These Highlights Do Not Include All The Information Needed To Use Testosterone Gel Safely And Effectively. See Full Prescribing Information For Testosterone Gel.

Dose Adjustment

To ensure proper dosing, serum testosterone concentrations should be measured. Morning, pre-dose serum testosterone concentrations should be measured approximately 14 days after initiation of therapy to ensure proper serum testosterone concentrations are achieved. If the serum testosterone concentration is below the normal range (300 ng/dL to 1,000 ng/dL), the daily testosterone gel dose may be increased from 50 mg testosterone (one tube, one packet, or 4 pump actuations) to 100 mg of testosterone (two tubes, two packets, or 8 pump actuations) once daily.

The maximum recommended dose of testosterone gel is 100 mg once daily.

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.

Androgens, including testosterone gel, 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. In addition to discontinuation of the drug, diuretic therapy may be required.

Changes in the serum lipid profile may occur. Monitor the lipid profile periodically, particularly after starting testosterone therapy and after any dose increases.

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 necessitate a decrease in the dose of anti-diabetic medication.

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.]

There were no reports of overdose in the testosterone gel clinical trials. There is a single report in the literature of acute overdosage after injection of testosterone enanthate. This subject had serum testosterone concentrations of up to 11,400 ng/dL, which were implicated in a cerebrovascular accident.

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

Testosterone gel, for topical use is a clear to translucent hydroalcoholic topical gel containing testosterone, an androgen. Testosterone gel provides continuous transdermal delivery of testosterone for 24 hours, following a single application to intact, clean, dry skin of the shoulders and/or upper arms.

Testosterone gel is available in unit-dose tubes, unit-dose packets, and a metered-dose pump. One 5-g or two 5-g tubes/packets of testosterone gel contains 50 mg or 100 mg of testosterone, respectively. One pump actuation dispenses 1.25 g of gel, which contains 12.5 mg of testosterone. Four pump actuations or eight pump actuations contain 50 mg or 100 mg of testosterone, respectively. Each metered-dose pump container is capable of dispensing 60 pump actuations.

The active pharmacological ingredient in testosterone gel is testosterone. Testosterone USP is a white to practically white crystalline powder chemically described as 17-β hydroxyandrost-4-en-3-one. The structural formula is shown in the following figure:

Inactive ingredients in testosterone gel are carbomer copolymer Type B, carbomer homopolymer Type C, diisopropyl adipate, ethyl alcohol, glycerin, methyl laurate, oleyl alcohol, polyethylene glycol, propylene glycol, purified water, and tromethamine.

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.

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.

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

Testosterone gel is supplied in unit-dose tubes in cartons of 30 and unit-dose packets in cartons of 30. Each tube or packet contains 50 mg testosterone in 5 g of gel.

Testosterone gel is also supplied in a metered-dose pump that delivers 12.5 mg of testosterone per complete pump actuation. Each 88 g metered-dose pump is capable of dispensing 75 g of gel or 60-metered pump actuations. Each pump actuation delivers 1.25 g of gel. The metered-dose pump is supplied in cartons of 2.

Testosterone gel is available as follows:

Gynecomastia occasionally develops and occasionally persists in patients being treated for hypogonadism [see Adverse Reactions (6.1)] .

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

The safety and efficacy of testosterone gel in pediatric patients less than 18 years old have not been established. Improper use may result in acceleration of bone age and premature closure of epiphyses.

There is insufficient long-term safety data in geriatric patients to assess the potentially increased risks of cardiovascular disease and prostate cancer [see Warnings and Precautions (5.1)] .

Androgens, including testosterone gel, 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.

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

• Most common adverse reactions (incidence ≥ 2% of the testosterone gel patients and greater than placebo) are application site reactions and increased hematocrit. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact UPSHER-SMITH LABORATORIES, LLC at 1-855-899-9180 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• Androgens may decrease blood glucose and therefore may decrease insulin requirements in diabetic patients. ( 7.1)
• Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of International Normalized Ratio (INR) and prothrombin time is recommended in patients taking warfarin. ( 7.2)
• Use of testosterone with corticosteroids may result in increased fluid retention. Use with caution, particularly in patients with cardiac, renal or hepatic disease. ( 7.3)

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

No studies were conducted in patients with renal impairment.

Read this Instructions for Use for testosterone gel 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 Testosterone gel:

Testosterone gel comes in tubes, packets, or in a pump.

