Therapeutic Class Overview
Topical Androgens
Therapeutic Class• Overview/Summary: The topical testosterone products listed in Table 1 are approved by the Foodand Drug Administration for testosterone replacement therapy in males with primary hypogonadism
1-6(congenital or acquired) or hypogonadotropic hypogonadism (congenital or acquired). There arefew differences between the topical testosterone products with the exception of formulation and site®
of administration. Androderm is the only testosterone product available as a transdermal patch.
®
®
®
®
AndroGel , Fortesta and Testim are available in gel preparations, while Axiron is formulated as a
topical solution. These products are available as metered-dose pumps or single-use packets/tubes.
®
1-6
Androderm is applied at night, while the others are generally applied in the morning. A higher
incidence of skin pruritus is associated with the transdermal patch compared to the topical gels;1
however, the use of hydrocortisone cream, may reduce skin irritations that develop. The topicaltestosterone product labeling includes a Black Box Warning regarding the risk of virilization of female
sexual partners that has been reported with male use of topical testosterone gels and solution. The®
occlusive backing film on Androderm prevents the partner from coming in contact with the active
1-6
material in the system, and therefore the warning is not included on this product. There are no
topical testosterone products available generically.
7-11

Hypogonadism refers to a defect of the reproductive system resulting in a lack of gonad function.
Hypogonadism is classified based on the level of the defect within the reproductive axis. Primary
hypogonadism results from a defect of the gonads and occurs when the serum testosterone
concentration and/or sperm counts are below normal, and the serum luteinizing hormone (LH) and/or
11
follicle-stimulating hormone (FSH) concentrations are above normal. Secondary hypogonadism,
known as hypogonadotropic hypogonadism, results from defects in the hypothalamus or pituitary.
This occurs when the serum testosterone concentration and/or sperm counts are below normal, and11
the serum LH and/or FSH concentrations are normal or reduced. Combined primary and secondary
hypogonadism may occur and results in below-normal testosterone concentrations and variable LH
9and/or FSH concentrations, depending upon which clinical condition predominates. Malehypogonadism may manifest as testosterone deficiency with or without infertility. Clinical signs andsymptoms depend primarily on the age at the onset of the condition. Postpubertal hypogonadism
usually results in slowly evolving clinical manifestations that may include a progressive decrease inmuscle mass, loss of libido, impotence, oligospermia or azoospermia, poor concentration, and an
7-11
increase in the risk of osteoporosis and fractures.
1-5

Table 1. Current Medications Available in the Therapeutic Class
Generic
Food and Drug Administration
Dosage Form/Strength(Trade Name)
Approved Indications®
Testosterone
Hypogonadism in males, primaryAndroderm :®
(Androderm )(congenital or acquired) and
2 mg/day patch
hypogonadotropic hypogonadism in
4 mg/day patch
males (congenital or acquired)®
Testosterone
Hypogonadism in males, primaryAndroGel 1%:®
(AndroGel )(congenital or acquired) andMetered-dose pump (60hypogonadotropic hypogonadism inactuations per container; 12.5
males (congenital or acquired)
mg testosterone per actuationin 1.25 g gel)
Packet (30 packets per carton;
25 mg testosterone in 2.5 g gelor 50 mg testosterone in 5 g
gel)Page 1 of 3
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Generic
Availability--

Therapeutic Class Overview: topical androgens

Generic(Trade Name)

Food and Drug Administration
Approved Indications

Dosage Form/Strength

Generic
Availability®

AndroGel 1.62%:
Metered-dose pump (60actuations per container; 20.25
mg testosterone per actuationin 1.25 g gel)

Testosterone®
(Axiron )Testosterone®
(Fortesta )Testosterone®
(Testim )Hypogonadism in males, primary(congenital or acquired) andhypogonadotropic hypogonadism inmales (congenital or acquired)
Hypogonadism in males, primary(congenital or acquired) andhypogonadotropic hypogonadism inmales (congenital or acquired)

Hypogonadism in males, primary(congenital or acquired) andhypogonadotropic hypogonadism inmales (congenital or acquired)

Packet (30 packets per carton;
20.25 mg testosterone in 1.25
g gel or 40.5 mg testosterone
in 2.5 g gel)®
Axiron :Metered-dose pump (60actuations per container; 30
mg testosterone per actuationin 1.5 mL of solution)®
Fortesta :Metered-dose pump (60actuations per container; 10
mg testosterone per actuation
in 0.5 g gel)

-

-

®

Testim 1%:
Unit-dose tubes (30 tubes per
carton; 50 mg testosterone in
5 g gel)-Evidence-based Medicine®
®
• In one study comparing Testim 50 and 100 mg, Androderm and placebo, all treatments significantly
increased serum testosterone and dihydrotestosterone (DHT) levels. All treatments increased lean®
body mass (LBM); however, the Testim 100 mg group increased LBM significantly more compared to®
®
®
the Androderm and placebo groups (P<0.05 for all). Testim and Androderm significantly decreased®
fat mass compared to placebo. Only Testim 100 mg produced significant improvements in sexual
12
function. There were no significant differences among groups with regard to improving mood.
®
®
• Compared to Androderm , AndroGel 100 mg significantly increased levels of testosterone and free®
®
testosterone compared to AndroGel 50 mg and Androderm . There were significant increases in®
®
serum DHT levels with both doses of AndroGel compared to Androderm . The discontinuation rate,® 13
mostly due to adverse skin reactions, was significantly greater with Androderm .
®
®
• In a study comparing AndroGel and Androderm , the average serum testosterone levels increased®
most with AndroGel 100 mg (P values not reported). A decrease in percent body fat and total fat mass®
occurred in all treatment groups; however, this was only significant for AndroGel . All treatment groups®
experienced significant improvements in sexual function. AndroGel treatment significantly increased
prostate specific antigen levels. Skin irritation at the application site was more frequent in the®
®
14
Androderm group compared to AndroGel 100 mg and 50 mg groups.
• The results from a study by Grober et al demonstrated the efficacy of changing from one testosterone®
gel preparation to another after suboptimal response (N=370). Among men switching from AndroGel to®
Testim , 69, 58 and 65% experienced improvements in libido, erectile function and energy levels,®
respectively. The rates of improvement for these parameters for men switching from Testim to®
15
AndroGel were 46, 39 and 46%, respectively.
®
• In an open-label study, Axiron topical solution applied to the axilla provided a serum testosterone level16
in the normal range for 84.1% of patients after 120 days of treatment. Results from a second open-

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Therapeutic Class Overview: topical androgens

label study reported that 76.2% of men achieved a mean serum testosterone level within the normal® 17physiologic range following 35 days of treatment with Fortesta .
Key Points within the Medication Class• According to Current Clinical Guidelines:o Intramuscular and topical testosterone preparations are generally recommended for the
8-10,18
management of hypogonadism in adult male patients.
o The oral alkylated androgens are not recommended due to poor androgen effects, adverse
lipid changes, and hepatic side effects, but may be considered when other agents are not
8,10
suitable.
o The selection of testosterone replacement therapy should be a joint decision between thepatient and physician and should be made after consideration of patient preferences, the8,10
pharmacokinetic profiles of the respective agents, treatment burden and cost.
o The short-acting preparations may be preferred over long-acting depot preparations when
initiating treatment in patients with late-onset hypogonadism due to the potential developmentof an adverse event that may require rapid discontinuation of testosterone replacement
8-10
therapy. Treatment guidelines do not recommend one topical preparation over another.
•

Other Key Facts:
o There are no generic topical testosterone products available.

References
1.
2.
3.
4.
5.
6.
7.
8.

9.

10.
11.
12.
13.
14.

15.
16.
17.

18.

Androderm® [package insert]. Corona (CA): Watson Pharma, Inc.; 2013 Apr.
AndroGel® [package insert]. North Chicago (IL): Abbott Laboratories; 2012 Sept.
Testim® [package insert]. Malvern (PA): Auxilium Pharmaceuticals, Inc.; 2011 Nov.
Axiron® [package insert]. Indianapolis (IN): Eli Lilly & Company; 2011 Dec.
Fortesta® [package insert]. Malvern (PA): Auxilium Pharmaceuticals, Inc.; 2012 Dec.
Micromedex® Healthcare Series [database on the Internet]. Greenwood Village (CO): Thomson Micromedex; 2013 [cited 2013
May 30]. Available from: http://www.thomsonhc.com/.
Snyder PJ. Testosterone treatment of male hypogonadism. In: Basow DS (Ed). UpToDate [database on the Internet]. Waltham(MA): UpToDate; 2013 [cited 2013 May 30]. Available from: http://www.utdol.com/online/index.do.
Petak SM, Nankin HR, Spark RF, Swerdloff RS, Rodriguez-Rigau, LJ; American Association of Clinical Endocrinologists. Medical
Guidelines for Clinical Practice for the Evaluation and Treatment of Hypogonadism in Adult Male Patients. Endocrine Practice.
2002 Dec;8(6):439-56. Available from: https://www.aace.com/sites/default/files/hypogonadism.pdf
Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS et al. The Endocrine Society. Testosterone
Therapy in Adult Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol
Metab. 2010;95(6):2536-59. Available from: http://www.endo-society.org/guidelines/final/upload/FINAL-Androgens-in-MenStandalone.pdf
Wang C, Nieschlag E, Swerdloff RS, et al. ISA, ISSAM, EAU, EAA and ASA recommendations: investigation, treatment andmonitoring of late-onset hypogonadism in males. The Aging Male. 2009;12(1):5-12.
Snyder PJ. Clinical features and diagnosis of male hypogonadism. In: Basow DS (Ed). UpToDate [database on the Internet].
Waltham (MA): UpToDate; 2013 [cited 2013 May 30]. Available from: http://www.utdol.com/online/index.do.
Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand et al. 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.
Swerdloff RS, Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM et al. Long-term Pharmacokinetics ofTransdermal Testosterone Gel in Hypogonadal Men. J Clin Endocrinol Metab. 2000;85:4500-10.
Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G et al. Transdermal Testosterone Gel Improves Sexual
Function, Mood, Muscle Strength, and Body Composition Parameters in Hypogonadal Men. J Clin Endocrinol Metab.
2000;85:2839-53.
Grober ED, Khera M, Soni SD, Espinoza MG, Lipshultz LI. Efficacy of changing testosterone gel preparations (AndroGel or
Testim) among suboptimally responsive hypogonadal men. Int J Impot Res. 2008 Mar-Apr;20(2):213-7.
Wang C, Ilani N, Arvert S, McLachlan RI, Soulis T, Watkinson A. Efficacy and safety of the 2% formulation of testosterone topicalsolution applied to the axillae in androgen-deficient men. Clin Endocrinol (Oxf). 2011 Dec;75(6):836-43.
Dobs AS, McGettigan J, Norwood P, Howell J, Waldie E, Chen Y. A novel testosterone 2% gel for the treatment of hypogonadal
males. Journal of Andrology. 2011 Oct 6 (e-published ahead of print); doi:10.2164/jandrol.111.014308. Available from:http://www.andrologyjournal.org/papbyrecent.shtml.
European Association of Urology. Guidelines on Male Hypogonadism [guideline on the internet]. The Netherlands: European
Association of Urology; 2012 [cited 2013 May 30]. Available from: http://www.uroweb.org/guidelines/online-guidelines/.

