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Description for AndroGel 1.62

AndroGel 1.62% for topical use is a clear, colorless gel containing testosterone. Testosterone is an androgen. AndroGel 1.62% is available in a metered-dose pump or unit dose packets.

The active pharmacologic ingredient in AndroGel 1.62% is testosterone. Testosterone USP is a white to almost white powder chemically described as 17-beta hydroxyandrost-4-en-3-one. The structural formula is:

The inactive ingredients in AndroGel 1.62% are: carbopol 980, ethyl alcohol, isopropyl myristate, purified water, and sodium hydroxide.

ADVERSE REACTIONS

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.

AndroGel 1.62% was evaluated in a two-phase, 364-day, controlled clinical study. The first phase was a multi-center, randomized, double-blind, parallel-group, placebo-controlled period of 182 days, in which 234 hypogonadal men were treated with AndroGel 1.62% and 40 received placebo. Patients could continue in an open-label, non-comparative, maintenance period for an additional 182 days [see Clinical Studies (14.1)].

The most common adverse reaction reported in the double-blind period was increased prostate specific antigen (PSA) reported in 26 AndroGel 1.62%-treated patients (11.1%). In 17 patients, increased PSA was considered an adverse event by meeting one of the two pre-specified criteria for abnormal PSA values, defined as (1) average serum PSA >4 ng/mL based on two separate determinations, or (2) an average change from baseline in serum PSA of greater than 0.75 ng/mL on two determinations.

During the 182-day, double-blind period of the clinical trial, the mean change in serum PSA value was 0.14 ng/mL for patients receiving AndroGel 1.62% and -0.12 ng/mL for the patients in the placebo group. During the double-blind period, seven patients had a PSA value >4.0 ng/mL, four of these seven patients had PSA less than or equal to 4.0 ng/mL upon repeat testing. The other three patients did not undergo repeat PSA testing.

During the 182-day, open-label period of the study, the mean change in serum PSA values was 0.10 ng/mL for both patients continuing on active therapy and patients transitioning onto active from placebo. During the open-label period, three patients had a serum PSA value > 4.0 ng/mL, two of whom had a serum PSA less than or equal to 4.0 ng/mL upon repeated testing. The other patient did not undergo repeat PSA testing. Among previous placebo patients, 3 of 28 (10.7%), had increased PSA as an adverse event in the open-label period.

Table 4 shows adverse reactions reported by >2% of patients in the 182-day, double-blind period of the AndroGel 1.62% clinical trial and more frequent in the AndroGel 1.62% treated group versus placebo.

Table 4: Adverse Reactions Reported in >2% of Patients in the 182-Day, Double-Blind Period of AndroGel 1.62% Clinical Trial

	Number (%) of Patients
Adverse Reaction	AndroGel 1.62% N=234	Placebo N=40
PSA increased*	26 (11.1%)	0%
Emotional lability**	6 (2.6%)	0%
Hypertension	5 (2.1%)	0%
Hematocrit or hemoglobin increased	5 (2.1%)	0%
Contact dermatitis***	5 (2.1%)	0%
*PSA increased includes: PSA values that met pre-specified criteria for abnormal PSA values (an average change from baseline > 0.75 ng/mL and/or an average PSA value >4.0 ng/mL based on two measurements) as well as those reported as adverse events.
**Emotional lability includes: mood swings, affective disorder, impatience, anger, and aggression.
***Contact dermatitis includes: 4 patients with dermatitis at non-application sites.

Other adverse reactions occurring in less than or equal to 2% of AndroGel 1.62%-treated patients and more frequently than placebo included: frequent urination, and hyperlipidemia.

In the open-label period of the study (N=191), the most commonly reported adverse reaction (experienced by greater than 2% of patients) was increased PSA (n=13; 6.2%) and sinusitis. Other adverse reactions reported by less than or equal to 2% of patients included increased hemoglobin or hematocrit, hypertension, acne, libido decreased, insomnia, and benign prostatic hypertrophy.

During the 182-day, double-blind period of the clinical trial, 25 AndroGel 1.62%-treated patients (10.7%) discontinued treatment because of adverse reactions. These adverse reactions included 17 patients with PSA increased and 1 report each of: hematocrit increased, blood pressure increased, frequent urination, diarrhea, fatigue, pituitary tumor, dizziness, skin erythema and skin nodule (same patient – neither at application site), vasovagal syncope, and diabetes mellitus. During the 182-day, open-label period, 9 patients discontinued treatment because of adverse reactions. These adverse reactions included 6 reports of PSA increased, 2 of hematocrit increased, and 1 each of triglycerides increased and prostate cancer.

Application Site Reactions

In the 182-day double-blind period of the study, application site reactions were reported in two (2/234; 0.9%) patients receiving AndroGel 1.62%, both of which resolved. Neither of these patients discontinued the study due to application site adverse reactions. In the open-label period of the study, application site reactions were reported in three (3/219; 1.4%) additional patients that were treated with AndroGel 1.62%. None of these subjects were discontinued from the study due to application site reactions.

