AndroGel FDA Approval History

The 2000 FDA Approval: NDA 021015

AndroGel 1% was approved by the FDA on February 28, 2000, making it the first commercially available testosterone gel in the United States. The approval was granted to Unimed Pharmaceuticals, a subsidiary of Solvay, under NDA 021015. The approved indication was testosterone replacement therapy in adult males with a confirmed diagnosis of hypogonadism, defined by consistently low serum testosterone and clinical symptoms.

What the Original Submission Showed

The key data package supporting NDA 021015 included three Phase III studies enrolling a combined total of 227 hypogonadal men. FDA drug approval package, NDA 021015 At 90 days, testosterone gel 5 g and 10 g daily produced mean serum testosterone levels within the normal range (300 to 1,000 ng/dL) in roughly 87% and 92% of participants, respectively. The comparator arm used a testosterone patch (Androderm), which achieved normal range in approximately 85% of participants. Skin tolerability strongly favored the gel: application-site reactions occurred in fewer than 6% of gel users versus roughly 49% of patch users.

The FDA's clinical pharmacology review noted that AndroGel produced steady-state testosterone concentrations within 24 hours of the first dose and maintained them with once-daily application. FDA clinical pharmacology review, NDA 021015

Approved Dosing in 2000

The original approved dose was 5 g of 1% gel (50 mg testosterone) applied once daily to the shoulders, upper arms, or abdomen. Dose could be titrated to 7.5 g or 10 g based on serum testosterone measured 14 days after starting or adjusting therapy.

NDA 202763: The 1.62% Formulation Approved in 2011

The FDA approved AndroGel 1.62% on March 11, 2011, under NDA 202763. FDA approval letter, NDA 202763 This higher-concentration formulation reduced the volume of gel applied per dose, which lowered the theoretical risk of accidental secondary transfer to a skin contact.

Clinical Data for the 1.62% Formulation

The key study enrolled 274 hypogonadal men in a 16-week, open-label, dose-titration trial. Starting dose was 40.5 mg testosterone (2.5 g gel), with allowed uptitration to 60.75 mg or 81 mg. At week 16, 76.9% of subjects achieved an average testosterone concentration (C-avg) within the normal range of 300 to 1,050 ng/dL on their final dose. FDA medical review, NDA 202763

Application Site Differences

The 1.62% formulation is applied only to the upper arms and shoulders, not the abdomen. This restriction was built into the label based on pharmacokinetic data showing higher absorption variability at abdominal sites with the more concentrated gel.

Secondary Exposure Risk and the 2009 Black Box Warning

The FDA added a black box warning to all topical testosterone products, including AndroGel, in May 2009. This was the single most consequential label change in the product's first decade.

Why the Warning Was Added

Postmarketing case reports described virilization in children who had skin-to-skin contact with adults using testosterone gel. Reported signs included premature pubic hair, clitoral or penile enlargement, advanced bone age, and aggressive behavior in children as young as nine months old. FDA MedWatch safety alert, 2009

The black box warning stated, in part: "Virilization has been reported in children who were secondarily exposed to testosterone gel. Children should avoid contact with unwashed or unclothed application sites in men using testosterone gel." This language was carried forward into every subsequent label revision.

Recommended Risk-Reduction Measures

The updated label directed patients to wash hands immediately after application, cover the application site with clothing after the gel dried, and shower before direct skin contact with children or women. The FDA also required the manufacturer to conduct a medication guide and risk-reduction program at that time.

2014 Label Revision: Venous Thromboembolism

On June 19, 2014, the FDA required a label update for all testosterone products to add a warning about venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. FDA Drug Safety Communication, June 2014

The revised warning language noted that cases of VTE had been reported in postmarketing surveillance, that some cases were fatal, and that no causal relationship had been firmly established at that time. Prescribers were directed to evaluate patients with symptoms of VTE and to consider discontinuation pending investigation.

This update arrived amid broader regulatory scrutiny of the entire testosterone replacement category following two observational studies published in late 2013 and early 2014 that found elevated cardiovascular event rates in men initiating testosterone therapy. Vigen R et al., JAMA 2013

March 2015: FDA Cardiovascular Safety Communication

The March 3, 2015 FDA Drug Safety Communication was the broadest regulatory action to affect AndroGel since its approval. FDA Drug Safety Communication, March 2015

What the FDA Required

The FDA required manufacturers to:

1. Add language to the Warnings and Precautions section stating that cardiovascular risk was possible.
2. Clarify the approved indication to specify that testosterone products are approved only for men with documented low testosterone caused by specific medical conditions, not for age-related decline alone.
3. Conduct postmarketing clinical trials to assess long-term cardiovascular outcomes.