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Topical Androgens
Overview/Summary
Testosterone products are available in various formulations including oral administration, intramuscular
injection, topical gel, transdermal patch, topical solution, implantable pellets administered by the
subcutaneous route and a buccal delivery system. This review will focus on the topically administered
testosterone products listed in Table 1. All of these products are approved by the Food and Drug
Administration (FDA) as testosterone replacement therapy in males with primary hypogonadism
1-5(congenital or acquired) or hypogonadotropic hypogonadism (congenital or acquired). There are few
differentiating factors between the topical testosterone products with the exception of formulation and site®
of administration. Androderm is the only testosterone product that is available as a transdermal patch.
®
®
®
®
AndroGel , Fortesta and Testim are available in gel preparations and Axiron is formulated as a topicalsolution. These products are available as metered-dose pumps and single-use packets/tubes and are®
applied once daily. The Androderm patch is applied at night, while the other products are generally
applied in the morning. A higher incidence of skin pruritus is associated with the transdermal patch
compared to the topical gels; however, hydrocortisone cream may be applied after patch has been
1-6
removed to reduce skin irritation. No topical testosterone products are available generically.
Hypogonadism refers to a defect of the reproductive system resulting in a lack of gonad (testes)
7-12
Hypogonadism is classified based on the level of the defect within the reproductive axis.
function.
Primary hypogonadism results from a defect of the gonads and occurs when the serum testosterone
concentration and/or sperm counts are below normal, and the serum luteinizing hormone (LH) and/or
12
follicle-stimulating hormone (FSH) concentrations are above normal. Secondary hypogonadism(hypogonadotropic) results from defects in the hypothalamus or pituitary and occurs when the serum
testosterone concentration and/or sperm counts are below normal, and the serum LH and/or FSH
12concentrations are normal or reduced. Combined primary and secondary hypogonadism may occur, andresults in below-normal testosterone concentrations and variable LH and/or FSH concentrations,10
depending upon which clinical condition predominates. Male hypogonadism may manifest as
testosterone deficiency with or without infertility. As a result, appropriate disease classification isnecessary since fertility can be restored with appropriate androgen stimulation in individuals with
10
secondary hypogonadism, but not in most individuals diagnosed with primary hypogonadism. Clinicalsigns and symptoms depend primarily on the age at the onset of the condition. Postpubertal
hypogonadism usually results in slowly evolving clinical manifestations that may include a progressive
decrease in muscle mass, loss of libido, impotence, oligospermia or azoospermia, poor concentration,
8,12
and an increase in the risk of osteoporosis and fractures.
Intramuscular and topical testosterone preparations are generally recommended for the management of
7-11
Oral alkylated androgens are not recommended due to poor
hypogonadism in adult male patients.
androgen effects, adverse lipid changes and hepatic adverse events; however, they may be consideredwhen other agents are not suitable. The selection of testosterone replacement therapy should be a joint
decision between the patient and physician and should be made after considering patient preferences,
pharmacokinetic profiles of the agents, treatment burden and cost. Short-acting preparations may be
preferred over long-acting depot preparations when initiating treatment in patients with late-onset
hypogonadism due to the potential development of an adverse event that may require rapid
discontinuation of therapy. Moreover, the guidelines do not recommend one topical preparation overanother. Several clinical studies have demonstrated that topically applied testosterone restores serum
testosterone concentrations to within normal limits and maintain sexual characteristics, sexual behavior,mood, muscle development and improves bone mineral density in hypogonadal men. The results of three
14-17
head-to-head trials favored the use of the gel over the patch.

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Medications
Table 1. Medications Included Within Class Review
Generic Name (Trade name)®
®
®
Testosterone (Androderm , AndroGel , Axiron ,®
®
Fortesta , Testim )Medication Class

Generic Availability

Androgens-

Indications
1-5

Table 2. Food and Drug Administration Approved Indications®
®
®
®
Testosterone (Androderm , AndroGel , Axiron , Fortesta ,Indication®
Testim )Hypogonadism in males, primary (all)(congenital or acquired)
Hypogonadotropic hypogonadism (all)in males (congenital or acquired)
In addition to the Food and Drug Administration-approved indications, testosterone has been used off-label for
male infertility, osteoporosis and weight gain. Testosterone has also been used concomitantly with estrogens forthe management of vasomotor symptoms associated with menopause and in postmenopausal women with6
decreased sexual desire. Testosterone replacement therapy is not indicated for the treatment of erectile
dysfunction in men with normal serum testosterone concentrations.
Pharmacokinetics
1-7

Table 3. Pharmacokinetics
Bioavailability Absorption
Drug
(%)
(%)
Testosterone,
2 to 8 (gel);transdermal
10 (gel)8 (patch);(gels, patch,†solution)

Renal
Excretion (%)
Urine (90)‡

ActiveMetabolites

Serum Half-Life(hours)

Estradiol, Dihydrotestosterone

0.2 to 1.7*

DHT=dihydrotestosterone.
* The half-life not reported for all products but range of 10 to 100 minutes referenced.
†
The parameters are reported for the respective delivery systems as available in the prescribing information.
‡ Based on intramuscular administration.

Clinical Trials
The clinical trials demonstrating the safety and efficacy of the topical testosterone products in their Food
14-22
and Drug Administration-approved indications are described in Table 4.
®

In a randomized, multicenter, active-controlled study comparing two doses of testosterone gel (Testim 50®
mg and 100 mg) and a transdermal testosterone system, Testim 100 mg produced significantly higher
serum levels of testosterone, free testosterone and dihydrotestosterone (DHT) compared to the transdermal®
system. All three treatments significantly increased lean body mass (LBM), while only Testim 100 mg
significantly decreased percentage of fat. Significant differences between treatment groups were observed®
in the alleviation of negative mood and improvements in spontaneous erections favoring Testim overtransdermal testosterone. All three treatment groups experienced significant improvements in sexualmotivation, sexual desire and sexual performance. The transdermal testosterone system was associated14with a higher incidence of treatment-emergent adverse events. In a second study comparing two doses of®
®
Testim , a transdermal testosterone patch (Androderm ) and placebo, all treatment groups achieved similar
increases in serum testosterone and DHT levels. All treatment groups experienced increases in LBM;®
however, the Testim 100 mg group experienced a significantly greater increase in LBM compared to the®
®
®
Androderm and placebo groups (P<0.05 for each). The use of both Testim and Androderm resulted in®
significant decreases in fat mass compared to placebo. Only Testim 100 mg significantly improved sexual

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Therapeutic Class Review: topical androgens

function compared to placebo. There were no significant differences among treatment groups in improving®
mood. Androderm was associated with more treatment-emergent adverse events compared to the other15
treatment groups.
®

®

®

When two doses of a testosterone gel (AndroGel ) were compared to Androderm , AndroGel 100 mg was
associated with significantly higher levels of serum testosterone and free testosterone compared to®
®
AndroGel 50 mg and Androderm . There were significant increases in serum DHT levels with both doses®
®
of AndroGel compared to Androderm . The discontinuation rate, mostly due to adverse skin reactions, was®
16®
significantly greater in the Androderm group. In a study by Wang et al comparing AndroGel and®
®
Androderm , average serum testosterone levels were increased greatest with AndroGel 100 mg (P values
not reported). A decrease in percent body fat and total fat mass occurred in all treatment groups; however,®
this was only significant in the AndroGel treatment group. All treatment groups experienced significant®
improvements in sexual function. Treatment with AndroGel resulted in significant increases in prostate
specific antigen levels. Skin irritation at the application site occurred in 65.8, 5.3 and 5.7% of patients in the®
®
Androderm , AndroGel 100 mg and 50 mg groups. This study also demonstrated that all treatments
caused a significant increase in hemoglobin (Hgb) and hematocrit (Hct) but had no overall effects on lipid
17
profiles or blood chemistries.
®

