Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trials in Hypogonadal Men
Table 2 shows the incidence of all adverse events judged by the investigator to be at least possibly related to treatment with AndroGel and reported by >1% of patients in a 180 Day, Phase 3 study.
Table 2: Adverse Events Possibly, Probably or Definitely Related to Use of AndroGel in the 180-Day Controlled Clinical Trial
* Lab test abnormal occurred in nine patients with one or more of the following events reported: elevated hemoglobin or hematocrit, hyperlipidemia, elevated triglycerides, hypokalemia, decreased HDL, elevated glucose, elevated creatinine, elevated total bilirubin.
** Prostate disorders included five patients with enlarged prostate, one with BPH, and one with elevated PSA results.
*** Testis disorders were reported in two patients: one with left varicocele and one with slight sensitivity of left testis.
|Adverse Event ||Dose of AndroGel |
|5 g ||7.5 g ||10 g |
| ||N = 77 ||N = 40 ||N = 78 |
|Acne ||1% ||3% ||8% |
|Alopecia ||1% ||0% ||1% |
|Application Site Reaction ||5% ||3% ||4% |
|Asthenia ||0% ||3% ||1% |
|Depression ||1% ||0% ||1% |
|Emotional Lability ||0% ||3% ||3% |
|Gynecomastia ||1% ||0% ||3% |
|Headache ||4% ||3% ||0% |
|Hypertension ||3% ||0% ||3% |
|Lab Test Abnormal* ||6% ||5% ||3% |
|Libido Decreased ||0% ||3% ||1% |
|Nervousness ||0% ||3% ||1% |
|Pain Breast ||1% ||3% ||1% |
|Prostate Disorder** ||3% ||3% ||5% |
|Testis Disorder*** ||3% ||0% ||0% |
Other less common adverse reactions, reported in fewer than 1% of patients included: amnesia, anxiety, discolored hair, dizziness, dry skin, hirsutism, hostility, impaired urination, paresthesia, penis disorder, peripheral edema, sweating, and vasodilation.
In this 180 day clinical trial, skin reactions at the site of application were reported with AndroGel, but none was severe enough to require treatment or discontinuation of drug.
Six patients (4%) in this trial had adverse events that led to discontinuation of AndroGel. These events included: cerebral hemorrhage, convulsion (neither of which were considered related to AndroGel administration), depression, sadness, memory loss, elevated prostate specific antigen, and hypertension No AndroGel patient discontinued due to skin reactions.
In a separate uncontrolled pharmacokinetic study of 10 patients, two had adverse events associated with AndroGel; these were asthenia and depression in one patient and increased libido and hyperkinesia in the other.
In a 3 year, flexible dose, extension study, the incidence of all adverse events judged by the investigator to be at least possibly related to treatment with AndroGel and reported by > 1% of patients is shown in Table 3.
Table 3: Adverse Events Possibly, Probably or Definitely Related to Use of AndroGel in the 3 Year, Flexible Dose, Extension Study
+ Lab test abnormal occurred in 15 patients with one or more of the following events reported: elevated AST, elevated ALT, elevated testosterone, elevated hemoglobin or hematocrit, elevated cholesterol, elevated cholesterol/LDL ratio, elevated triglycerides, elevated HDL, elevated serum creatinine.
* Urinary symptoms included nocturia, urinary hesitancy, urinary incontinence, urinary retention, urinary urgency and weak urinary stream.
** Testis disorders included three patients. There were two with a non-palpable testis and one with slight right testicular tenderness.
|Adverse Event ||Percent of Subjects |
| ||(N = 162) |
|Lab Test Abnormal+ || 9.3 |
|Skin dry || 1.9 |
|Application Site Reaction || 5.6 |
|Acne || 3.1 |
|Pruritus || 1.9 |
|Enlarged Prostate || 11.7 |
|Carcinoma of Prostate || 1.2 |
|Urinary Symptoms* || 3.7 |
|Testis Disorder** || 1.9 |
|Gynecomastia || 2.5 |
|Anemia || 2.5 |
Two patients reported serious adverse events considered possibly related to treatment: deep vein thrombosis (DVT) and prostate disorder requiring a transurethral resection of the prostate (TURP).
