AndroGel Side Effects: Severity Distribution by Patient Phenotype

What the data report instead of severity grades

TRAVERSE randomized 5,246 men aged 45 to 80 with hypogonadism and existing or high cardiovascular risk to daily 1.62% testosterone gel or placebo gel [1]. The composite of cardiovascular death, nonfatal heart attack or nonfatal stroke occurred in 7.0% (182) on testosterone and 7.3% (190) on placebo, hazard ratio 0.96 (95% CI 0.78 to 1.17), meeting noninferiority [1].

A separate testosterone gel 1% label lists reactions by daily dose rather than by severity or patient type [2]. The most common reactions, at 5% or more, are acne, application-site reaction, abnormal lab tests and prostatic disorders [2].

Which patient groups carry which risks

• Men with high blood pressure. In the 24-hour blood pressure study on a testosterone gel 1% label, pressure rose 1.9/1.3 mm Hg overall at week 16 and 3.0/2.2 mm Hg in men with hypertension on antihypertensive therapy; the label does not recommend the gel in uncontrolled hypertension [2].
• Men with BPH or prostate concerns. The label says men with BPH treated with androgens are at increased risk of worsening signs and symptoms, that androgen-treated men may be at increased risk of prostate cancer, and that the gel is contraindicated in men with known or suspected prostate cancer or breast cancer [2].
• Men with heart, kidney or liver disease. Edema, with or without congestive heart failure, may complicate treatment in men with pre-existing cardiac, renal or hepatic disease [2].
• Men with sleep apnea risk factors. The label says sleep apnea may occur in men with risk factors [2].
• Older men. The label says there are insufficient long-term safety data in geriatric patients to assess the risks of cardiovascular disease and prostate cancer [2].
• Men planning fertility. The label warns that exogenous androgens may lead to azoospermia, and the Endocrine Society guideline recommends against starting testosterone in men planning fertility in the near term [2][7].
• Men with other conditions. The guideline also recommends against starting testosterone in men with breast or prostate cancer, elevated hematocrit, untreated severe sleep apnea, uncontrolled heart failure, or a heart attack or stroke within 6 months [7].

Hematocrit by route

A network meta-analysis of 29 randomized trials in 3,393 men found mean hematocrit rose 3.0% with gel and 4.0% with intramuscular enanthate/cypionate versus placebo; the gel-versus-injection difference was not statistically significant [3]. One retrospective review of 178 men found erythrocytosis above 50% in 66.7% on injections and 12.8% on gels [4]. The injection group was younger (42.5 versus about 54 years) with higher baseline hematocrit, and the study was not randomized [4]. Reviews describe short-acting injectables as having the highest erythrocytosis incidence, but this comparison cannot separate route from differences between the men [4][5].

What does the boxed warning cover?

On one testosterone gel 1% label, the boxed warning covers secondary exposure, not heart attack [2]. Testosterone gel can transfer through contact with an unwashed or unclothed application site and has caused virilization in children [2]. Signs have included genital enlargement, pubic hair, aggressive behavior and advanced bone age [2]. The label also contraindicates the gel in women who are pregnant [2].