Blood Pressure Increases

In a 4-month clinical study, 24-hour ambulatory blood pressure monitoring (ABPM) was conducted on 246 patients. ABPM was conducted at baseline and at Week 16 of AndroGel 1.62% therapy. A total of 169 patients had acceptable ABPM recordings at both baseline and Week 16 and were at least 85% compliant with study drug. In that group, the mean change in 24-hour systolic blood pressure (BP) and diastolic BP from baseline to end-of-treatment at Week 16 (n=169) was 1.9 mm Hg (95% CI 0.6, 3.1) and 1.3 mm Hg (95% CI 0.5, 2.1), respectively. In patients with a history of hypertension who were receiving antihypertensive therapy, the mean ABPM systolic and diastolic BP increased by 3.0 mm Hg [95% CI 0.8, 5.2] and 2.2 mm Hg [95% CI 0.8, 3.5], respectively [n=72]). In patients with no history of hypertension, the mean systolic and diastolic blood pressure increased by 1.2 mm Hg [95% CI -0.2, 2.7] and 0.9 mm Hg [95% CI -0.1, 1.8], respectively [n=91].

Four patients (2.8 %) on AndroGel 1.62%, all of whom were receiving antihypertensive medications at baseline, either started new antihypertensive medications (n=2) or had their antihypertensive medication regimen adjusted (n=2) during the ABPM study.

Of the 246 patients in the ABPM study who used AndroGel 1.62%, 10 patients (4.1%) were reported to have either an adverse reaction of hypertension (5 patients, 2.0%) or increased blood pressure (5 patients, 2.0%).

Cardiovascular Outcomes

TRAVERSE was a randomized, double-blind, cardiovascular outcomes study to assess the cardiovascular (CV) safety of Androgel 1.62% compared to placebo in 5198 hypogonadal men aged 45 to 80 years with a history of CV disease or with multiple CV risk factors. The primary outcome was the incidence of the composite endpoint of major adverse cardiovascular events (MACE), consisting of CV death, non-fatal myocardial infarction (MI), and non-fatal stroke.

The mean duration of therapy was approximately 22 months. The mean duration of follow-up was 33 months. Approximately 61% of all patients discontinued AndroGel 1.62% or placebo therapy. The mean (±SD) daily dose of testosterone was 65±22 mg.

The mean patient age (±SD) was 63.3 (7.9) years, with 2452 patients aged 65 years or more (47%); 2847 (about 55%) patients had pre-existing cardiovascular disease, whereas 2357 (about 45%) patients had an elevated cardiovascular risk at baseline, and mean BMI was 35kg/m2. Approximately 80% of patients were White, 17% were Black, and 3% were of other races or ethnic groups. Approximately 69%, 84%, and 93% had diabetes mellitus, hyperlipidemia, and hypertension, respectively.

The mean serum testosterone concentration at baseline in patients receiving AndroGel 1.62% was 220.4 ng/dL (n=2596). The mean serum testosterone concentrations at 12 months, 24 months, 36 months, and 48 months in patients receiving AndroGel 1.62% were 440.5 ng/dL (n=1683), 420.9 ng/dl (n=1125), 428.7 ng/dL (n=731), and 365.2 ng/dL (n=220), respectively.

For patients treated with AndroGel 1.62%, the incidence of MACE was 7.0% (n=182 events) and for those receiving placebo, the incidence of MACE was 7.3% (n=190 events). The study demonstrated non-inferiority of AndroGel 1.62% versus placebo because the upper bound of 95% CI was less than the pre-specified risk margin, of 1.5 for MACE (Hazard Ratio 0.96 [95% CI: 0.78, 1.17]).

Additional Adverse Reactions Reported in TRAVERSE

Additional adverse reactions reported in TRAVERSE at an incidence rate >2% in either treatment group and greater in AndroGel 1.62% versus placebo included: nonfatal arrythmias warranting intervention (5.2% vs 3.3%), atrial fibrillation (3.5% vs 2.4%), acute kidney injury (2.3% vs 1.5%) and bone fracture (3.5% vs 2.5%). For the adverse reaction of bone fracture, each event was adjudicated by clinical review.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of AndroGel 1.62%. 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 5).

Table 5: Adverse Reactions from Post Approval Experience of AndroGel 1.62% by System Organ Class

System Organ Class	Adverse Reaction
Blood and lymphatic system disorders:	Elevated hemoglobin or hematocrit, polycythemia, anemia
Cardiovascular disorders:	Myocardial infarction, stroke
Endocrine disorders:	Hirsutism
Gastrointestinal disorders:	Nausea
General disorders:	Asthenia, edema, malaise
Genitourinary disorders:	Impaired urination*
Hepatobiliary disorders:	Abnormal liver function tests
Investigations:	Lab test abnormal**, elevated PSA, electrolyte changes (nitrogen, calcium, potassium [includes hypokalemia], phosphorus, sodium), impaired glucose tolerance, hyperlipidemia, HDL, fluctuating testosterone levels, weight increase
Neoplasms:	Prostate cancer
Nervous system disorders:	Dizziness, headache, insomnia, sleep apnea
Psychiatric disorders:	Amnesia, anxiety, depression, hostility, emotional lability, decreased libido, nervousness
Reproductive system and breast disorders:	Gynecomastia, mastodynia, oligospermia, priapism (frequent or prolonged erections), prostate enlargement, BPH, testis disorder***
Respiratory disorders:	Dyspnea
Skin and subcutaneous tissue disorders:	Acne, alopecia, application site reaction (discolored hair, dry skin, erythema, paresthesia, pruritus, rash), skin dry, pruritus, sweating
Vascular disorders:	Hypertension, vasodilation (hot flushes), venous thromboembolism
* Impaired urination includes nocturia, urinary hesitancy, urinary incontinence, urinary retention, urinary urgency and weak urinary stream
**Lab test abnormal includes elevated AST, elevated ALT, elevated testosterone, elevated hemoglobin or hematocrit, elevated cholesterol, elevated cholesterol/LDL ratio, elevated triglycerides, or elevated serum creatinine
***Testis disorder includes atrophy or non-palpable testis, varicocele, testis sensitivity or tenderness

