AndroGel Side Effects: Withdrawal and Discontinuation Syndrome

Which label these rules come from

The prescribing information described here covers a generic testosterone gel 1% (Actavis), and it states that its dosing differs from testosterone gel 1.62% [1]. AndroGel is sold as both strengths; AndroGel's own label wording may differ.

Where the gel label mentions stopping

• Hematocrit rises. Hematocrit is checked before treatment, re-checked 3 to 6 months in and then annually; if it becomes elevated, the label says to stop therapy until hematocrit decreases to an acceptable concentration [1].
• A clot is suspected. Venous thromboembolism, including deep vein thrombosis and pulmonary embolism, has been reported with testosterone products, and the label says to discontinue if a venous thromboembolic event is suspected [1]. In TRAVERSE, VTE occurred in 1.7% of men on testosterone gel versus 1.2% on placebo [1].
• A household contact shows virilization. The gel carries a boxed warning about secondary exposure, and the label says the gel should be promptly discontinued until the cause of virilization is identified [1].

For people taking an oral anticoagulant, the label recommends more frequent INR and prothrombin time checks, especially when androgen therapy starts or ends [1].

Where withdrawal appears in the label

The label's Dependence section lists addiction behaviors with continued abuse of testosterone, often with other anabolic steroids: taking greater dosages than prescribed, continuing despite medical and social problems, giving drug use priority over other obligations, difficulty discontinuing despite wanting to, and experiencing withdrawal symptoms upon abrupt discontinuation [1]. It also says physical dependence is characterized by withdrawal symptoms after abrupt discontinuation or a significant dose reduction, and that individuals taking supratherapeutic doses may have withdrawal symptoms lasting weeks or months, including depressed mood, fatigue and craving [1]. Testosterone gel 1% is a Schedule III controlled substance [1].

Sperm production and recovery after stopping

The label warns that exogenous androgens may lead to azoospermia [1]. Sperm recovery after testosterone has been studied more than symptom recovery, mostly in men treated for infertility.

• In a retrospective series of 66 men who stopped testosterone and took high-dose hCG plus a selective estrogen receptor modulator, 46 (70%) reached a total motile count above 5 million within 12 months. That figure was 64.8% in men who were azoospermic versus 91.7% in men with cryptozoospermia, and older age and longer testosterone use predicted slower recovery [2].
• A retrospective series of 49 men with azoospermia or severe oligospermia on testosterone used hCG 3,000 units subcutaneously every other day plus clomiphene, tamoxifen, anastrozole or recombinant FSH; spermatogenesis returned or improved in 47 (95.9%), at an average of 4.6 months and a mean first density of 22.6 million/mL [3].
• In 1,549 healthy men using hormonal contraception, the median time for sperm concentration to return to 20 million/mL was 3.4 months, and 90% had recovered by 12 months; that population did not have hypogonadism [4].