AndroGel Overdose and Accidental Excess Dose: Recognition, Risks, and Clinical Management

What the label says about overdosage

The overdosage section of the testosterone gel 1% label describes one report of acute overdose with an approved injectable testosterone product: serum testosterone concentrations of up to 11,400 ng/dL, with a cerebrovascular accident [1]. The label says treatment of overdosage would consist of discontinuation of the gel, washing the application site with soap and water, and appropriate symptomatic and supportive care [1].

Two details frame how much testosterone a gel application delivers. In a multicenter study of 227 hypogonadal men using a 1% hydroalcoholic gel, about 9 to 14% of the testosterone applied was bioavailable, and serum testosterone rose into the normal adult male range on the first day of use; the authors cite an earlier study in which steady state was reached 48 to 72 hours after the first application [3]. The label says serum concentrations are at steady state by the second or third day of dosing [1]. For the 1% gel, the label allows 50 mg, 75 mg or 100 mg of testosterone once daily, starting at 50 mg and adjusted on the basis of total serum testosterone [1]. The 1.62% gel is dosed differently and has its own prescribing information; the label for the 1% product says so directly [1].

The exposure that matters most: transfer to a child or a woman

The boxed warning for testosterone gel is not about the patient's own dose at all. Cases of secondary exposure causing virilization in children have been reported in postmarketing surveillance, with signs including enlargement of the penis or clitoris, pubic hair, increased erections and libido, aggressive behavior and advanced bone age [1]. In most cases these signs regressed once the exposure was removed; in a few, enlarged genitalia did not fully return to age-appropriate normal size and bone age remained modestly greater than chronological age [1]. The risk of transfer was increased in some cases by not adhering to the precautions for use [1].

The label states that children and women should avoid contact with unwashed or unclothed application sites [1]. Testosterone gel is contraindicated in women who are pregnant, and the label says a pregnant woman exposed to the gel should be told of the potential hazard to the fetus, because androgens can cause virilization of a female fetus [1].

It also says that inappropriate changes in genital size, new pubic hair or libido in a child, or a significant increase in body hair or acne in an adult woman should be brought to a physician's attention along with the possibility of secondary exposure, and that testosterone gel should be promptly discontinued until the cause of virilization has been identified [1].

What sustained excess looks like in the label

Testosterone has been subject to abuse, typically at doses above those recommended and in combination with other anabolic androgenic steroids [1]. The label lists the serious reactions reported with anabolic steroid abuse: cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, stroke, hepatotoxicity, and psychiatric effects including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility and aggression [1]. It also lists transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility and infertility in men; hirsutism, virilization, voice deepening, clitoral enlargement, breast atrophy, male-pattern baldness and menstrual irregularities in women; and premature closure of the bony epiphyses and precocious puberty in adolescents [1]. These are voluntary reports, so the label says frequency cannot be reliably estimated [1].

Hematocrit, blood pressure and clots

Increases in hematocrit, reflecting increases in red blood cell mass, may require lowering or discontinuation of testosterone, and the label notes that an increase in red blood cell mass may raise the risk of thromboembolic events [1]. Hematocrit even rises at labeled doses: a network meta-analysis of 29 placebo-controlled trials in 3,393 men found a mean increase of 3.0% with gel (95% CI 1.8 to 4.3), compared with 4.0% for intramuscular enanthate or cypionate [2].

Blood pressure behaves the same way. In a 4-month study, 169 men with usable 24-hour ambulatory recordings on gel 1% had mean systolic and diastolic rises of 1.9 and 1.3 mm Hg at week 16; in men with hypertension already on antihypertensive therapy the rises were 3.0 and 2.2 mm Hg [1]. The gel is not recommended for men with uncontrolled hypertension [1]. Deep vein thrombosis and pulmonary embolism have been reported with testosterone products, and the label reports VTE in 1.7% of testosterone recipients versus 1.2% on placebo in TRAVERSE [1].

What the label tells a clinician to check

The label calls for periodic monitoring of serum testosterone, PSA, hemoglobin, hematocrit, liver function tests and lipid concentrations [1]. Hematocrit is checked before starting, re-evaluated 3 to 6 months after starting, and then annually; if it becomes elevated, the label says to stop therapy until it decreases to an acceptable concentration [1]. Blood pressure is measured periodically, especially in men with hypertension [1]. With oral anticoagulants, the label advises more frequent INR and prothrombin time monitoring, particularly when androgen therapy is started or stopped [1].

For clots, the label directs that lower-extremity pain, edema, warmth and erythema be evaluated as possible DVT and that acute shortness of breath be evaluated as possible PE; if a venous thromboembolic event is suspected, testosterone gel is discontinued and workup begun [1].