Secondary Exposure to Testosterone in Children

Cases of secondary exposure to testosterone resulting in virilization of children have been reported in postmarketing surveillance of testosterone gel products. Signs and symptoms of these reported cases have included enlargement of the clitoris (with surgical intervention) or the penis, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases with a reported outcome, these signs and symptoms were reported to have regressed with removal of the testosterone gel exposure. In a few cases, however, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronological age. In some of the cases, direct contact with the sites of application on the skin of men using testosterone gel was reported. In at least one reported case, the reporter considered the possibility of secondary exposure from items such as the testosterone gel user's shirts and/or other fabric, such as towels and sheets [see Warnings and Precautions (5.2)].

Drug Interactions for AndroGel 1.62

Insulin

Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease insulin requirements.

Oral Anticoagulants

Changes in anticoagulant activity may be seen with androgens, therefore more frequent monitoring of international normalized ratio (INR) and prothrombin time are recommended in patients taking anticoagulants, especially at the initiation and termination of androgen therapy.

Corticosteroids

The concurrent use of testosterone with adrenocorticotropic hormone (ACTH) or corticosteroids may result in increased fluid retention and requires careful monitoring particularly in patients with cardiac, renal or hepatic disease.

DRUG ABUSE AND DEPENDENCE

Controlled Substance

AndroGel 1.62% contains testosterone, a Schedule III controlled substance in the Controlled Substances Act.

Abuse

Drug abuse is intentional non-therapeutic use of a drug, even once, for its rewarding psychological and physiological effects. Abuse and misuse of testosterone are seen in male and female adults and adolescents. Testosterone, often in combination with other anabolic androgenic steroids (AAS), and not obtained by prescription through a pharmacy, may be abused by athletes and bodybuilders. There have been reports of misuse by men taking higher doses of legally obtained testosterone than prescribed and continuing testosterone despite adverse events or against medical advice.

Abuse-Related Adverse Reactions

Serious adverse reactions have been reported in individuals who abuse anabolic androgenic steroids and include cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and serious psychiatric manifestations, including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility and aggression.

The following adverse reactions have also been reported in men: transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility.

The following additional adverse reactions have been reported in women: hirsutism, virilization, deepening of voice, clitoral enlargement, breast atrophy, male-pattern baldness, and menstrual irregularities.

The following adverse reactions have been reported in male and female adolescents: premature closure of bony epiphyses with termination of growth, and precocious puberty.

Because these reactions are reported voluntarily from a population of uncertain size and may include abuse of other agents, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dependence

Behaviors Associated with Addiction

Continued abuse of testosterone and other anabolic steroids, leading to addiction is characterized by the following behaviors:

• Taking greater dosages than prescribed
• Continued drug use despite medical and social problems due to drug use
• Spending significant time to obtain the drug when supplies of the drug are interrupted
• Giving a higher priority to drug use than other obligations
• Having difficulty in discontinuing the drug despite desires and attempts to do so
• Experiencing withdrawal symptoms upon abrupt discontinuation of use

Physical dependence is characterized by withdrawal symptoms after abrupt drug discontinuation or a significant dose reduction of a drug. Individuals taking supratherapeutic doses of testosterone may experience withdrawal symptoms lasting for weeks or months which include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypogonadism.

Drug dependence in individuals using approved doses of testosterone for approved indications has not been documented.

Warnings for AndroGel 1.62

Included as part of the PRECAUTIONS section.

Precautions for AndroGel 1.62

Potential for Secondary Exposure to Testosterone

Cases of secondary exposure resulting in virilization of children have been reported in postmarketing surveillance. Signs and symptoms have included enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases, these signs and symptoms regressed with removal of the exposure to testosterone gel. In a few cases, however, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronological age. The risk of transfer was increased in some of these cases by not adhering to precautions for the appropriate use of the topical testosterone product. Children and women should avoid contact with unwashed or unclothed application sites in men using AndroGel 1% [see Dosage and Administration (2.2), Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].

Inappropriate changes in genital size or development of pubic hair or libido in children, or changes in body hair distribution, significant increase in acne, or other signs of virilization in adult women should be brought to the attention of a physician and the possibility of secondary exposure to testosterone gel should also be brought to the attention of a physician. Testosterone gel should be promptly discontinued until the cause of virilization has been identified.

Polycythemia

Increases in hematocrit, reflective of increases in red blood cell mass, may require lowering or discontinuation of testosterone. Check hematocrit prior to initiating treatment. It would also be appropriate to re-evaluate the hematocrit 3 to 6 months after starting treatment, and then annually. If hematocrit becomes elevated, stop therapy until hematocrit decreases to an acceptable concentration. An increase in red blood cell mass may increase the risk of thromboembolic events.

Venous Thromboembolism

There have been postmarketing reports of venous thromboembolic events (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products such as AndroGel 1%.

In the Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) Study, a randomized, double-blind, placebo-controlled, cardiovascular (CV) outcomes study, compared to placebo, AndroGel 1.62% was associated with a numerically higher incidence of VTE (1.7% vs 1.2%) which included DVT (0.6% vs 0.5%) and PE events (0.9% vs 0.5%) [see Adverse Reactions (6.1)].