The agency stated: "FDA has determined that there is a possible increased cardiovascular risk associated with testosterone use. We are requiring manufacturers to add information to the labeling about this potential risk." This communication explicitly addressed the practice of prescribing testosterone for men with low-normal testosterone related to aging, which the FDA said was not an approved use.

The Observational Data That Prompted Action

Two studies drove the regulatory timeline. Vigen et al. (JAMA, 2013, N=8,709 men with coronary artery disease) found a 29% absolute increase in adverse outcomes (25.7% vs. 19.9%) among testosterone initiators compared to non-initiators. Vigen R et al., JAMA 2013 Finkle et al. (PLOS ONE, 2014) reported a 36% increase in non-fatal myocardial infarction rates in the 90 days after testosterone prescription compared to the 12 months preceding it. Finkle WD et al., PLOS ONE 2014

Both studies had significant methodological limitations, and the FDA's 2015 action stopped short of requiring a black box warning for cardiovascular events. The agency instead required postmarketing trials to generate prospective data.

The T-Trials and Post-Approval Evidence Base

The Testosterone Trials (T-Trials), a coordinated set of seven double-blind, placebo-controlled trials conducted at 12 U.S. Sites, enrolled 790 men aged 65 years and older with serum testosterone below 275 ng/dL and age-related symptoms. Snyder PJ et al., NEJM 2016

Primary Outcomes

The Sexual Function Trial, the Physical Function Trial, and the Vitality Trial served as the three co-primary trials. Testosterone gel (titrated to achieve levels of 500 to 800 ng/dL) significantly improved self-reported sexual activity compared to placebo. Physical function improvements did not reach statistical significance. Vitality, measured by the FACIT-Fatigue scale, showed modest but statistically significant improvement in the testosterone arm.

Cardiovascular Signal in the T-Trials

The Cardiovascular Trial enrolled 788 of the same men and measured coronary artery plaque volume by CT angiography. Testosterone gel increased noncalcified plaque volume by a mean of 41 mm3 compared to a 0.3 mm3 increase in the placebo arm (P<0.001). Budoff MJ et al., JAMA 2017 This finding did not establish causation for hard cardiovascular events, but it supported continued regulatory caution. The study authors noted: "The increase in noncalcified plaque volume associated with testosterone compared with placebo among older men with low testosterone raises concern about the potential long-term cardiovascular effects of testosterone treatment."

Anemia and Bone Density Results

The Anemia Trial (N=126 men with unexplained mild anemia) found that testosterone gel raised hemoglobin by a mean of 1.0 g/dL compared to 0.1 g/dL with placebo, a clinically meaningful and statistically significant difference. Snyder PJ et al., NEJM 2016 The Bone Trial showed increased volumetric bone density and estimated bone strength in the testosterone arm, though fracture outcomes were not assessed.

The TRAVERSE Trial: Prospective Cardiovascular Evidence

The FDA-required postmarketing cardiovascular trial for testosterone therapy was the TRAVERSE study, published in the New England Journal of Medicine in 2023. This was a randomized, double-blind, placebo-controlled trial enrolling 5,246 men aged 45 to 80 years with hypogonadism and pre-existing cardiovascular disease or elevated cardiovascular risk. Lincoff AM et al., NEJM 2023

What TRAVERSE Found

Over a median follow-up of 33 months, the primary endpoint (a composite of death from cardiovascular causes, non-fatal MI, or non-fatal stroke) occurred in 7.0% of the testosterone group versus 7.3% of the placebo group (hazard ratio 0.96, 95% CI 0.78 to 1.17), meeting the prespecified non-inferiority margin. Testosterone gel did not increase the rate of major adverse cardiovascular events in this high-risk population.

Atrial fibrillation was more common in the testosterone arm: 3.5% vs. 2.4% (P<0.001). Acute kidney injury occurred more often with testosterone as well (2.3% vs. 1.5%, P=0.02). These signals were added to the testosterone product labeling after the trial results were reviewed.

Regulatory Impact of TRAVERSE

The FDA reviewed the TRAVERSE data and issued a label update in 2023 adding atrial fibrillation as a risk to be discussed with patients. FDA Drug Safety Communication, 2023 The cardiovascular non-inferiority finding partially addressed the 2015 safety concern, though the FDA maintained its position that testosterone is indicated only for confirmed hypogonadism from specific medical causes.

Current Approved Label: Key Provisions

The current AndroGel label (as of the most recent revision) reflects over two decades of accumulated postmarketing data. Current AndroGel prescribing information, FDA

Indication and Limitation of Use

The label states that AndroGel is indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone. The limitation of use section reads: "Safety and efficacy of AndroGel have been established in males with primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired). Safety and efficacy of testosterone in males with age-related hypogonadism (also referred to as late-onset hypogonadism) have not been established."

Contraindications

The current label lists four contraindications:

• Men with known or suspected breast carcinoma or prostate carcinoma.
• Women, because of the risk of fetal harm.
• Pregnant women specifically, due to potential virilization of a female fetus.
• Patients with known hypersensitivity to any component of the formulation.