In an extension study, patients treated with three doses of AndroGel were observed for a period of 36®
months. Long-term treatment with AndroGel maintained increased levels of serum testosterone andimprovements in sexual function, positive mood and body composition. A gradual but significant
improvement in hip and spine bone mineral density was also observed. Increases in Hgb and Hct plateauedat 12 months and clinically insignificant increases in high-density lipoprotein cholesterol, serum creatinine
and total bilirubin were observed. Serum levels of prostate specific antigen showed no further significant
increases past six months of treatment. Treatment-emergent adverse events included application site
18
reactions, acne and gynecomastia.
Grober et al evaluated the efficacy of changing from one testosterone gel preparation to another after
suboptimal response. Of the 370 hypogonadal men on testosterone replacement therapy, 20% of men®
underwent a brand substitution due to initial suboptimal response. Among men switching from AndroGel to®
Testim a total of 69, 58 and 65% experienced improvements in libido, erectile function and energy levels,®
respectively. The rates of improvement for these same parameters among men switching from Testim to®
®
®
AndroGel were 46, 39 and 46%, respectively. Changing from AndroGel to Testim was reported to have®
®
resulted in improved clinical and biochemical responsiveness. Changing from Testim to AndroGel
19
eliminated or minimized unwanted side effects (primarily scent).
In a multicenter, randomized controlled trial by Korbonits et al, testosterone buccal 30 mg applied twice®
daily was compared to the testosterone transdermal patch (Andropatch [not commercially available in the®
U.S.] or Androderm ) 5 mg once-daily for seven days. The investigators concluded (results not reported)
testosterone buccal was non-inferior to the testosterone patch formulation. At all measured time points, themean testosterone levels were within the established physiological range among patients receiving the
buccal formulation compared to five measured time points falling outside of this range among patients
receiving the patch formulation. Also, the proportion of patients with levels outside the physiological range
was lower in the buccal group compared to the patch group for both the mean (zero to 24 hour) andminimum testosterone levels (P<0.001 for each). The serum testosterone concentrations over the 24-hour
period were higher for patients receiving buccal testosterone compared to those receiving the patch(P<0.00001). The mean maximum and mean minimum 24-hour testosterone levels were within thephysiological range for the testosterone buccal group; whereas only the mean maximum 24-hour
testosterone level was within the physiological range for the testosterone patch group. A total of 84.8% of
patients in the buccal group were within the physiological range over 24 hours compared to 55.1% of
patients in the patch group. The most common adverse events reported among both groups were20
application site reactions.
In an open-label efficacy trial (N=155), Wang et al evaluated varying doses of testosterone 2% topical®
solution (Axiron ) applied to the axilla once daily. During the open-label phase of the trial, the mean serum

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testosterone level before and after application of the testosterone solution was within the adult male range
over the 24-hour measurement period on days 15, 60 and 120. Among subjects who were responders at
study endpoint (120 days), the geometric mean of serum testosterone values for subjects on any dose was
16.86 nmol/L. In addition, the proportion of patients completing the study with an average testosterone
concentration (C avg ) in the normal range was 76.1% on day 15/16, 84.8% on day 60/61, and 84.1% at day
120. Serum DHT levels and serum free testosterone remained relatively stable over the 24 hours following
dosing. The DHT/testosterone ratio values among patients completing the study and among responders
remained relatively constant from baseline. Improvements in sexual desire and activity were apparent 15
days after application of testosterone solution and were sustained throughout the study. Statisticallysignificant changes from baseline were seen in sexual desire, sexual activity, positive mood and negative
mood as assessed by the Psychosexual Daily Questionnaire domain for the seven days prior to visits one,15, 60 and 120. Mean changes from day 1 to 120 in the SF-36 Physical Component and SF-36 Mental
Component scores were also statistically significant. Treatment-emergent adverse events in the open-label
study included application site irritation, application site erythema, headache, increased hematocrit,21
nasopharyngitis, diarrhea and vomiting.
®

Dobs et al evaluated the efficacy of testosterone topical gel (Fortesta ) 40 mg applied to the thighs once
daily in varying doses depending upon serum testosterone response. At study endpoint (90 days), the mean
serum total testosterone concentration over 24 hours (C avg zero to 24hr ± SD) for the 129 individuals withdata available for analysis, was 438.56±162.51 ng/dL, a total of 77.5% of patients achieving a mean serum
testosterone level within the pre-defined normal physiological range of ≥300 and ≤1140 ng/dL (95% CI, 70.3
to 84.7). By day 35, 76.2% (95% CI, 68.8 to 83.6) of patients had reached the primary endpoint and on day
90, 22.5% of patients had a total testosterone level <300 ng/dL. The most commonly reported adverse
events were skin reactions, upper respiratory infections and sinusitis. Skin reactions considered
possibly/probably related to study medication were reported in 16.1% of patients, of which 79.2% were
22
determined to be mild in severity.

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Table 4. Clinical Trials
Study and Drug Regimen

Study Design
and
Demographics

Treatment of Hypogonadism
14
McNicholas et al
AC, DB, MC, OL,
RCT®
Testosterone gel (Testim )50 mg daily in the morning Hypogonadalmen, 31 to 80
vsyears old,morning serum®
testosterone gel (Testim )testosterone
100 mg daily in thelevel ≤10.4
morning
nmol/L atscreening withvsone or more
symptoms of low
testosterone patch
testosterone®
(Andropatch *) 2.5 mg two
patches daily in themorning

Sample Sizeand Study
Duration
N=208
90 days

End Points

Results

Primary:
24-hour PK
profiles at 30, 60
and 90 days;
treatment
effectiveness asmeasured bybodycomposition,mood, andsexual function
data at 30, 60
and 90 days;
safetyPrimary:
At 90 days, mean increases in serum testosterone levels were significant for
testosterone gel 100 mg (12.41 nmol/L) compared to testosterone gel 50 mg(6.54 nmol/L; P<0.05) and testosterone patch (3.82 nmol/L; P<0.001). Results
at 30 and 60 days were consistent with those at 90 days. The same results
were also seen with the mean increase from baseline in free testosterone
levels.

Secondary:Not reported

At 90 days, the mean change in DHT levels with testosterone gel 100 mg
were significantly greater compared to testosterone gel 50 mg (P<0.05) andtestosterone patch (P<0.001). In addition, the mean change in DHT levels
with testosterone gel 50 mg was also significant compared to testosterone
patch at 90 days (P<0.001). Results at 30 and 60 days were consistent withthose observed at 90 days.
Significant within-treatment group changes in LBM were seen for all threetreatment groups; 0.9 kg (P<0.05), 1.5 kg (P<0.001) and 1.0 kg (P<0.05) for
testosterone gel 50 mg, testosterone gel 100 mg, and testosterone patch,
respectively. Significant within-treatment group mean changes in percentage
fat were only seen with testosterone gel 100 mg (-0.7; P<0.05). There wereno statistically significant changes in BMD within any of the three treatmentgroups.
No significant differences in improvement in positive mood were seen among
the three treatment groups. There were significant differences between
treatment groups at 90 days in the alleviation of negative mood favoring
testosterone gel over the testosterone patch (P<0.05).
At 90 days there were significant within-treatment group improvements frombaseline in all three groups in sexual motivation, sexual desire and sexual
performance (P<0.05). Both testosterone gel groups had a statisticallysignificant within-treatment improvement in spontaneous erections at all times
from baseline (P<0.05). Testosterone patch produced no significant
improvement in spontaneous erections at any time.

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Study and Drug Regimen

Study Design
and
Demographics

Sample Sizeand Study
Duration

End Points

Results

The incidence of treatment-emergent adverse events was 35% for
testosterone gel 50 mg, 29% for testosterone gel 100 mg, and 63% for
testosterone patch groups. The most commonly reported adverse eventswere erythema, irritation, and reactions at the application site.

Steidle et al

15®

Testosterone gel (Testim )50 mg daily in the morningvs®

testosterone gel (Testim )100 mg daily in themorningvstestosterone patch®
(Androderm ) 2.5 mg two
patches daily in themorningvsplacebo

AC, DB, MC, OL,
PC, RCT

N=406
90 days

Hypogonadalmen, 20 to 80
years old,morning serum
testosterone
level ≤10.4
nmol/L atscreening with
one or more
symptoms of low
testosterone

Primary:
Periodic 24-hour
PK profiles;
effect ofnormalizing
serum
testosterone on
body
composition,
sexual function,
mood and BMD;
safetySecondary:Not reported

Secondary:Not reported
Primary:
At 30 days, all treatment groups had increased mean serum testosterone and
DHT concentrations. Patients treated with testosterone gel 100 mg had asignificant increase in mean changes in testosterone concentrations
compared to patients treated with the testosterone patch (P<0.001). The
testosterone gel 50 mg and 100 mg groups experienced a significant
increases in mean changes in DHT concentrations compared to thetestosterone patch (P<0.001 for each comparison). By 90 days, similar results
were observed across treatment groups.
At 90 days, the mean change in LBM was 1.5±4.5, 1.7±2.6, 0.9±1.8 and
0.6±1.8 kg for patients receiving testosterone gel 50 mg, testosterone gel 100
mg, testosterone patch and placebo, respectively. Increases in LBM weresignificantly higher with testosterone gel 100 mg compared to thetestosterone patch and placebo (P<0.05 for each comparison). With the
exception of placebo treatment, all treatments resulted in a significant
decrease in FM compared to placebo (P<0.01).
At 90 days, testosterone gel 100 mg treatment was associated with significant
improvements in spontaneous erections (P<0.001), sexual motivation(P<0.05), sexual desire (P<0.01) and sexual performance (P<0.05) comparedto placebo. No other treatment groups had significant improvements
compared to placebo.
All treatments resulted in mean improvements from baseline in both positive
and negative mood scores with no significant differences among thetreatment groups.

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Study and Drug Regimen

Study Design
and
Demographics

Sample Sizeand Study
Duration

End Points

Results
The incidence of treatment-related adverse events was 29.1, 36.9, 62.7, and40.4% for testosterone gel 50 mg, testosterone gel 100 mg, testosterone patch,and placebo, respectively.
At 90 days, clinically notable decreases in total-C, LDL-C, and HDL-C wereseen with testosterone gel 100 mg (P value not reported). Increases in Hgb
and Hct were the highest with testosterone gel compared to the testosterone
patch and placebo. Increases in PSA values were highest in the testosterone
patch group (6.6%).

