject at 3, 7, and 10 min post-allergen challenge after single- and multiple-dose treatments. Other ocular signs and symptoms were assessed at 7, 10, and 15 min post-dose. A total of 133 subjects were randomized to single-dose treatment; 105 were evaluable for efficacy. Of these, 60 were re-randomized to multiple-dose treatment, and 55 were evaluable for efficacy. After single and multiple doses, ketotifen fumarate significantly inhibited ocular itching compared with placebo at all post-challenge timepoints (p < 0.001) and also significantly reduced hyperemia, chemosis, and lid swelling (p = 0.031). No drug-related systemic adverse events were reported, and ocular adverse events were comparable to placebo. No subject discontinued prematurely due to an adverse event. These results indicate that ketotifen fumarate 0.025% ophthalmic solution is an effective and safe treatment option for children with allergic conjunctivitis.

Single dose of ketotifen fumarate .025% vs 2 weeks of cromolyn sodium 4% for allergic conjunctivitis.

This single-masked, contralateral-eye, active-controlled allergen-challenge study compared ketotifen fumarate .025% and cromolyn sodium 4% ophthalmic solutions in the prevention of ocular itching, tearing, and redness induced by allergen challenge. After a confirmatory conjunctival provocation test (CPT), 56 patients randomly received masked study medication (placebo in one eye, cromolyn in the other eye) four times daily for 2 weeks. At visit 3, patients received one drop of ketotifen in the eye previously treated with placebo and cromolyn in the other eye. Ocular comfort was assessed 30 seconds postinstillation, and a CPT was conducted 15 minutes and 4 hours postinstillation to evaluate ocular itching, tearing, and redness. Forty-seven patients were analyzed for efficacy. At the 15-minute and 4-hour challenges, ketotifen was superior to cromolyn in preventing itching (P < .001) at all assessments and redness (ciliary, conjunctival, and episcleral) (P < or = .001) at most assessments. Tearing scores were higher in cromolyn-treated eyes than in ketotifen-treated eyes. Patients reported greater comfort in the ketotifen-treated than in the cromolyn-treated eye (P = .066). The most common adverse event was burning/stinging with cromolyn. A single dose of ketotifen was superior to a 2-week four-times-daily regimen of cromolyn in alleviating symptoms of allergic conjunctivitis in the conjunctival allergen-challenge model.