Posted by Wesley Inman - Owner of GYMnTONIC and Former Bodybuilder and Strongman on 1st Nov 2024
Everything you have wanted to know about Testosterone Gel is right here!
The first transdermal patches found to be efficacious were scrotal patches in the 1980s (21). This application allowed for maximal absorption through a thin-skinned area. Disadvantages included smaller skin surface area and application challenges (hair clipping). As such, scrotal testosterone patches fell out of favor for other transdermal options and are no longer available in the USA.
Non-scrotal transdermal patches, Androderm®, (Actavis, Parsippany, NJ, USA) achieved USA FDA approval in 1995. The patches are available in either 2 or 4 mg/day formulations (24). The recommended starting dose is one 4 mg/day patch (not 2×2 mg/day patches) every 24 hours applied nightly. The patch is to be applied to the back, abdomen, upper arms, or thighs. Sites should be rotated and not re-used within 7 days. Two weeks after initiation of therapy, a serum testosterone level should be measured (early morning after patch application the night prior) and patch dosing adjusted as necessary. Levels <400 ng/dL require a dose escalation to 6 mg/day (1×4 mg/day patch plus 1×2 mg/day patch), while levels >930 ng/dL should be reduced to 2 mg/day.
A multi-center, prospective randomized trial compared the PKs, efficacy, and safety of the transdermal system to IM testosterone enanthate (TE) injections (25). Treatment was for 24 weeks and 33 subjects were enrolled per group. For the transdermal system group, the starting dose was 5 mg/day (2×2.5 mg/day patches, no longer commercially available). Dose adjustments were allowed for adverse effects or serum testosterone levels not within physiologic range. PK analysis occurred at week 16. Twenty-seven transdermal subjects were eligible for PK analysis. Baseline serum testosterone was 55.4 ng/mL and increased to an average of 517 ng/dL. The Cmax was 765 ng/dL within 8.2 hours of application. Transdermal administration allows testosterone to be continuously absorbed for 24 hours with no dose accumulations, mimicking normal circadian pattern when applied nightly. The approximate half-life is 1.3 hours and hypogonadal concentrations are achieved within 24 hours of patch removal (26).
The efficacy of the transdermal patch is often limited by lack of adherence or discontinuation due to skin blistering, pruritus, or irritation. This is due to permeation enhancers included in the transdermal system which are necessary to increase absorption. Combined clinical trials data report the overall incidence of any application site reactions as 48% with pruritus being most common (24). Topical corticosteroid application to the affected area is recommended for alleviation of symptoms (24). Advantages to transdermal patch use include non-invasive, easy application, quick reversal after removal, and normal circadian pattern of testosterone. Risk of transference to others is not concerning as there is an occlusive backing film on the patch system preventing others from contact with the active ingredient.
Since 2002, several testosterone gels and liquids have been developed for transdermal TRT. Due to the concern for testosterone gel or liquid being transferred to females and children who come into contact with a patient’s skin after use, these formulations have received a USA Boxed Warning. Patients should be reminded to wash their hands after application and to avoid skin contact with others. Recommended sites of application for these agents are areas that will be covered by clothing to minimize transfer. The potential advantages of testosterone transdermal gels and liquids include ease of application, less skin irritation than patches, and more consistent serum testosterone levels than other formulations, such as IM testosterone (27). The four branded, USA FDA approved testosterone hydroalcoholic gels available include AndroGel® (AbbVie Inc., North Chicago, IL, USA), Fortesta® (Endo Pharmaceuticals, Malvern, PA, USA), Testim® (Auxilium Pharmaceuticals Inc., Malvern, PA, USA), and Vogelxo® (Upsher-Smith Laboratories Inc., Maple Grove, MN, USA). There are generic formulations available for some gel products. Additionally, there is one testosterone transdermal solution, Axiron® (Eli Lilly, Indianapolis, IN, USA).
Androgel® is available in 1% and 1.62% concentrations. Dosage forms for the 1% concentration include a metered-dose pump, which delivers 12.5 mg of testosterone per actuation (generic only), and unit-dose packets that contain either 25 mg/2.5 g or 50 mg/5 g of testosterone (brand or generic) (28). The recommended starting dose is 50 mg applied topically once daily in the morning. Areas for application include the shoulders, upper arms, or abdomen. Based on serum testosterone levels, the dose can be increased in 25 mg increments up to 100 mg of testosterone daily. The 1.62% concentration is also available in a metered-dose pump and unit-dose packets (brand only). The metered-dose pump provides 20.25 mg of testosterone per actuation, while the unit-dose packets contain either 20.25 mg/1.25 g or 40.5 mg/2.5 g of testosterone (29). The recommended starting dose of AndroGel® 1.62% is 40.5 mg applied topically once daily in the morning. Serum testosterone levels should be measured 14 and 28 days after initiation prior to the morning dose. It should be noted that application sites for 1.62% gel only include the shoulders and upper arms, and not the abdomen. Dose adjustments between 20.25–81 mg increments are recommended for levels outside the range of 350 to 750 ng/dL.