Current Warnings and Precautions

The warnings and precautions section covers secondary exposure (black box), worsening of benign prostatic hyperplasia, polycythemia (hematocrit must be checked at 3 to 6 months after initiation and then annually), sleep apnea, lipid changes, hypercalcemia in patients with cancer, decreased sperm production, venous thromboembolism, cardiovascular risk, and atrial fibrillation. Current AndroGel prescribing information, FDA

Postmarketing Surveillance and the FDA Sentinel System

The FDA has used its Sentinel System to conduct ongoing safety surveillance for testosterone products, including AndroGel, since 2016. Sentinel uses claims and electronic health record data from over 100 million covered lives to detect safety signals in real-world use. FDA Sentinel System overview

A Sentinel query published in 2017 examined VTE rates in testosterone initiators across multiple product types. Among men initiating testosterone therapy who did not have a prior VTE, the incidence rate in the first 6 months was approximately 3.9 events per 1,000 person-years, compared to 2.0 per 1,000 in matched non-users. Glueck CJ et al., blood coagulation data via PubMed The absolute excess risk remained small, but the relative doubling was sufficient to maintain the VTE warning in the label.

Polycythemia monitoring requirements stem from consistent postmarketing reports and clinical trial data showing that testosterone gel raises hematocrit by a mean of 3 to 5 percentage points. Bhasin S et al., NEJM 2010 Hematocrit above 54% increases whole-blood viscosity and thromboembolic risk, which is why the current label requires dose interruption if hematocrit exceeds that threshold.

Pediatric and Adolescent Prescribing Restrictions

AndroGel is not approved for use in pediatric patients. The label explicitly states that the drug has not been established as safe or effective in boys under 18 years old. Accidental exposure, not intentional pediatric use, was the driver of the 2009 black box warning.

The Endocrine Society's 2019 clinical practice guideline on testosterone therapy in men specifies that testosterone replacement should not be initiated in men with suspected prostate cancer, active thromboembolic disease, or hematocrit above 54%. Bhasin S et al., J Clin Endocrinol Metab 2018 These contraindications align closely with the current AndroGel label.

Controlled Substance Scheduling and DEA Classification

Testosterone is classified as a Schedule III controlled substance under the Anabolic Steroids Control Act of 1990. This classification applies to AndroGel regardless of formulation or strength. Prescriptions for Schedule III substances may be refilled up to five times within six months of the original prescription date under DEA regulations. DEA Diversion Control Division, controlled substance schedules

The Schedule III classification means that prescribers must have a valid DEA registration number to prescribe AndroGel, and pharmacies must maintain dispensing logs subject to DEA inspection.

Manufacturing and Generic Availability

The first generic testosterone gel 1% was approved by the FDA in 2007. Multiple authorized generics and independent generics are now available. AbbVie holds the branded NDA for both the 1% and 1.62% formulations. The Orange Book lists AndroGel 1% (NDA 021015) and AndroGel 1.62% (NDA 202763) with patent and exclusivity information updated annually. FDA Orange Book, AndroGel entry

The table below summarizes the major regulatory milestones in chronological order.

| Year | Event | |------|-------| | 2000 | NDA 021015 approved (AndroGel 1%, February 28) | | 2007 | First generic testosterone gel 1% approved | | 2009 | Black box warning added (secondary exposure) | | 2011 | NDA 202763 approved (AndroGel 1.62%, March 11) | | 2014 | VTE warning added to label (June) | | 2015 | FDA cardiovascular safety communication (March) | | 2016 | T-Trials published in NEJM (N=790) | | 2017 | JAMA cardiovascular sub-trial published (plaque volume data) | | 2023 | TRAVERSE trial published; atrial fibrillation label update |

Clinical Monitoring Requirements Under the Current Label

The current prescribing information specifies a concrete monitoring schedule. Serum testosterone should be measured 14 days after starting therapy or after any dose adjustment, with the sample drawn 2 to 8 hours after application to approximate average steady-state concentration. Hematocrit must be checked at baseline, at 3 to 6 months, and then annually. Prostate-specific antigen (PSA) and digital rectal exam are recommended at baseline and per standard prostate cancer screening guidelines thereafter. Current AndroGel prescribing information, FDA

The Endocrine Society guideline recommends checking testosterone, PSA, hematocrit, and bone mineral density (in patients with osteoporosis at baseline) at 3 months, 6 months, and annually once stable. Bhasin S et al., J Clin Endocrinol Metab 2018

If hematocrit rises above 54%, the label directs the prescriber to withhold therapy until levels fall to an acceptable level, then restart at a lower dose. A hematocrit above 54% is an absolute reason to interrupt AndroGel per both the FDA label and Endocrine Society guidance.