Evaluate patients who report symptoms of pain, edema, warmth and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE. If a venous thromboembolic event is suspected, discontinue treatment with AndroGel 1% and initiate appropriate workup and management [see Adverse Reactions (6.2)].

Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer

• Patients with BPH treated with androgens are at an increased risk for worsening of signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms.
• Patients treated with androgens may be at increased risk for prostate cancer. Evaluate patients for prostate cancer prior to initiating and during treatment with androgens [see Contraindications (4), Adverse Reactions (6.1) and Nonclinical Toxicology (13.1)].

Blood Pressure Increases

AndroGel 1% can increase blood pressure. In an ambulatory blood pressure monitoring (ABPM) study, Androgel 1.62% increased the mean systolic/diastolic blood pressure by 1.9/1.3 mm Hg from baseline after 16 weeks of treatment. In patients with hypertension on antihypertensive therapy, AndroGel 1.62% increased the mean systolic/diastolic BP by 3.0/2.2 mm Hg from baseline. Blood pressure increases can increase cardiovascular (CV) risk over time.

The CV risk associated with Androgel 1.62% was evaluated in TRAVERSE, a randomized, double-blind, placebo-controlled, CV outcomes study in men with a history of CV disease or multiple CV risk factors. In TRAVERSE, mean systolic blood pressure in the group treated with Androgel 1.62% increased by 1.0 mm Hg from baseline to 36 months, whereas a mean decrease from baseline of 0.5 mm Hg was observed in the placebo group at this timepoint, for a mean between-group difference of 1.5 mm Hg. However, the incidences of major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction [MI] and non-fatal stroke, were similar between treatment groups (7% for Androgel 1.62% vs 7.3% for placebo) [See Adverse Reactions (6.1)].

Monitor blood pressure periodically in men using Androgel 1.62%, especially men with hypertension. Androgel 1.62% is not recommended for use in patients with uncontrolled hypertension.

Abuse of Testosterone and Monitoring of Serum Testosterone Concentrations

Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. Anabolic androgenic steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions [see Drug Abuse and Dependence (9)].

If testosterone abuse is suspected, check serum testosterone concentrations to ensure they are within therapeutic range. However, testosterone levels may be in the normal or subnormal range in men abusing synthetic testosterone derivatives. Counsel patients concerning the serious adverse reactions associated with abuse of testosterone and anabolic androgenic steroids. Conversely, consider the possibility of testosterone and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events.

Not for Use in Women

Due to the lack of controlled evaluations in women and potential virilizing effects, AndroGel 1.62% is not indicated for use in women [see Contraindications (4) and Use in Specific Populations (8.1, 8.2)].

Potential for Adverse Effects on Spermatogenesis

With large doses of exogenous androgens, including AndroGel 1.62%, spermatogenesis may be suppressed through feedback inhibition of pituitary FSH possibly leading to adverse effects on semen parameters including sperm count.

Hepatic Adverse Effects

Prolonged use of high doses of orally active 17-alpha-alkyl androgens (e.g., methyltestosterone) has been associated with serious hepatic adverse effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatis can be a life-threatening or fatal complication. Long-term therapy with intramuscular testosterone enanthate has produced multiple hepatic adenomas. AndroGel 1.62% is not known to cause these adverse effects.

Edema

Androgens, including AndroGel 1.62%, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease [see Adverse Reactions (6.2)].

Gynecomastia

Gynecomastia may develop and persist in patients being treated with androgens, including AndroGel 1.62%, for hypogonadism.

Sleep Apnea

The treatment of hypogonadal men with testosterone may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung diseases.

Lipid Changes

Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy, such as AndroGel 1.62%. Monitor the lipid profile periodically, particularly after starting testosterone therapy.

Hypercalcemia

Androgens, including AndroGel 1.62 %, should be used with caution in cancer patients at risk of hypercalcemia (and associated hypercalciuria). Regular monitoring of serum calcium concentrations is recommended in these patients.

Decreased Thyroxine-binding Globulin

Androgens, including AndroGel 1.62%, may decrease concentrations of thyroxin-binding globulins, resulting in decreased total T4 serum concentrations and increased resin uptake of T3 and T4. Free thyroid hormone concentrations remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.

Flammability

Alcohol based products, including AndroGel 1.62%, are flammable; therefore, patients should be advised to avoid fire, flame or smoking until the AndroGel 1.62% has dried.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Testosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical-uterine tumors which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.

Mutagenesis

Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays.

Impairment of Fertility

The administration of exogenous testosterone has been reported to suppress spermatogenesis in rats, dogs, and non-human primates, which was reversible on cessation of the treatment.

Patient Information for AndroGel 1.62

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Patients should be informed of the following:

Use in Men with Known or Suspected Prostate or Breast Cancer

Men with known or suspected prostate or breast cancer should not use AndroGel 1.62% [see Contraindications (4) and Warnings and Precautions (5.1)].

Potential for Secondary Exposure to Testosterone and Steps to Prevent Secondary Exposure

Secondary exposure to testosterone in children and women can occur with the use of testosterone gel in men [see Warnings and Precautions (5.2)]. Cases of secondary exposure to testosterone have been reported in children.