16

Swerdloff et al

Testosterone gel®
(AndroGel ) 50 mg daily
vstestosterone gel®
(AndroGel ) 100 mg daily
vstestosterone patch®
(Androderm ) 2.5 mg two
patches daily
At 60 days, men withserum testosterone levels<10.4 nmol/L who were®
applying AndroGel 50 mg
and men with serum
testosterone levels >34.7
nmol/L who were applying®
AndroGel 100 mg were

DB, MC, OL,
PG, RCT

N=227
180 days

Hypogonadalmen, 19 to 68
years old,morning serum
testosterone
level ≤10.4
nmol/L atscreening

Primary:Serum
testosterone andfree testosterone
levels at zero,one, 30, 90 and
180 days; serum
DHT, E 2 , FSH,
LH, SHBG levels
on 0, 30, 60, 90,
120, 150 and
180 days; safety
Secondary:Not reported

Secondary:Not reported
Primary:
At 30 and 90 days, testosterone gel 100 mg produced significantly higher C avg
testosterone levels compared to testosterone 50 mg and testosterone patch(27.46±1.12 vs 19.17±1.06 and 14.46±0.68 nmol/L, respectively; P=0.0001).
At 180 days, serum testosterone levels and PK parameters were similar to
those on days 30 and 90 in patients who continued their initial randomized
treatment. Patients switched to testosterone gel 75 mg had a C avg
testosterone level of 20.84±1.76 nmol/L at 180 days. This value was between
the 180 day C avg testosterone levels achieved with testosterone gel 50 mg(19.24±1.18) and testosterone gel 100 mg (24.72±1.05).
PK parameters of serum free testosterone levels on days one, 30, 90 and 180
mirrored those of serum testosterone levels. The free testosterone levels in
the testosterone gel 100 mg group was 1.4- and 1.7-fold higher than the
testosterone gel 50 mg and testosterone patch groups (P=0.001).
The discontinuation rate at 90 days for the testosterone patch (27.6%) was
significantly higher than testosterone gel 50 and 100 mg (8.2 and 6.4%,
respectively; P=0.0002). Most patients discontinued treatment due to adverse
skin reactions.
Throughout the 180 days, increases in serum DHT levels were significant withtestosterone gel 50 and 100 mg compared to the testosterone patch(P=0.0001). Mean serum increases to stable levels of E 2 occurred in 9.2,

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Study and Drug Regimen

Study Design
and
Demographics

Sample Sizeand Study
Duration

End Points

instructed to apply®
AndroGel 75 mg once
daily for days 91 through180.

Results
30.9, and 45.5% of patients in the testosterone patch, testosterone gel 50 and
testosterone gel 100 mg groups, respectively (P=0.001).
All three treatment groups demonstrated a small decrease in serum SHBG
levels (P=0.0046).
The mean percent suppression of serum LH levels was the smallest withtestosterone patch (30 to 40%), intermediate with testosterone gel 50 mg (55to 60%), and greatest with testosterone gel 100 mg (80 to 85%; P<0.01). The
suppression of serum FSH paralleled that of serum LH levels.

17

Wang et al

Testosterone gel®
(AndroGel ) 50 mg daily
vstestosterone gel®
(AndroGel ) 100 mg daily
vstestosterone patch®
(Androderm ) 2.5 mg two
patches daily
At 90 days, dose
adjustments were made in®
the AndroGel groups
based on the preapplication serum
testosterone levels on day
60. Twenty subjects in theDB, MC, OL,
PG, RCT

N=227
180 days

Hypogonadalmen, 19 to 68
years old,morning serum
testosterone
level ≤10.4
nmol/L atscreening

Primary:
Mean change
from baseline inserum
testosterone
concentrations,bodycomposition, andmuscle strength
at 90 and 180
days; meanchange frombaseline insexual function
and mood at 30,
60, 90, 120, 150
and 180 days;
degree of skinirritation; meanchange frombaseline inserum PSA
levels at 30 andSecondary:Not reported
Primary:
On day 90, the average serum testosterone concentration with testosteronegel 100 mg (27.46±1.12 nmol/L) was 1.4-fold higher than testosterone gel 50
mg (19.17±1.06 nmol/L) and 1.9-fold higher than the testosterone patch(14.46±0.68 nmol/L; P value not reported). On day 180, average serum
testosterone concentrations for the treatment groups were 24.72±1.05nmol/L, 19.24±1.18 nmol/L and 14.14±0.88 nmol/L, respectively.
The percent body fat and FM decreased in all treatment groups but was only
significant with testosterone gel. At 90 days, the total FM was significantly
decreased with testosterone gel 50 mg and testosterone gel 100 mg(P=0.0065 and P=0.0001, respectively). At 180 days, the total FM decreased
further with testosterone gel 100 mg (P=0.008). At 90 days, the percent body
fat was significantly decreased with testosterone gel 50 mg and testosteronegel 100 mg (P=0.0018 and P=0.001) and remained significant at 180 days.
Significant increases in arm and leg muscle strength were observed in all
three treatment groups without intergroup differences at 90 and 180 days.
All subjects experienced significant improvements in sexual motivation(P=0.0001), sexual desire (P=0.0001), sexual performance (P=0.0001), selfassessment of satisfaction of erection (P=0.0001) and percentage of full
erection (P=0.0001). All three treatment groups had significant improvements

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Study and Drug Regimen

Study Design
and
Demographics

Sample Sizeand Study
Duration®

AndroGel 50 mg group
had their dose increased
to 75 mg and 20 subjects®
in the AndroGel 100 mg
group had their dose
reduced to 75 mg.

End Points

Results

90 days; meanchange frombaseline in Hgb,
Hct, lipid profiles
and bloodchemistries

in positive mood scores (P=0.0001) and a decrease in negative mood scores(P=0.0001) without significant between-group differences.

Secondary:Not reported

Minimal skin irritation at the application site was observed in 5.7 and 5.3% of
patients receiving testosterone gel 50 mg and 100 mg, respectively. Minimal
to severe skin irritation occurred in 65.8% of patients in the testosterone patch
group.
Mean serum PSA levels significantly increased with testosterone gel 100 mg(P=0.008) and testosterone gel 50 mg (P=0.05) with no significant increase in
the testosterone patch group.
As a group, both Hgb and Hct increased (P=0.0001) with statisticalsignificance across treatment groups (P=0.0001). There were no overall
treatment effects or intergroup differences in serum concentrations of total-C,
HDL-C, LDL-C or TG (data not provided).

18

Wang et al

Testosterone gel®
(AndroGel ) 50 mg daily
vstestosterone gel®
(AndroGel ) 75 mg daily
vstestosterone gel®
(AndroGel ) 100 mg daily

ES, MC, OL, PG,
RCT

N=163
36 months

Hypogonadalmen, 19 to 68
years old, single
morning serum
testosterone
level atscreening of≤10.4 nmol/L

Primary:
Mean changes
from baseline inserum
testosterone,freetestosterone,
DHT, E2, SHBG,
LH and FSH;
mean changes
from baseline insexual function
and mood, bodycomposition,bone turnovermarkers, muscle
strength andSecondary:Not reported
Primary:
Mean serum testosterone levels were significantly different (P=0.012)
between dosing groups at baseline (six months of TRT). At 12 months,
differences among the dosing groups became smaller but remained
significant (P=0.042). Serum free testosterone levels followed the same
pattern as testosterone.
Mean serum DHT levels were significantly different in the three dosing groups
at 12 (P=0.0031) and 24 (P=0.018) months with the highest levels seen withtestosterone gel 100 mg. Mean serum E 2 levels progressively increased fromsix to 24 months (P=0.0001) with significant differences between treatmentgroups. The highest levels of serum E 2 were seen with testosterone gel 100
mg. No significant change in SHBG was seen. Suppression of LH and FSH
was maintained throughout with no significant changes after six months. The
suppression was more pronounced with testosterone gel 100 mg.
Significant improvements in sexual desire, enjoyment with or without aPage 9 of 27
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Study and Drug Regimen

Study Design
and
Demographics

Sample Sizeand Study
Duration

End Points
BMD; meanchanges frombaseline in Hgb,
Hct, lipid profiles
and bloodchemistries;
mean changes
from baseline inserum PSA andprostate disease;safetySecondary:Not reported

Results
partner, percent full erection, and self-assessment of satisfaction witherections were maintained as a group throughout the study period.
Positive mood scores were significantly improved with treatment and were
sustained (P=0.0022). Negative mood parameters were decreased andremained significantly lower (P=0.0013) than baseline without further changes
after six months.
Average total body mass increased by 1.2±0.3 kg at six months (P=0.0157)
and did not significantly change with continued therapy. The LBM increased
significantly (P=0.0001) from baseline and remained increased throughout the
study. A significant decrease in FM was seen at 30 months (P=0.088) without
significant differences between doses.
Serum PTH levels significantly increased from baseline (P=0.0001) andcontinued to increase from six (P=0.0002) until 12 months when it remained
stable throughout the rest of the treatment period. Serum SALP levels
followed the same pattern (P=0.001). At 12 months, serum osteocalcin was
significantly elevated and remained elevated throughout treatment(P=0.0001). Serum procollagen levels transiently increased then steadily
increased from six months to reach significant levels by 36 months(P=0.0001).
Muscle strength increased but did not reach significance over time due to thelarge variation in patients.
The BMD of the hip (P=0.0004) and spine (P=0.0001) showed a gradual andprogressive increase with treatment. No significant differences among
treatment doses or older and younger patients were observed.
Serum Hgb and Hct concentrations increased, compared toto month zero
(P=0.0001) and month six (P=0.001) and plateaued at 12 months.
Small statistically significant increases in serum HDL-C levels (P<0.001),
creatinine (P<0.001), and total bilirubin (P=0.001) were seen but were notclinically significant. No significant changes in total-C, LDL-C, serum liver

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Study and Drug Regimen

Study Design
and
Demographics

Sample Sizeand Study
Duration

End Points

Results
enzymes, or other clinical chemistry parameters were observed.
The mean serum PSA was 1.11±0.08 at six months and showed no further
significant increases with continued treatment.
Application-site reactions occurred in 12 of 163 (7.4%) patients. Acne
occurred in 12 of patients and gynecomastia was observed in eight morepatients.