Discontinuation for adverse events in this study included: two patients with application site reactions, one with kidney failure, and five with prostate disorders (including increase in serum PSA in 4 patients, and increase in PSA with prostate enlargement in a fifth patient).
Increases in Serum PSA Observed in Clinical Trials of Hypogonadal Men
During the initial 6-month study, the mean change in PSA values had a statistically significant increase of 0.26 ng/mL. Serum PSA was measured every 6 months thereafter in the 162 hypogonadal men on AndroGel in the 3-year extension study. There was no additional statistically significant increase observed in mean PSA from 6 months through 36 months. However, there were increases in serum PSA observed in approximately 18% of individual patients. The overall mean change from baseline in serum PSA values for the entire group from month 6 to 36 was 0.11 ng/mL.
Twenty-nine patients (18%) met the per-protocol criterion for increase in serum PSA, defined as >2X the baseline or any single serum PSA >6 ng/mL. Most of these (25/29) met this criterion by at least doubling of their PSA from baseline. In most cases where PSA at least doubled (22/25), the maximum serum PSA value was still <2 ng/mL. The first occurrence of a pre-specified, post-baseline increase in serum PSA was seen at or prior to Month 12 in most of the patients who met this criterion (23 of 29; 79%).
Four patients met this criterion by having a serum PSA >6 ng/mL and in these, maximum serum PSA values were 6.2 ng/mL, 6.6 ng/mL, 6.7 ng/mL, and 10.7 ng/mL. In two of these patients, prostate cancer was detected on biopsy. The first patient's PSA levels were 4.7 ng/mL and 6.2 ng/mL at baseline and at Month 6/Final, respectively. The second patient's PSA levels were 4.2 ng/mL, 5.2 ng/mL, 5.8 ng/mL, and 6.6 ng/mL at baseline, Month 6, Month 12, and Final, respectively.
The following adverse reactions have been identified during post approval use of AndroGel. Because the reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Table 4 includes adverse reactions that have been identified postmarketing.
Table 4: Adverse Drug Reactions from Postmarketing Experience of AndroGel by MedDRA System Organ Class
|Blood and the lymphatic system disorders: ||Elevated Hgb, Hct (polycythemia) |
|Endocrine disorders: ||Hirsutism |
|Gastrointestinal disorders: ||Nausea |
|General disorders and administration site reactions: ||Asthenia, edema, malaise |
|Genitourinary disorders: ||Impaired urination |
|Hepatobiliary disorders: ||Abnormal liver function tests (e.g. transaminases, elevated GCTP, bilirubin) |
|Investigations: ||Elevated PSA, electrolyte changes (nitrogen, calcium, potassium, phosphorus, sodium), changes in serum lipids (hyperlipidemia, elevated triglycerides, decreased HDL), impaired glucose tolerance, fluctuating testosterone levels, weight increase |
|Neoplasms benign, malignant and unspecified (cysts and polyps): ||Prostate cancer |
|Nervous system: ||Headache, dizziness, sleep apnea, insomnia |
|Psychiatric disorders: ||Depression, emotional lability, decreased libido, nervousness, hostility, amnesia, anxiety |
|Reproductive system and breast disorders: ||Gynecomastia, mastodynia, prostatic enlargement, testicular atrophy, oligospermia, priapism (frequent or prolonged erections) |
|Respiratory disorders: ||Dyspnea |
|Skin and subcutaneous tissue disorders: ||Acne, alopecia, application site reaction (pruritus, dry skin, erythema, rash, discolored hair, paresthesia), sweating |
|Vascular disorders: ||Hypertension, vasodilation (hot flushes) |