Physicians should advise patients of the reported signs and symptoms of secondary exposure, which may include the following:

• In children: unexpected sexual development including inappropriate enlargement of the penis or clitoris, premature development of pubic hair, increased erections, and aggressive behavior.
• In women: changes in hair distribution, increase in acne, or other signs of testosterone effects.
• The possibility of secondary exposure to testosterone gel should be brought to the attention of a healthcare provider.
• AndroGel 1.62% should be promptly discontinued until the cause of virilization is identified.

Strict adherence to the following precautions is advised to minimize the potential for secondary exposure to testosterone from AndroGel 1.62% in men [see Medication Guide]:

• Children and women should avoid contact with unwashed or unclothed application site(s) of men using AndroGel 1.62%.
• Patients using AndroGel 1.62% should apply the product as directed and strictly adhere to the following:

  • Wash hands with soap and water immediately after application.

  • Cover the application site(s) with clothing after the gel has dried.

  • Wash the application site(s) thoroughly with soap and water prior to any situation where skin-to-skin contact of the application site with another person is anticipated.

• In the event that unwashed or unclothed skin to which AndroGel 1.62% has been applied comes in contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible [see Dosage and Administration (2.2), Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Potential for Venous Thromboembolism

Inform patients that AndroGel 1.62% can cause venous thromboembolism. Advise patients of the signs and symptoms of venous thromboembolism, which may include the following: lower limb pain, edema, or erythema; and dyspnea or chest pain. Advise patients to promptly report the signs and symptoms of venous thromboembolism, discontinue use of AndroGel 1.62%, and seek urgent medical care.

Potential for Increase in Blood Pressure

Inform patients that AndroGel 1.62% can increase BP which can increase cardiovascular risk over time. Instruct patients about the importance of monitoring BP periodically while on Androgel 1.62%. If BP increases while on AndroGel 1.62%, antihypertensive medications may need to be started, added, or adjusted to control BP, or AndroGel 1.62% may need to be discontinued.

Potential Adverse Reactions with Androgens

Patients should be informed that treatment with androgens may lead to adverse reactions which include:

• Changes in urinary habits such as increased urination at night, trouble starting the urine stream, passing urine many times during the day, having an urge to go to the bathroom right away, having a urine accident, being unable to pass urine and weak urine flow.
• Breathing disturbances, including those associated with sleep, or excessive daytime sleepiness.
• Too frequent or persistent erections of the penis.
• Nausea, vomiting, changes in skin color, or ankle swelling.

Patients Should Be Advised of the Following Instructions for Use

• Read the Medication Guide before starting AndroGel 1.62% therapy and to reread it each time the prescription is renewed.
• AndroGel 1.62% should be applied and used appropriately to maximize the benefits and to minimize the risk of secondary exposure in children and women.
• Keep AndroGel 1.62% out of the reach of children.
• AndroGel 1.62% is an alcohol based product and is flammable; therefore avoid fire, flame or smoking until the gel has dried.
• It is important to adhere to all recommended monitoring.
• Report any changes in their state of health, such as changes in urinary habits, breathing, sleep, and mood.
• AndroGel 1.62% is prescribed to meet the patient's specific needs; therefore, the patient should never share AndroGel 1.62% with anyone.
• Wait 2 hours before swimming or washing following application of AndroGel 1.62%. This will ensure that the greatest amount of AndroGel 1.62% is absorbed into their system.

Marketed by: ASCEND Therapeutics US, LLC Bridgewater, NJ 00807, USA 1-877-204-1013 © 2025 ASCEND Therapeutics US, LLC®2023AG0014

OVERDOSAGE

There is a single report of acute overdosage after parenteral administration of an approved testosterone product in the literature. This subject had serum testosterone concentrations of up to 11,400 ng/dL, which were implicated in a cerebrovascular accident. There were no reports of overdosage in the AndroGel 1.62% clinical trial.

Treatment of overdosage would consist of discontinuation of AndroGel 1.62%, washing the application site with soap and water, and appropriate symptomatic and supportive care.

Contraindications for AndroGel 1.62

• AndroGel 1.62% is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
• AndroGel 1.62% is contraindicated in women who are pregnant. AndroGel 1.62% can cause virilization of the female fetus when administered to a pregnant woman. Pregnant women need to be aware of the potential for transfer of testosterone from men treated with AndroGel 1.62%. If a pregnant woman is exposed to AndroGel 1.62%, she should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1)].

Clinical Pharmacology for AndroGel 1.62

Mechanism of Action

Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis and scrotum; the development of male hair distribution, such as facial, pubic, chest and axillary hair; laryngeal enlargement; vocal cord thickening; and alterations in body musculature and fat distribution. Testosterone and DHT are necessary for the normal development of secondary sex characteristics.

Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter's syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

Pharmacodynamics

No specific pharmacodynamic studies were conducted using AndroGel 1.62%.

Pharmacokinetics

Absorption

AndroGel 1.62% delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate normal levels (300 – 1000 ng/dL) seen in healthy men. AndroGel 1.62% provides continuous topical delivery of testosterone for 24 hours following once daily application to clean, dry, intact skin of the shoulders and upper arms. Average serum testosterone concentrations over 24 hours (Cavg) observed when AndroGel 1.62% was applied to the upper arms/shoulders were comparable to average serum testosterone concentrations (Cavg) when AndroGel 1.62% was applied using a rotation method utilizing the abdomen and upper arms/shoulders. The rotation of abdomen and upper arms/shoulders was a method used in the pivotal clinical trial [see Clinical Studies (14.1)].