The PK effects of AndroGel® 1% on serum testosterone levels was evaluated in a randomized, parallel study that compared gel 50 mg/day to gel 100 mg/day and patches 5 mg/day for three months in 227 hypogonadal men (30). After three months, the patients could receive either testosterone gel 50, 75, 100 mg/day or patch 5 mg/day. On day one, serum testosterone was within physiological range in both gel groups, reaching a Cmax of 560±31 ng/dL in the 50 mg/day group after 22 hours of application and 745±40 ng/dL in the 100 mg/day group after 16 hours. By day 30, the Cmax in the 50 mg/day gel group was 875±57 ng/dL with a Cmin of 360±39 ng/dL; for the 100 mg/day gel group, the serum testosterone Cmax was 1,198±56 ng/dL with a Cmin of 504±27 ng/dL. The 1% transdermal testosterone gel was able to increase serum testosterone to the upper range of normal after a few days of use and maintain levels with repeated daily use. The range of levels between the two doses illustrates the flexibility available with transdermal testosterone gel (30).
The most common adverse effect associated with AndroGel® 1% included acne (1% to 8% incidence) and application site reaction (3% to 5% incidence) (28). The most common adverse effect of AndroGel® 1.62% was increased PSA level (29). The incidence was 11.1% in a multi-phase, 364 day study of 234 hypogonadal men. Increased PSA was defined as an adverse event if there was a level >4 ng/mL or an increase >0.75 ng/mL from baseline on two separate occasions. All other reported adverse effects were <3% incidence.
Fortesta® 2% testosterone gel is available (both brand and generic) as a metered-dose pump delivering 10 mg of testosterone per actuation. The recommended starting dose is 40 mg (four actuations) applied once daily in the morning to the thighs. The dose can be adjusted in increments of 10 mg, based on serum levels measured two hours after morning application 14 and 35 days after initiation or adjustments. Fortesta® dosing range is 10 to 70 mg/day (31).
The effects of Fortesta® 2% gel on serum testosterone levels was evaluated in a multicenter, open-label study of 129 men with hypogonadism (32). The subjects applied Fortesta® 2% gel initially at 40 mg/day to their front and inner thighs for 90 days. Dose adjustments between 10 to 70 mg/day were allowed at clinic visits on days 14, 35, and 60. Serum levels were measured on days 14, 35, 60, and 90. On day 90, the Cavg was 438±162 ng/dL with a mean Cmax of 827±356 ng/dL. Normal physiologic range of testosterone was defined as 300 to 1,140 ng/dL, and 77.5% of patients had Cavg within this range at 90 days. Additionally, the 24-hour PK profile showed testosterone peaked 2–4 hours after application. Fortesta® 2% gel at doses between 10 to 70 mg/day achieved physiologic serum testosterone levels (32).
Adverse effects of Fortesta® 2% gel were reported in a controlled multi-center, open 90-day study of 149 hypogonadal patients (31). Adverse effects occurred in 22.8% (34/149) of patients. Most common was skin reactions at site of application (16.1%); 79% were mild and the remainder were moderate. Only two patients discontinued therapy for skin related issues.
Testim® 1% gel is supplied in unit-dose tubes containing 50 mg of testosterone/5 g (33). The recommended starting dose is 50 mg applied once daily in the morning to the shoulders or upper arms. Monitoring of serum testosterone should be performed 14 days after starting Testim®. The dose can be increased up to 100 mg of testosterone daily if indicated.
The PKs of Testim® gel was compared to AndroGel® in a randomized, open-label, two-way complete cross-over study that included 29 hypogonadal male subjects (34). Several blood samples were collected over a 48-hour period to evaluate serum testosterone levels. The dose of testosterone for both formulations was 50 mg. For Testim® gel, the mean Cmax was 480 ng/dL compared to 368 ng/dL for AndroGel®. The mean AUC0-24 was also higher with Testim® gel, measuring 5,864 ngh/dL, compared to 4,499 ngh/dL for AndroGel®. Since the ratios of Testim® gel to AndroGel® for Cmax and AUC0-24 were both 1.30, with 90% confidence intervals outside the bioequivalence limits of 0.80 to 1.25, it was concluded that Testim® gel is not equivalent to AndroGel® (34).