19

Grober et al

OL

Testosterone gel®
(AndroGel ) 5 to 10 g

Hypogonadal
men ontestosterone gel
who underwent a
brand
substitution due
to initialsuboptimalbiochemical or
symptomatic
response, mean
age of men
switched to®
Testim was 60
years, mean ageof men switched®
to AndroGel
was 52 years

vs®

testosterone gel (Testim )5 to 10 g

N=370
Treatment
duration afterswitch, 4
weeks

Primary:
Reasons for
brand
substitution, total
and freetestosterone,
presence of
hypogonadal
symptoms
Secondary:Not reported

Secondary:Not reported
Primary:
Twenty percent of the 370 hypogonadal men using testosterone gel®
underwent a brand substitution. The reasons for switching from AndroGel to®
Testim (N=62) were poor efficacy (92%), hypertension (2%), skin reaction(2%), worsening symptoms (2%), and insurance coverage (2%). The reasons®
®
for switching from Testim to AndroGel (N=13) were scent (46%), poor
efficacy (30%), fear of transfer to partner (8%), flushing (8%) and skinreaction (8%).
®

Prior to substitution, patients initially treated with AndroGel , had mean total
and free testosterone levels of 311 ng/dL and 10.4 pg/mL, respectively. Total
testosterone levels were <300 ng/dL in 58% of these patients. Following a®
change to Testim , mean total and free testosterone levels increased to 484
ng/dL (P<0.001) and 14.6 pg/mL (P=0.01), respectively. Total testosterone
levels remained <300 ng/dL in 17% of these patients.
®

Among patients initially treated with Testim , the mean total and freetestosterone levels were 544 ng/dL and 18.0 pg/dL, respectively. Total
testosterone levels were <300 ng/dL in 15% of men. Following a change to®
AndroGel , mean total and free testosterone levels were 522 ng/dL (P=0.7)
and 16.1 pg/mL (P=0.6), respectively. Total testosterone levels remained<300 ng/dL in 27% of these patients.
Secondary:Not reported

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Study and Drug Regimen
20

Korbonits et al

Testosterone buccal®
(Striant ) 30 mg BID
vstestosterone patch®
(Andropatch * or®
Androderm ) 5 mg once
daily

Study Design
and
Demographics
IT, MC, RCTSample Sizeand Study
Duration
N=66

Men with
testosterone
deficiency with amorning serum
testosterone<6.94 nmol/L,
normal agerelated PSA
levels, and Hct<50

7 daysEnd Points
Primary:
Non-inferiority
analysis(endpoints notdefined)Secondary:
Efficacy analysis
of superiority(endpoints notdefined)Results
Primary:
Investigators concluded that non-inferiority was established (results notreported).
Secondary:In the buccal testosterone group, the mean testosterone concentrations at allmeasured time points (days three, four, six, seven and eight) were within thephysiological range; whereas mean concentrations at five time points wereoutside of the physiological range among patients in the testosterone patch
group.
For both mean (zero to 24 hour) and minimum testosterone levels, theproportion of patients with levels outside the physiological range was lower inthe buccal group than in the patch group (P<0.001 for each).
The serum testosterone concentrations over the 24-hour period were higher
for patients receiving buccal testosterone compared to those receiving thepatch (mean AUC ± SD; 451.31±140.71 h*nmol/L vs. 304.63±134.46
h*nmol/L; 95% CI, 1.25 to 1.91; P <0.00001).
The mean maximum and mean minimum 24-hour testosterone levels were
within the physiological range for the testosterone buccal group.
Comparatively, the mean maximum 24-hour testosterone level was within thephysiological range for the testosterone patch group; however, the mean
minimum 24-hour testosterone level was below the physiological range. A
total of 84.8% of patients in the buccal group were within the physiologicalrange over 24 hours compared to 55.1% of patients in the patch group.
Testosterone concentrations were within the physiological range in the buccal
group for a significantly greater portion of the 24-hour treatment period
compared to the patch group (84.9 vs 54.9%; P<0.001).
Mean DHT levels were within the normal range (1.03 to 2.92 nmol/L) for boththe buccal group (2.36±0.99 nmol/liter) and the patch group (1.2±0.57nmol/L).

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Study and Drug Regimen

Study Design
and
Demographics

Sample Sizeand Study
Duration

End Points

Results
The median estradiol concentrations increased from baseline to day seven,but returned to baseline levels at the follow-up visit. The median increase
from baseline to day seven was greater in the buccal group compared to thepatch group (55.07 vs 34.87 pmol/liter; P<0.001).

21

Wang et al

OL with ES

Testosterone topical®
solution (Axiron ) 60 mg
applied to each axilla oncedaily

Men ≥18 years
with androgen
deficiency(hypogonadism)
and a BMI <35.02kg/m withtestosterone
levels on two
consecutive
samples <10.4nmol/L and abaseline Hgblevel ≥110.5 g/L.

N=155 OLstudy
120 days
N=71
extension
study
60 daysPrimary:
Total
testosterone and
DHT (OL phase)
Secondary:
PDQ domain
assessing sexualdesire,enjoyment andperformance,
sexual activity,and mood, SF36 health survey(ES)

A total of 51.5% of patients in the buccal group reported an adverse event
compared to 47.1% in the patch group. The most commonly reported adverse
events among both groups were application site disorders.
Primary:
At day 120, the proportion of patients completing the study with an average
testosterone concentration (C avg ) in the normal range was 84.1%. Also,
76.1% and 84.8% of patients completed the study with a C avg in the
responder range on days 15/16 and 60/61, respectively.
The mean serum testosterone level before and after dosing was within theadult male range over the 24-hour period on days 15, 60 and 120. The
geometric mean of serum testosterone over 24 hours was 15.62 nmol/L (CV;38%). Among subjects who were responders at day 120, the geometric meanof serum testosterone values for subjects on any dose was 16.86 nmol/L.
Serum DHT levels and serum free testosterone remained relatively stable
over the 24-hours following dosing. The mean 15 day baseline pre-dose
DHT/testosterone ratio was 0.23, and the mean DHT/testosterone ratio
remained between 0.17 to 0.26 throughout the 24-hour period. The ratio
values among patients completing the study and among responders remained
relatively constant from baseline.
Secondary:
Improvements in sexual desire and activity were apparent 15 days after
application of testosterone and were sustained throughout the study.
Statistically significant changes from baseline were seen in sexual desire,sexual activity, positive mood and negative mood as assessed by the PDQ
domain for the seven days prior to visits one, 15, 60 and 120. Significant
mean changes from day one to 120 for SF-36 Physical Component and SF36 Mental Component scores were 1.55 (SD=7.72; P=0.0254) and 4.54
(SD=9.20; P<0.0001), respectively.

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Study and Drug Regimen

22

Study Design
and
Demographics

Sample Sizeand Study
Duration

Dobs et al

MC, NC, OL

N=149

Testosterone gel®
(Fortesta ) 40 mg applied
to the thighs once daily

Men 18 to 75
years, withprimary or
secondary hypogonadism(defined as asingle serum
testosterone
concentration<250 ng/dL or two
consecutive
serum
testosterone
levels <300 ng/dL
at least one week
apart) and a BMI
2≥22 kg/m and2<35 kg/m

90 days

Dose adjustments allowed
for a downward titration toa minimum of 10 mg daily
and an upward titration to70 mg daily.

End Points

Primary:
The average
serum total
testosterone
concentration
over 24 hours(C avg zero to24h) on day 90
Secondary:
The maximum
serum
testosterone
concentration(C max ) on day 90

Results

Treatment-emergent adverse events occurring in >2% of patients receiving atleast one dose of testosterone in the OL study included application site
irritation, application site erythema, headache, increased hematocrit,nasopharyngitis, diarrhea, and vomiting. Three patients withdrew from the OL
phase of the study due to adverse events, including superficial
thrombophlebitis, effects on lability/anger, and malignant melanoma. Twopatients withdrew from the ES of the study due to application site irritation andapplication site erythema.
Primary:
Of the 129 patients with available data for analysis, the mean C avg over 24hours was 438.56±162.51 ng/dL with 77.5% of patients achieving a mean
serum testosterone level within the pre-defined normal physiological range(≥300 and ≤1140 ng/dL) (95% CI, 70.3 to 84.7). By day 35, 76.2% (95% CI,
68.8 to 83.6) of patients had reached the primary endpoint. On day 90, 22.5%
of patients had a total testosterone level <300 ng/dL.
Secondary:
The C max ± SD was 827.6±356.5 ng/dL on day 90. At endpoint, a total of
94.6% of patients achieved a C max ≤1500 ng/dL, 1.6% of patients had levels
between 1880 and 2500 ng/dL, and no patients had levels >2500 ng/dL. This
C max was evident by treatment day 35.
Adverse events were reported in 46.3% of patients; however, on 22.8% wereconsidered related to the study medication. The most commonly reported
adverse events were skin reactions, upper respiratory infections and sinusitis.
Skin reactions were considered ‘possibly’ or ‘probably’ related to study
medication in 16.1% of patients, of which 79.2% were mild in severity.

*Agent not available in the United States.
Study abbreviations: AC=active-controlled, DB=double-blind, ES=extension study, IT=international, MA=meta-analysis, MC=multicenter, NC=non-comparative, OL=open-label, PC=placebocontrolled, PG=parallel-group, PK=pharmacokinetic, RCT=randomized controlled trial
Miscellaneous abbreviations: AUC=area under the curve, BMD=bone mineral density, BMI=body mass index, C=cholesterol, C avg =average concentration, CV=coefficient of variation,
DHT=dihydrotestosterone, E 2 =Estradiol, FM=fat mass, FSH=follicle-stimulating hormone, Hct=hematocrit, HDL=high density lipoprotein, Hgb=hemoglobin, LBM=lean body mass, LDL=low
density lipoprotein, LH=luteinizing hormone, PDQ=psychosexual daily questionnaire, PK=pharmacokinetics, PSA=prostate specific antigen, PTH=parathyroid hormone, SALP=bone-specificalkaline phosphatase, SD=standard deviation, SHBG=sex hormone-binding globulin, SF-36=short form 36 questions, TG=triglycerides, TRT=testosterone replacement therapy

Page 14 of 27
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Special Populations
Table 5. Special Populations
Generic
Name
Testosterone
gel

1-6

Elderly/
ChildrenNo dosage adjustment isrequired in the elderly.
Safety and efficacy inmales <18 years havenot been established.

Testosterone
patch

Children should avoid
contact with unwashedor unclothed applicationsites in men using
testosterone gel.
No dosage adjustment isrequired in the elderly.