Figure 2: Mean (±SD) Serum Total Testosterone Concentrations on Day 7 in Patients Following AndroGel 1.62% Once-Daily Application of 81 mg of Testosterone (N=33) for 7 Days

Distribution

Circulating testosterone is primarily bound in the serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is loosely bound to albumin and other proteins.

Metabolism

Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are estradiol and DHT.

Excretion

There is considerable variation in the half-life of testosterone concentration as reported in the literature, ranging from 10 to 100 minutes. About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic acid and sulfuric acid conjugates of testosterone and its metabolites. About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.

When AndroGel 1.62% treatment is discontinued, serum testosterone concentrations return to approximately baseline concentrations within 48-72 hours after administration of the last dose.

Potential for testosterone transfer

The potential for testosterone transfer following administration of AndroGel 1.62% when it was applied only to upper arms/shoulders was evaluated in two clinical studies of males dosed with AndroGel 1.62% and their untreated female partners. In one study, 8 male subjects applied a single dose of AndroGel 1.62% 81 mg to their shoulders and upper arms. Two (2) hours after application, female subjects rubbed their hands, wrists, arms, and shoulders to the application site of the male subjects for 15 minutes. Serum concentrations of testosterone were monitored in female subjects for 24 hours after contact occurred. After direct skin-to-skin contact with the site of application, mean testosterone Cavg and Cmax in female subjects increased by 280% and 267%, respectively, compared to mean baseline testosterone concentrations. In a second study evaluating transfer of testosterone, 12 male subjects applied a single dose of AndroGel 1.62% 81 mg to their shoulders and upper arms. Two (2) hours after application, female subjects rubbed their hands, wrists, arms, and shoulders to the application site of the male subjects for 15 minutes while the site of application was covered by a t-shirt. When a t-shirt was used to cover the site of application, mean testosterone Cavg and Cmax in female subjects increased by 6% and 11%, respectively, compared to mean baseline testosterone concentrations.

A separate study was conducted to evaluate the potential for testosterone transfer from 16 males dosed with AndroGel 1.62% 81 mg when it was applied to abdomen only for 7 days, a site of application not approved for AndroGel 1.62%. Two (2) hours after application to the males on each day, the female subjects rubbed their abdomens for 15 minutes to the abdomen of the males. The males had covered the application area with a T-shirt. The mean testosterone Cavg and Cmax in female subjects on day 1 increased by 43% and 47%, respectively, compared to mean baseline testosterone concentrations. The mean testosterone Cavg and Cmax in female subjects on day 7 increased by 60% and 58%, respectively, compared to mean baseline testosterone concentrations.

Effect of showering

In a randomized, 3-way (3 treatment periods without washout period) crossover study in 24 hypogonadal men, the effect of showering on testosterone exposure was assessed after once daily application of AndroGel 1.62% 81 mg to upper arms/shoulders for 7 days in each treatment period. On the 7th day of each treatment period, hypogonadal men took a shower with soap and water at either 2, 6, or 10 hours after drug application. The effect of showering at 2 or 6 hours post-dose on Day 7 resulted in 13% and 12% decreases in mean Cavg, respectively, compared to Day 6 when no shower was taken after drug application. Showering at 10 hours after drug application had no effect on bioavailability. The amount of testosterone remaining in the outer layers of the skin at the application site on the 7th day was assessed using a tape stripping procedure and was reduced by at least 80% after showering 2-10 hours post-dose compared to on the 6th day when no shower was taken after drug application.

Effect of hand washing

In a randomized, open-label, single-dose, 2-way crossover study in 16 healthy male subjects, the effect of hand washing on the amount of residual testosterone on the hands was evaluated. Subjects used their hands to apply the maximum dose (81 mg testosterone) of AndroGel 1.62% to their upper arms and shoulders. Within 1 minute of applying the gel, subjects either washed or did not wash their hands prior to study personnel wiping the subjects’ hands with ethanol dampened gauze pads. The gauze pads were then analyzed for residual testosterone content. A mean (SD) of 0.1 (0.04) mg of residual testosterone (0.12% of the actual applied dose of testosterone, and a 96% reduction compared to when hands were not washed) was recovered after washing hands with water and soap.

Effect of sunscreen or moisturizing lotion on absorption of testosterone

In a randomized, 3-way (3 treatment periods without washout period) crossover study in 18 hypogonadal males, the effect of applying a moisturizing lotion or a sunscreen on the absorption of testosterone was evaluated with the upper arms/shoulders as application sites. For 7 days, moisturizing lotion or sunscreen (SPF 50) was applied daily to the AndroGel 1.62% application site 1 hour after the application of AndroGel 1.62% 40.5 mg. Application of moisturizing lotion increased mean testosterone Cavg and Cmax by 14% and 17%, respectively, compared to AndroGel 1.62% administered alone. Application of sunscreen increased mean testosterone Cavg and Cmax by 8% and 13%, respectively, compared to AndroGel 1.62% applied alone.

MEDICATION GUIDE
ANDROGEL® (AN DROW JEL) CIII
(testosterone gel) 1.62% for topical use

What is the most important information I should know about ANDROGEL 1.62%?

1. ANDROGEL 1.62% can transfer from your body to others including, children and women. Children and women should avoid contact with the unwashed or not covered (unclothed) areas where ANDROGEL 1.62% has been applied to your skin. Early signs and symptoms of puberty have occurred in young children who have come in direct contact with testosterone by touching areas where men have used ANDROGEL 1.62%.
   • Children
   • Signs and symptoms of early puberty in a child when they come in direct contact with ANDROGEL 1.62% may include:
   • Abnormal sexual changes:
   • • enlarged penis or clitoris.
     • early growth of hair near the vagina or around the penis (pubic hair).
     • erections or acting out sexual urges (sex drive).
   • Behavior problems:
   • • acting aggressively, behaving in an angry or violent way.