Adverse effects were reported from a controlled clinical study where 304 patients were treated with Testim® 50 mg, 100 mg or placebo up to 90 days (33). The only reported adverse effect with greater than 3% incidence was application site reactions at 4% in the 100 mg group.
Vogelxo® 1% gel is available in a multi-dose metered pump, unit-dose tubes and packets. All formulations are also available as generic. Each unit-dose tube or packet contains 50 mg of testosterone/5 g. The multi-dose metered pump provides 12.5 mg of testosterone per actuation. It is recommended to start Vogelxo® at a dose of 50 mg applied once daily to the shoulders or upper arms. Dose adjustments are based on serum testosterone levels measured 14 days after starting therapy. The dose of Vogelxo® can be increased to 100 mg/day to achieve therapeutic serum testosterone levels (35).
In a randomized, parallel treatment group study of 406 subjects with low serum testosterone, two doses of Vogelxo® were compared to a testosterone patch and placebo gel (36). Study subjects received either 50 or 100 mg of Vogelxo® daily, while the patch delivered 5 mg of testosterone daily. The study was conducted over 90 days, with measuring of serum testosterone to assess 24-hour PK profiles on days 30 and 90. At day 30, the mean Cavg for the 50 mg gel group increased 50% from baseline compared to a 173% increase in the 100 mg gel group. The patch group had an increase in Cavg similar to the 50 mg gel group. Normal adult range for testosterone was defined as 300–1,000 ng/dL, and 55% of subjects in the 50 mg gel group achieved a Cavg above 300 ng/dL compared to 95% in the 100 mg gel group, 68% in the patch group, and 8% of placebo. While 30 patients in the 100 mg gel group had a Cmax above 1,000 ng/dL, the Cavg remained within normal range for 87% of them. Both gel groups had significantly less fluctuation in testosterone levels over 24 hours compared to the patch group. On day 60, patients subtherapeutic in the 50 mg gel group were increased to 100 mg/day, while supratherapeutic subjects in the 100 mg group were decreased to 50 mg/day. On day 90, Cavg above 300 ng/dL was achieved in 75% of the 50 mg gel group and 80% of the 100 mg group compared to 57% in the patch group.
Overall, there was a significantly lower number of skin irritation events in the gel groups compared to the patch group. Only six of 205 subjects in the gel groups discontinued therapy; two were related to drug specific adverse effects (hypertension and mood swings). The study concluded that Vogelxo® gel is better tolerated than transdermal testosterone patches, and can better normalize serum testosterone levels with titration (36).
Axiron® is supplied as a solution in a metered-dose pump that provides 30 mg of testosterone per actuation. The solution must be applied to the underarms using the provided applicator and is not recommended for application on other body parts. The suggested starting dose of Axiron® is 60 mg applied once daily in the morning. Dose adjustments should be made based on serum testosterone levels measured 14 days after initiation, and drawn two to eight hours after dose application. The dose can be adjusted in 30 mg increments up to a maximum of 120 mg or a minimum of 30 mg/day (37).
A multicenter, open label study in men with documented androgen deficiency was conducted to evaluate the effects of Axiron® at a dose of 60 mg/day (38). Normal physiological range of serum testosterone was defined as 300–1,050 ng/dL, and doses were adjusted on days 45 and 90. On day 15, all subjects (n=135) were receiving 60 mg/day and the mean Cavg was 456 ng/dL with a Cmin of 257 ng/dL and a Cmax of 743 ng/dL. By day 120, 84.1% of patients had a Cavg within normal range. At this time, 10 patients were receiving 120 mg, 25 were titrated to 90 mg, 97 were still receiving 60 mg, and 3 patients had decreased to 30 mg/day. Mean Cavg and Cmax for all dosing regimens were within normal range on day 120. Adverse events occurring in greater than 3% of subjects who received at least one dose included application site irritation (7%), application site erythema (5%), headache (5%), increased hematocrit (4%), and nasopharyngitis (4%). The authors concluded Axiron® was well tolerated and achieved therapeutic testosterone levels with appropriate dose adjustments (38). Axiron® is novel in its use of an applicator which prevents users from touching the solution, potentially decreasing transmission risk to others unlike testosterone gels.