Testosterone
solution

Safety and efficacy inmales <18 years havenot been established.
No dosage adjustment isrequired in the elderly.

Population and Precaution
Renal
Hepatic
Pregnancy Excreted in
Dysfunction Dysfunction Category Breast Milk
Not studied in Not studied in
X
Contrarenal
hepatic
indicated
dysfunction.
dysfunction.
.

Not studied inrenaldysfunction.

Not studied inhepatic
dysfunction.

X

Contraindicated

Not studied inrenaldysfunction.

Not studied inhepatic
dysfunction.

X

Contraindicated

Safety and efficacy inmales <18 years havenot been established.
Adverse Drug Events
Table 6 outlines the most frequently reported adverse events for topical testosterone. In general, all
topical testosterone agents share the same safety concerns; however, the transdermal patch is
associated with a higher incidence of application-site reactions compared to other topical formulations.
1-5

Table 6. Adverse Drug Events (%)®
Adverse Event
Androderm
Central Nervous System
Abnormal dreams
Anxiety
Asthenia
Depression
Dizziness
Emotional lability(including anger)
Headache<4
Insomnia
Libido, increased or
decreased
Migraine
Mood swings
Nervousness
Smell disorder-®

AndroGel

Axiron

<3
1
-

®

®

Fortesta

Testim


-

1.3


-

2.6 to 3



-

-

<4
-

5 to 6
-

-

1
1

<3

-

-

-

-


-


-

1
1

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Therapeutic Class Review: topical androgens

Adverse Event
Dermatologic
Acne
Allergic contact blistering
Alopecia
Application site burning
Application site edema
Application site erythema
Application site exfoliation
Application site induration
Application site irritation
Application site reaction
Application site vesicles
Application site warmthContact dermatitis
Folliculitis
Pruritus
Rash
Skin reactions
Endocrine and Urogenital
Benign prostatic
hyperplasia
Blood testosterone,
increased
Blood testosterone,decreased
Breast pain
Breast tenderness
Erectile dysfunction
Gynecomastia
Hot flushes
Penile erections, excess
frequency and duration
Penile erection,
spontaneous
Polyuria
Prostate abnormalities
Prostate disorder

Androderm

Prostate enlarged
Prostate specific antigen,increased
Testes disorder
Urinary symptoms
Gastrointestinal
Abdominal symptoms
Diarrhea
Gastrointestinal bleeding
Gastroesophageal reflux
disease
Vomiting
Hematologic
Bleeding®

®

AndroGel

Axiron

12
3
<7
<3
3
6
17 to 37<3-

1 to 31
3 to 5
2.1
-

-

®

®

Fortesta

Testim
5 to 77 to 8


-






16.1

2 to 4
-

-

-

-

1

-

-



-

-

-

-

-

-



-

<3
<3
-


-


-

1
1

-

-

-



-

-

-

-

-

1

<3
5

-

-

-

-

-

3 to 5

-

-

-

<3

-

-

-

-

-

11.1

1 to 4

1.3

-

-

<3
<2

-

-

-

<3
<3

-

3 to 4
-


-

-

<3

-

-

-

-

-

-

3 to 4

-

-

<3

-

-

-

-

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Therapeutic Class Review: topical androgens

Adverse Event
Hematocrit/ hemoglobin
increased
Polycythemia
Red blood cell count,elevation
Metabolic
Blood glucose, increased
Cholesterol, increased
Other
Back pain
Blood pressure increase
Fatigue
Influenza likeillness/malaise
Laboratory test, abnormal
Lacrimation, increased
Nasopharyngitis
Pain in extremities
Pelvic pain
Taste sense, diminished
Vitreous detachment

Androderm®

®

AndroGel

Axiron

-

2.1

-

®

®

Fortesta

Testim4 to 7



2

-

-



-

-

-



-

-

-

<2


-

-

-

6
<3

<4
-


-



1
-

-

-

-



-

<3
-

3 to 6
-



-




1
1
-

Frequency of adverse event not reported.
- Incidence ≤1% or not reported.

®

Contraindications
Table 7. Contraindications
Contraindication
Men with carcinoma of thebreast or known orsuspected carcinoma of
the prostate
Women who are, or who
may become pregnant, or
who are breastfeeding

1-5

Androderm®

AndroGel®

Axiron®

®

Fortesta

Testim





















®

®

®

®

® 2-5

Black Box Warnings Regarding Testosterone (AndroGel , Axiron , Fortesta and Testim )WARNING
Secondary Exposure to Testosterone
Virilization has been reported in children who were secondarily exposed to topical testosterone
products.
Children should avoid contact with any unwashed or unclothed application sites in men using
testosterone gel/solution.

Healthcare providers should advise patients to strictly adhere to recommended instructions for use.
Warnings/Precautions
1-5

Table 8. Warnings and Precautions®
Warning/Precaution
Androderm
Worsening of benignAndroGel®

Axiron®

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Fortesta

Testim®

Therapeutic Class Review: topical androgens

Warning/Precaution
prostatic hyperplasia;
monitor patients forworsening symptoms
Prostate cancer risk;
evaluate patients prior totreatment and three to six
months following initiationof treatment
Polycythemia; increases inhematocrit, reflective of
increases in red blood cellmass, may dose
modification
Spermatogenesis; may besuppressed by large dosesof exogenous androgens
and may lead to adverse
effects on semen
parameters
Hepatic effects; prolonged
use of high doses of orally
active 17-alpha-alkyl
androgens has been
associated with serious
hepatic adverse effects
Edema; androgens may
promote sodium and water
retention, resulting incomplications in patientswith pre-existing cardiac,renal or hepatic disease
Gynecomastia; potential
development in patientstreated with androgens
Sleep apnea; androgens
may potentiate sleep
apnea in some patients,
especially those withobesity and chronic lungdisease
Lipids; changes in serum
lipids may require dose
adjustment or
discontinuation of therapy
Hypercalcemia; use withcaution in cancer patientsat risk of hypercalcemia
Decreased thyroxinebinding globulin; may
result in decreased total
T4 serum concentrationand increased uptake of
T3 and T4
Magnetic resonanceAndroderm®

AndroGel®

Axiron®

®

Fortesta

Testim















































































-









-









-



-

-

-

-

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Therapeutic Class Review: topical androgens

Warning/Precaution
imaging; skin burns havebeen reported at theapplication site in patientswearing an aluminizedtransdermal system duringa magnetic resonanceimaging scanPotential secondary
exposure; cases ofsecondary exposure
resulting in virilization ofchildren have beenreported in postmarketingsurveillance
Flammability; alcohol
based products areflammable

Androderm®

AndroGel®

Axiron®

®

Fortesta

Testim

-









-









®

Drug Interactions
1-5

Table 9. Drug Interactions
Drug
Interacting Medication
Potential Result
Testosterone
Anticoagulants
The concurrent administration of androgens with oral
anticoagulants may decrease anticoagulant requirements.
Testosterone
Antidiabetic drugs
In diabetic patients, the metabolic effects of androgens may(including insulin)
decrease blood glucose and insulin requirements.
Testosterone
Adrenocorticotropin & Concurrent administration of androgens withcorticosteroids
adrenocorticotropin or corticosteroids may enhance edema
formation.
Testosterone
Oxyphenbutazone
Concurrent administration of oxyphenbutazone andandrogens may result in elevated serum levels of
oxyphenbutazone.
Testosterone
Propranolol
Administration of testosterone cypionate in a PK study led to
an increased clearance of propranolol.
Testosterone
Triamcinolone
Pretreatment of the skin with triamcinolone ointment
patch
ointment
significantly reduced testosterone absorption from the patch
drug delivery system.
PK=pharmacokinetic
1-6

Dosage and Administration
Testosterone products are controlled substances under the Anabolic Steroid Control Act and have all
been assigned as Schedule III products.
1-5

Table 10. Dosing and Administration
Generic Name
Adult Dose
Testosterone gel
Hypogonadism in males, primary(CIII)(congenital or acquired),hypogonadotropic hypogonadism
in males (congenital or acquired):®
AndroGel 1% gel: initial, 50 mg(four pump actuations, two 25 mg
packets or one 50 mg packet)
applied once daily in the morning
to the shoulders, upper arms or

Pediatric Dose
Safety andefficacy in males<18 years havenot beenestablished.

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Availability®
AndroGel 1%:
Metered-dose pump (60actuations per container;
12.5 mg testosterone
per actuation in 1.25 g
gel)
Packet (30 packets per
carton; 25 mg

Therapeutic Class Review: topical androgens

Generic Name

Adult Doseabdomen area; maintenance, 50
mg to 100 mg applied once daily inthe morning to the shoulders,
upper arms or abdomen area

Pediatric Dose®

AndroGel 1.62%:
Metered-dose pump (60actuations per container;
20.25 mg testosterone
per actuation in 1.25 ggel)®

AndroGel 1.62% gel: initial, 40.5
mg (two pump actuations or one
40.5 mg packet) applied once daily
in the morning to shoulders andupper arms; maintenance, 20.25
mg to 81 mg applied once daily inthe morning to shoulders andupper arms; maximum, 81 mg
applied once daily in the morning
to shoulders and upper arms

Packet (30 packets per
carton; 20.25 mg
testosterone in 1.25 g
gel or 40.5 mg
testosterone in 2.5 g gel)®

Fortesta gel: initial, 40 mg (fourpump actuations) applied once
daily in the morning to thighs;
maintenance, 10 mg to 70 mg
applied once daily in the morning
to thighs; maximum, 70 mg applied
once daily in the morning to thighs®

Fortesta :Metered-dose pump (60actuations per container;
10 mg testosterone per
actuation in 0.5 g gel)®

Testim 1%:
Unit-dose tubes (30tubes per carton; 50 mg
testosterone in 5 g gel)®

Testosterone
solution (CIII)

Testosterone
transdermal
system(CIII)

Testim 1% gel: initial, 50 mg (onetube) applied once daily in themorning to shoulders and/or upper
arms; maintenance, 5 mg to 10 mg
applied once daily in the morning
to shoulders and/or upper arms;
maximum, 10 mg applied once
daily in the morning applied toshoulders and/or upper arms
Hypogonadism in males, primary(congenital or acquired),hypogonadotropic hypogonadism
in males (congenital or acquired):
Topical solution: initial, 60 mg (twopump actuations) applied once
daily to axilla; maintenance, 60 mg
to 120 mg applied once daily toaxilla; maximum, 120 mg applied
once daily to axilla
Hypogonadism in males, primary(congenital or acquired),hypogonadotropic hypogonadism
in males (congenital or acquired):Transdermal system: initial, 4mg/day applied once nightly toback, abdomen, upper arms, orthighs; maintenance, 2 to 6 mg/day
applied once nightly to back,abdomen, upper arms, or thighs

Availability
testosterone in 2.5 g gelor 50 mg testosterone in
5 g gel)®

Safety andefficacy in males<18 years havenot beenestablished.