   • Women

     Signs and symptoms in women when they come in direct contact with ANDROGEL 1.62% may include:

     • changes in body hair.
     • an abnormal increase in pimples (acne).

   Stop using ANDROGEL 1.62% and call your healthcare provider right away if you see any signs and symptoms in a child or a woman that may have happened through accidental touching of the area where you have applied ANDROGEL 1.62%.

2. To lower the risk of transfer of ANDROGEL 1.62% from your body to others, follow these important instructions:
   • Apply ANDROGEL 1.62% only to your shoulders and upper arms that will be covered by a short sleeve t-shirt.
   • Wash your hands right away with soap and water after applying ANDROGEL 1.62%.
   • After the gel has dried, cover the application area with clothing. Keep the area covered until you have washed the application area well or have showered.
   • If you expect to have skin-to-skin contact with another person, first wash the application area well with soap and water.
   • If a child or woman touches the area where you have applied ANDROGEL 1.62%, that area on the child or woman should be washed well with soap and water right away.

What is ANDROGEL 1.62%?

ANDROGEL 1.62% is a prescription medicine that contains testosterone. ANDROGEL 1.62% is used to treat adult males who have low or no testosterone due to certain medical conditions.

• Your healthcare provider will test your blood before you start and while you are using ANDROGEL 1.62%.
• It is not known if ANDROGEL 1.62% is safe or effective to treat men who have low testosterone due to aging.
• It is not known if ANDROGEL 1.62% is safe or effective in children younger than 18 years old. Improper use of ANDROGEL 1.62% may affect bone growth in children.

ANDROGEL 1.62% is a controlled substance (CIII) because it contains testosterone that can be a target for people who abuse prescription medicines. Keep your ANDROGEL 1.62% in a safe place to protect it. Never give your ANDROGEL 1.62% to anyone else, even if they have the same symptoms you have. Selling or giving away this medicine may harm others and is against the law.

ANDROGEL 1.62% is not meant for use in women.

Do not use ANDROGEL 1.62% if you:

• have breast cancer.
• have or might have prostate cancer.
• are pregnant. ANDROGEL 1.62% may harm your unborn baby.
• Women who are pregnant should avoid contact with the area of skin where ANDROGEL 1.62% has been applied.

Before using ANDROGEL 1.62%, tell your healthcare provider about all of your medical conditions, including if you:

• have breast cancer.
• have or might have prostate cancer.
• have urinary problems due to an enlarged prostate.
• have heart problems.
• have high blood pressure or are being treated for high blood pressure.
• have kidney or liver problems.
• have problems breathing while you sleep (sleep apnea).

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using ANDROGEL 1.62% with certain other medicines can affect each other. Especially, tell your healthcare provider if you take:

• insulin
• medicines that decrease blood clotting (blood thinners)
• corticosteroids

How should I use ANDROGEL 1.62%?

• See the detailed Instructions for Use about how to use ANDROGEL 1.62% at the end of this Medication Guide.
• It is important that you apply ANDROGEL 1.62% exactly as your healthcare provider tells you to.
• Your healthcare provider may change your ANDROGEL 1.62% dose. Do not change your ANDROGEL 1.62% dose without talking to your healthcare provider.
• Apply ANDROGEL 1.62% at the same time each morning. ANDROGEL 1.62% should be applied after showering or bathing.

What are the possible side effects of ANDROGEL 1.62%?

ANDROGEL 1.62% can cause serious side effects including:

See “What is the most important information I should know about ANDROGEL 1.62%?”

• If you already have enlargement of your prostate gland your signs and symptoms can get worse while using ANDROGEL 1.62%. This can include:
  • increased urination at night.
  • trouble starting your urine stream.
  • having to pass urine many times during the day.
  • having an urge to go to the bathroom right away.
  • having a urine accident.
  • being unable to pass urine or weak urine flow.
• Possible increased risk of prostate cancer. Your healthcare provider should check you for prostate cancer or any other prostate problems before you start and while you use ANDROGEL 1.62%.
• Blood clots in the legs or lungs. Signs and symptoms of a blood clot in your leg can include leg pain, swelling, or redness. Signs and symptoms of a blood clot in your lungs can include difficulty breathing or chest pain.
• Increase in blood pressure. AndroGel 1.62% can increase your blood pressure. Increases in blood pressure can increase the risk of heart attack or stroke over time. If your blood pressure increases while on AndroGel 1.62%, blood pressure medicines may need to be started. If you are taking blood pressure medicines, new blood pressure medicines may need to be added or your current blood pressure medicines may need to be adjusted to control your blood pressure. If your blood pressure cannot be controlled, AndroGel 1.62% may need to be stopped. Your healthcare provider will monitor your blood pressure while you are being treated with AndroGel 1.62%.
• In large doses ANDROGEL 1.62% may lower your sperm count.
• Swelling of your ankles, feet, or body, with or without heart failure.
• Enlarged or painful breasts.
• Have problems breathing while you sleep (sleep apnea).

Call your healthcare provider right away if you have any of the serious side effects listed above.