Axiron :Metered-dose pump (60actuations per container;
30 mg testosterone per
actuation in 1.5 mL ofsolution)

Safety andefficacy in males<18 years havenot beenestablished.

Androderm :2 mg/day patch
4 mg/day patch

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Therapeutic Class Review: topical androgens

Clinical Guidelines
Table 11. Clinical Guidelines Using the Androgens
Clinical Guideline
Recommendations
European Association• The diagnosis of testosterone deficiency should be restricted to men withof Urology:
persistent symptoms suggesting hypogonadism.
Guidelines on Male
• Total testosterone assessment should be repeated at least on two
Hypogonadism
occasions in men with:
7(2012)o Total testosterone levels close to the lower normal range (8 to 12
nmol/L).
o Suspected or known abnormal sex hormone-binding globulinlevels. Free testosterone should also be included.
• Testosterone assessment is recommended in men with a disease ortreatment in which testosterone deficiency is common and in whom
treatment may be indicated, including men with:o Pituitary mass, following radiation involving the sellar region andother diseases in the hypothalamic and sellar region;o End-stage renal disease receiving hemodialysis;
o Medications that may suppress testosterone levels;o Moderate to severe chronic obstructive lung disease;o Infertility;
o Osteoporosis or low-trauma fractures;o Human immunodeficiency virus infection (HIV) with sarcopenia;
o Type 2 diabetes.
• Luteinizing hormone serum levels should be analyzed to differentiate
between primary, secondary and late-onset hypogonadism.
• Testosterone replacement therapy (TRT) is recommended in patients with:o A decline in muscle mass and strength.
o Reduced bone mineral density at the lumbar spine.
o Decreased libido and erection.
• The selection of the preparation should be a joint decision by an informed
patient and the physician.
• Short-acting preparations may be preferred over long-acting depot
administration for initial treatment.
• Human chorionic gonadotropin (hCG) treatment is only recommended for
hypogonadal patients with simultaneous fertility treatment.
• Perform hematological, cardiovascular, breast and prostatic assessment
prior to initiating treatment. Continue hematocrit and hemoglobin
monitoring, prostate-specific antigen (PSA) and digital rectal examinationof prostate and breast during TRT therapy.
• In patients who have undergone surgery for localized prostate cancer,
testosterone therapy should not be considered for at least one year postsurgery and without PSA recurrence.
• Assess response to TRT at three, six and 12 months and then annually.
• In men with an abnormal bone mineral density (BMD), BMD
measurements should be repeated six and 12 months after the start of
TRT and thereafter annually.
• Routine screening of cardiovascular effects is not indicated.
• Men with cardiovascular co-morbidity should be assessed by a cardiologist
before TRT is initiated and closely monitored during TRT.
The American• TRT should maintain testosterone levels within the physiologic range (280
Association of Clinicalto 800 ng/dL).
Endocrinologists:• TRT can be used in men with hypogonadism who are not interested in
Medical Guidelines
fertility or who are not able to achieve fertility.
for Clinical Practice

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Therapeutic Class Review: topical androgens

Clinical Guideline
for the Evaluation
and Treatment of
Hypogonadism in
Adult Male Patients
9(2002)

International Societyof Andrology,
International Society
for the Study of theAging Male, European
Association of
Urology, European
Academy ofAndrology, American
Society of Andrology:
International Societyof Andrology,
International Society
for the Study of theAging Male, European
Association of
Urology, European
Academy ofAndrology, American
Society of Andrology:
Recommendations:
Investigation,
Treatment andMonitoring of LateOnset
Hypogonadism in
11
Males (2009)2

Recommendations• Treatment of men with hypogonadism with TRT results in increased sexualinterest and increased number of spontaneous erections.
• Secondary sex characteristics (i.e., increased muscle mass, beard growth,
growth of pubic and axillary hair, and phallus growth) improve with TRT.
• In adolescent male patients with hypogonadotropic hypogonadism, TRT
increases BMD in comparison with that in male patients with hypogonadism
not receiving TRT. In prepubertal-onset hypogonadotropic hypogonadism,
diminished bone mass may be only marginally improved by TRT.
• No specific recommendations can be made on the possible normalization of
growth hormone levels in elderly men with TRT. Further research is needed
to clarify the potential risks and benefits associated with therapy.
• Whether TRT in men with hypogonadism increases, decreases, or has aneutral effect on cardiovascular risk remains uncertain.
• Orally administered testosterone is quickly metabolized by the liver andcannot achieve sufficient blood levels over time to be useful. The orally
administered alkylated androgen preparations currently available in the
Unites States are generally not recommended because of poor androgeneffects, adverse lipid changes and hepatic side effects, such as
hemorrhagic liver cysts, cholestasis, and hepatocellular adenoma.
• Late-onset hypogonadism is a clinical and biochemical syndrome associatedwith advancing age and characterized by symptoms and a deficiency inserum testosterone levels (below the young healthy adult male reference
range). This condition may result in significant detriment in the quality of life
and adversely affect the function of multiple organ systems.
• Response to TRT should be assessed. If there is no improvement of signs
symptoms within a reasonable time interval (three to six months is adequate
for libido and sexual function, muscle function, and improved body fat; alonger interval is required to see improvement in BMD), TRT should be
withdrawn.
• TRT improves body composition (i.e., decrease of fat mass, increase oflean body mass) in men with hypogonadal values of testosterone.
Secondary benefits of these changes of body composition on strength,
muscle function, metabolic, and cardiovascular dysfunction are suggested
by available data but require confirmation by large-scale studies.
• Osteopenia, osteoporosis and fracture prevalence rates are greater in
hypogonadal younger and older men. BMD in hypogonadal men of all ages
increases under TRT. Fracture data are not yet available and thus the longterm benefit of TRT requires further investigation.
• Men with erectile dysfunction (ED) and/or diminished libido anddocumented testosterone deficiency are candidates for TRT. In thepresence of a clinical picture of testosterone deficiency and borderline
serum testosterone levels, a short (i.e., three months) therapeutic trial may
be justified. An absence of response calls for discontinuation of TRT. Thereis evidence suggesting therapeutic synergism with combined use of TRT
and phosphodiesterase-5 (PDE5) inhibitors in hypogonadal or borderline
eugonadal men; however, these observations require additional study. The
combination treatment should be considered in hypogonadal patients with
ED failing to respond to either treatment alone. It is unclear whether men
with hypogonadism and ED should be treated initially with testosterone,
PDE5 inhibitors, or the combination.
• Currently available intramuscular (IM), subdermal, transdermal, oral, andbuccal preparations of testosterone are safe and effective. The treating
physician should have sufficient knowledge and adequate understanding of
the pharmacokinetics as well as of the advantages and drawbacks of each

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Therapeutic Class Review: topical androgens

Clinical Guideline
•

•

•
•

•

•
•

American College ofPhysicians: Hormonal
Testing andPharmacologic
Treatment of Erectile
13
Dysfunction (2009)

•
•
•
•
•
•

•
•

Recommendations
preparation. The selection of the preparation should be a joint decision of
an informed patient and physician.
Short-acting preparations may be preferred over long-acting depot
preparations in the initial treatment of patients with late-onset
hypogonadism because of the possible development of an adverse eventthat may require rapid discontinuation of TRT.
Inadequate data are available to determine the optimal serum testosterone
level for efficacy and safety. For the present time, mid-to-lower young adultmale serum testosterone levels seem appropriate as the therapeutic goal.
Sustained supraphysiological levels should be avoided. No evidence exists
for or against the need to maintain the physiological circadian rhythm ofserum testosterone levels.
The 17-α-alkylated androgen preparations such as methyltestosterone are
obsolete because of their potential liver toxicity and should no longer beprescribed.
Due to insufficient data regarding the therapeutic and adverse effects of hCG
treatment in older men and its higher cost, the treatment cannot berecommended in late-onset hypogonadism except when fertility is an issue.
Antiestrogens and aromatase inhibitors have been shown to increase
endogenous testosterone levels. Adequate evidence does not exist to
recommend their use.
TRT is contraindicated in men with prostate or breast cancer. TRT isrelatively contraindicated in men at high risk of developing prostate cancer.
It is unclear whether localized low-grade prostate cancer represents a
relative or absolute contraindication for treatment.
Men with significant erythrocytosis, untreated obstructive sleep apnea, anduntreated severe congestive heart failure should not be started on TRT
without prior resolution of the comorbid condition.
Age is not a contraindication to initiate TRT. Individual assessment ofcomorbidities (as possible causes of symptoms) and potential risks vsbenefits of TRT is particularly important in elderly men.
Treatment with a PDE5 inhibitor should be initiated in men who seek
treatment for erectile dysfunction and who do not have a contraindication totherapy.
The clinical benefit associated with the use of PDE5 inhibitors wasdemonstrated regardless of the cause (such as diabetes, depression, or
prostate cancer) or baseline severity of erectile dysfunction.
Improvement in erectile functioning was related to higher doses for sildenafil
and vardenafil but not for tadalafil; however, higher doses were associatedwith a greater risk for adverse events.
There is insufficient evidence to compare the efficacy and adverse events ofthe different PDE5 inhibitor agents.
The choice of which PDE5 inhibitor to administer should be made based on
the individual preferences of men with erectile dysfunction, including theease of use, cost, and tolerability.
Due to inconclusive evidence, there are no recommendations against or forroutine use of hormonal blood tests or hormonal treatment(i.e., testosterone oral, injection, gel, patch, and cream) in the managementof erectile dysfunction.
Clinicians should individualize decisions to measure hormone levels on thebasis of clinical presentation and physical findings that suggest hormonal
abnormality.
There is insufficient evidence to determine whether PDE5 inhibitors are