The most common side effects of ANDROGEL 1.62% include:

• increased prostate specific antigen (a test used to screen for prostate cancer)
• mood swings
• hypertension
• increased red blood cell count
• skin irritation where ANDROGEL 1.62% is applied

Other side effects include more erections than are normal for you or erections that last a long time.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of ANDROGEL 1.62%. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of ANDROGEL 1.62%

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ANDROGEL 1.62% for a condition for which it was not prescribed. Do not give ANDROGEL 1.62% to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ANDROGEL 1.62% that is written for health professionals.

What are the ingredients in ANDROGEL 1.62%?

Active ingredient: testosterone

Inactive ingredients: carbopol 980, ethyl alcohol, isopropyl myristate, purified water and sodium hydroxide.

Marketed by: ASCEND Therapeutics US, LLC, Bridgewater, NJ 00807, USA © Year ASCEND Therapeutics US, LLC For more information about ANDROGEL 1.62%, call 1-877-204-1013 or go to www.androgel.com.

This Medication Guide has been approved by the U.S. Food and Drug Administration

INSTRUCTIONS FOR USE
ANDROGEL® (AN DROW JEL) CIII
(testosterone gel) 1.62% for topical use

Read this Instructions for Use for ANDROGEL1.62% before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment.

Applying ANDROGEL 1.62%:

• ANDROGEL 1.62% comes in a pump or in packets.
• Before applying ANDROGEL 1.62% make sure that your shoulders and upper arms are clean, dry, and that there is no broken skin.
• ANDROGEL 1.62% is to be applied to the area of your shoulders and upper arms that will be covered by a short sleeve t-shirt (See Figure A). Do not apply ANDROGEL 1.62% to any other parts of your body such as your stomach area (abdomen), penis, scrotum, chest, armpits (axillae), or knees.

If you are using ANDROGEL 1.62% pump:

• Before using a new bottle of ANDROGEL 1.62 % for the first time, you will need to remove the cap and then prime the pump. To prime the ANDROGEL 1.62% pump, slowly push the pump all the way down 3 times, over the sink drain. Do not use any ANDROGEL 1.62% that came out while priming. Wash it down the sink to avoid accidental exposure to others. Your ANDROGEL 1.62% pump is now ready to use.
• Remove the cap from the pump. Then, put the spout opening at the top of the pump where the medicine comes out over the palm of your hand and slowly push the pump all the way down. Apply ANDROGEL 1.62% to the application site. You may also apply ANDROGEL 1.62% directly to the application site. Your healthcare provider will tell you the number of times to press the pump for each dose.
• Wash your hands with soap and water right away.

Find Your Dose as Prescribed by Your Healthcare Provider		Application Method
1 pump	20.25 mg	Apply 1 pump of ANDROGEL 1.62% to 1 upper arm and shoulder.
2 pumps	40.5 mg	Apply 1 pump of ANDROGEL 1.62% to 1 upper arm and shoulder and then apply 1 pump of ANDROGEL 1.62% to the opposite upper arm and shoulder.
3 pumps	60.75 mg	Apply 2 pumps of ANDROGEL 1.62% to 1 upper arm and shoulder and then apply 1 pump of ANDROGEL 1.62% to the opposite upper arm and shoulder.
4 pumps	81 mg	Apply 2 pumps of ANDROGEL 1.62% to 1 upper arm and shoulder and then apply 2 pumps of ANDROGEL 1.62% to the opposite upper arm and shoulder.

If you are using ANDROGEL 1.62% packets:

• Tear open the packet completely at the dotted line. Squeeze from the bottom of the packet to the top.
• Squeeze all of the ANDROGEL 1.62% out of the packet into the palm of your hand.
• Apply ANDROGEL 1.62% to the application site. You may also apply ANDROGEL 1.62% directly to the application site.
• Let the application site dry completely before putting on a t-shirt.
• ANDROGEL 1.62% is flammable until dry. Let ANDROGEL 1.62% dry before smoking or going near an open flame.
• Avoid showering, swimming or bathing for at least 2 hours after you apply ANDROGEL 1.62%.
• Wash your hands right away with soap and water after applying ANDROGEL 1.62%.

Find Your Dose as Prescribed by Your Healthcare Provider		Application Method
One 20.25 mg packet	20.25 mg	Apply 1 packet of ANDROGEL 1.62% to 1 upper arm and shoulder.
One 40.5 mg packet	40.5 mg	Apply half of the 40.5 mg packet of ANDROGEL 1.62% to 1 upper arm and shoulder and then apply the remaining packet contents to the opposite upper arm and shoulder.
One 40.5 mg packet and one 20.25 mg packet	60.75 mg	Apply one 40.5 mg packet of ANDROGEL 1.62% to 1 upper arm and shoulder and then apply one 20.25 mg packet of ANDROGEL 1.62% to the opposite upper arm and shoulder.
Two 40.5 mg packets	81 mg	Apply one 40.5 mg packet of ANDROGEL 1.62% to 1 upper arm and shoulder and then apply one 40.5 mg packet of ANDROGEL 1.62% to the opposite upper arm and shoulder.

How should I store ANDROGEL 1.62%?

• Store ANDROGEL 1.62% at room temperature between 68ºF to 77ºF (20ºC to 25ºC).
• When it is time to throw away the pump or packets, safely throw away used ANDROGEL 1.62% in the household trash. Be careful to prevent accidental exposure of children or pets.
• Keep ANDROGEL 1.62% away from fire.

Keep ANDROGEL 1.62% and all medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.