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Clinical Guideline

The Endocrine
Society:
Clinical Practice
Guidelines:
Testosterone
Therapy in Adult Men
With Androgen
Deficiency
10
Syndromes (2010)

•

•
•

•
•

•
•

•
•
•
•

Recommendations
associated with an increased risk for non-arteritic anterior ischemic optic
neuropathy.
TRT is recommended for symptomatic men with classical androgen
deficiency syndromes to induce and maintain secondary sex characteristics
and to improve their sexual function, sense of well-being, muscle mass andstrength, and bone mineral density.
TRT is not recommended for use in patients with breast or prostate cancer.
TRT is not recommended without further urological evaluation in patientswith palpable prostate nodule or induration or a PSA 4 ng/mL or PSA 3
ng/mL in men at high risk of prostate cancer (i.e., African Americans or men
with first degree relatives with prostate cancer).
TRT is not recommended in patients with a hematocrit >50%, untreatedsevere sleep apnea, severe lower urinary tract symptoms, uncontrolled or
poorly controlled heart failure or in those desiring fertility).
Initiating TRT is recommended with any of the following regimens after
evaluating patient preference, consideration of pharmacokinetics, treatment
burden, cost:o Testosterone enanthate or cypionate: 75 mg to 100 mg IM weekly; or 150
mg to 200 mg IM every two weeks.
o Testosterone patches: one or two 5-mg non-genital patches appliednightly over the skin of the back, thigh, or upper arm, away frompressure areas.
o Testosterone 1% gel: 5 g to 10 g applied daily over a covered area of
non-genital skin (patients should wash hands after application).
o Testosterone buccal: apply one 30 mg tablet to buccal mucosa every 12hours.
o Testosterone pellets implanted subcutaneously at intervals of three to six
months; the dose and regimen vary with the formulation used.
o Oral testosterone undecanoate, injectable testosterone undecanoate,
testosterone-in-adhesive matrix patch, and testosterone pellets whereavailable. (Note: testosterone undecanoate is not available in the UnitedStates.)Monitoring is advised three to six months after treatment initiation and thenannually to assess symptom response, the presence of any adverse effects,
and to check compliance.
Recommendations aim at achieving serum testosterone levels during
treatment in the mid-normal range. In men receiving testosterone enanthateor cypionate, aiming for testosterone levels between 400 and 700 ng/dL one
week after the injection is recommended.
Hematocrit monitoring is advised at baseline, at three to six months, thenannually; if exceeds 54% therapy should be discontinued until reduced to asafe level.
BMD testing of the lumbar spine, femoral neck, and hip after one to two
years of testosterone therapy is advised in hypogonadal men withosteoporosis or low trauma fracture.
Digital rectal exam is advised in men ≥40 years with a baseline PSA >0.6
ng/mL, prior to initiating therapy, at three to six months, and then based
upon evidence-based guideline recommendations.
Urological consultation is advised if there is an increase in serum or plasma
PSA >1.4 ng/mL within any 12-month period of testosterone treatment; a
PSA velocity of more than 0.4 ng/mL·yr using the PSA level after six
months of testosterone administration as the reference (PSA velocity should
be used only if there are longitudinal PSA data for more than two years);
detection of a prostatic abnormality on digital rectal examination; or a

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Therapeutic Class Review: topical androgens

Clinical Guideline
•

•
•
•
•

Recommendations
American Urological Association/International Prostate Symptom Score>19.
TRT should be offered to men with low testosterone levels and low libido toimprove libido and to men with erectile dysfunction (ED) who have low
testosterone levels after evaluation of underlying causes of ED andconsideration of established therapies for ED.
TRT should not be offered to all older men with a low testosterone level.
Clinicians should consider offering TRT on an individualized basis to older
men with low testosterone levels on more than one occasion and clinicallysignificant symptoms of androgen deficiency.
Short-term TRT may be considered as adjunctive therapy in HIV-infected
men with low testosterone levels and weight loss to promote weight
maintenance and gains in lean body mass and muscle strength.
Short-term TRT may be offered to men receiving high dose glucocorticoids
who have low testosterone levels to promote preservation of lean bodymass and bone mineral density.

Conclusions®
®
®
®
The topical testosterone products included in this review are Androderm , AndroGel , Axiron , Fortesta®
and Testim . The agents primarily differ in their formulations and site of administration. These products areavailable as gels, solutions and transdermal patches. None of these agents are currently available
generically. All of the products are indicated for testosterone replacement therapy in males with primary
1-6
hypogonadism (congenital or acquired) or hypogonadotropic hypogonadism (congenital or acquired).
®
®
Available head-to-head studies suggest that Testim and AndroGel may produce higher serum® 14-17
One study suggests that
testosterone concentrations, and reduce body fat more than Androderm .
®
patients with a suboptimal response to AndroGel may experience symptomatic improvements in libido,® 19
erectile function and energy levels following a switch to Testim . No studies are available that evaluate®
®
Axiron or Fortesta compared to other androgens or topical testosterone products.
According to current consensus guidelines, intramuscular and topical testosterone preparations are
generally recommended for the management of hypogonadism in adult male patients while the oral
androgen therapies are not recommended due to poor androgen effects, adverse lipid changes, and hepatic
7-11
The selection of a specific testosterone replacement therapy should be a joint decision
adverse events.
between an informed patient and physician after considering patient preferences, the pharmacokinetic
profiles of the respective agents, treatment burden, and cost. Furthermore, currently available guidelines do
not give preference to one topical preparation vs another.

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Therapeutic Class Review: topical androgens

References®
1. Androderm [package insert]. Corona (CA): Watson Pharma, Inc.; 2013 Apr.
®
2. AndroGel [package insert]. North Chicago (IL): Abbott Laboratories; 2012 Sept.
®
3. Testim [package insert]. Malvern (PA): Auxilium Pharmaceuticals, Inc.; 2011 Nov.
®
4. Axiron [package insert]. Indianapolis (IN): Eli Lilly & Company; 2011 Dec.
®
5. Fortesta [package insert]. Malvern (PA): Auxilium Pharmaceuticals, Inc.; 2012 Dec.
®
6. Micromedex Healthcare Series [database on the Internet]. Greenwood Village (CO): Thomson
Micromedex; 2013 [cited 2013 May 30]. Available from: http://www.thomsonhc.com/.
7. European Association of Urology. Guidelines on Male Hypogonadism [guideline on the internet]. The
Netherlands: European Association of Urology; 2012 [cited 2013 May 30]. Available from:http://www.uroweb.org/guidelines/online-guidelines/.
8. Snyder PJ. Testosterone treatment of male hypogonadism. In: Basow DS (Ed). UpToDate [database on
the Internet]. Waltham (MA): UpToDate; 2013 [cited 2013 May 30]. Available from:http://www.utdol.com/online/index.do.
9. Petak SM, Nankin HR, Spark RF, Swerdloff RS, Rodriguez-Rigau, LJ; American Association of Clinical
Endocrinologists. Medical Guidelines for Clinical Practice for the Evaluation and Treatment of
Hypogonadism in Adult Male Patients. Endocrine Practice. 2002 Dec;8(6):439-56. Available from:https://www.aace.com/sites/default/files/hypogonadism.pdf
10. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS et al. The Endocrine
Society. Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes: An Endocrine
Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2010;95(6):2536-59. Available from:http://www.endo-society.org/guidelines/final/upload/FINAL-Androgens-in-Men-Standalone.pdf
11. Wang C, Nieschlag E, Swerdloff RS, et al. ISA, ISSAM, EAU, EAA and ASA recommendations:investigation, treatment and monitoring of late-onset hypogonadism in males. The Aging Male.
2009;12(1):5-12.
12. Snyder PJ. Clinical features and diagnosis of male hypogonadism. In: Basow DS (Ed). UpToDate[database on the Internet]. Waltham (MA): UpToDate; 2013 [cited 2013 May 30]. Available from:http://www.utdol.com/online/index.do.
13. Qaseem A, Snow V, Denberg TD, Casey DE Jr., Forclea MA, Owens DK et al. Hormonal Testing andPharmacologic Treatment of Erectile Dysfunction: A Clinical Practice Guideline From the American
College of Physicians. Ann Intern Med. 2009;15(9):1-12.
14. 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 sexualfunction. BJU International. 2003;91:69-74.
15. Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand et al. 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.
16. Swerdloff RS, Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM et al. Long-term
Pharmacokinetics of Transdermal Testosterone Gel in Hypogonadal Men. J Clin Endocrinol Metab.
2000;85:4500-10.
17. Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G et al. Transdermal
Testosterone Gel Improves Sexual Function, Mood, Muscle Strength, and Body Composition
Parameters in Hypogonadal Men. J Clin Endocrinol Metab. 2000;85:2839-53.
18. Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ et al. Long-term
Testosterone Gel (AndroGel) Treatment Maintains Beneficial Effects on Sexual Function and Mood,
Lean and Fat Mass, and Bone Mineral Density in Hypogonadal Men. J Clin Endocrinol Metab.
2004;89:2085-98.
19. Grober ED, Khera M, Soni SD, Espinoza MG, Lipshultz LI. Efficacy of changing testosterone gel
preparations (AndroGel or Testim) among suboptimally responsive hypogonadal men. Int J Impot Res.
2008 Mar-Apr;20(2):213-7.
20. Korbonits M, Slawik M, Cullen D, Ross RJ, Stalla G, Schneider H, et al. A comparison of a novel
testosterone bioadhesive buccal system, Striant, with a testosterone adhesive patch in hypogonadal
males. J of Clin Endo & Metab. 2004;89(5):2039-43.

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Therapeutic Class Review: topical androgens

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Copyright 2013 • Review Completed on 05/31/2013