• Before applying testosterone gel, make sure that your shoulders and upper arms are clean, dry, and there is no broken skin.
• The application sites for testosterone gel are the shoulders and the upper arms that will be covered by a short sleeve t-shirt (See Figure A). Do notapply testosterone gel to any other parts of your body such as your penis, scrotum, or stomach area (abdomen).

If you are using testosterone gel tubes:

• Remove the cap from the tube and use the top of the cap to puncture the metal seal on the top of the tube.
• Squeeze from the bottom of the tube to the top.
• Squeeze all of the testosterone gel out of the tube into the palm of your hand.
• Testosterone gel is to be applied only to the areas of your shoulders and upper arms that will be covered by a short sleeve t-shirt.
• Apply testosterone gel to the application site. Rub the gel onto your skin for several seconds.
• Testosterone gel is flammable until dry. Let testosterone gel dry before smoking or going near an open flame.
• Let the application site dry for a few minutes before putting on a t-shirt.
• Wash your hands with soap and water right away after applying testosterone gel.
• Put the cap back on the tube.
• Avoid showering, swimming, or bathing for at least 2 hours after you apply testosterone gel.

If you are using testosterone gel packets:

• Tear open the packet completely at the notch on the top edge. Squeeze from the bottom of the packet to the top.
• Squeeze all of the testosterone gel out of the packet into the palm of your hand. Apply testosterone gel to the application site. Rub the gel onto your skin for several seconds.
• Let the application site dry for a few minutes before putting on a t-shirt.
• Wash your hands with soap and water right awayafter applying testosterone gel .

If you are using the testosterone gel pump:

• Before using a new bottle of testosterone gel for the first time, you will need to prime the pump. To prime the testosterone gel pump, remove the cap and slowly push the pump all the way down 3 times.
• Do not use any testosterone gel that came out while priming. Wash it down the sink to avoid accidental exposure to others. Your testosterone gel pump is now ready to use.
• Remove the cap from the pump. Then position the nozzle over the palm of your hand and slowly push the pump all the way down. Your healthcare provider will tell you the number of times to press the pump for each dose.
• Apply testosterone gel to the application site. Rub the gel onto your skin for several seconds.
• Let the application site dry for a few minutes before putting on a t-shirt.
• Wash your hands with soap and water right away.
• Put the cap back on the pump.

How should I store testosterone gel?

• Store testosterone gel at room temperature between 68° to 77°F (20° to 25°C).
• Safely throw away used testosterone gel containers in the household trash. Be careful to prevent accidental exposure of children or pets.
• Keep testosterone gel away from fire.

Keep testosterone gel and all medicines out of the reach of children.

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

Revised 5/2020

No specific pharmacodynamic studies were conducted using testosterone gel.

In a single-dose, replicate crossover clinical study evaluating 58 hypogonadal males, the serum testosterone exposures (AUC _0-24and AUC _0-t) and maximum testosterone concentration (C _max) following a topical administration of 100 mg testosterone administration as a 2 × 5 g testosterone gel tubes (applied to the shoulders/upper arms) were bioequivalent to those following a topical administration of an approved testosterone gel product.

No studies were conducted in patients with hepatic impairment.

Testosterone gel is indicated for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone:

• Primary hypogonadism (congenital or acquired): testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter's syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone levels and gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) above the normal range.
• Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum levels but have gonadotropins in the normal or low range.

Limitations of Use:

• Safety and efficacy of testosterone gel in men with "age-related hypogonadism" (also referred to as "late-onset hypogonadism") have not been established.
• Safety and efficacy of testosterone gel in males less than 18 years old have not been established [see Use in Specific Populations (8.4)] .
• Topical testosterone products may have different doses, strengths, or application instructions that may result in different systemic exposure [see Dosage and Administration (2)and Clinical Pharmacology (12.3)] .

Long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of testosterone replacement therapy in men. To date, epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of major adverse cardiovascular events (MACE), such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the use of testosterone compared to non-use. Some studies, but not all, have reported an increased risk of MACE in association with use of testosterone replacement therapy in men. Patients should be informed of this possible risk when deciding whether to use or to continue to use testosterone gel.

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 warfarin, especially at the initiation and termination of androgen therapy.

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 the 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.

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).

Testosterone gel contains testosterone, a Schedule III controlled substance in the Controlled Substances Act.

Used testosterone gel tubes, packets or pumps should be discarded in household trash in a manner that prevents accidental exposure of women, children, or pets [see Boxed Warningand Warnings and Precautions (5.2)] . Contents are flammable [see Warnings and Precautions (5.16)] .

• Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH. ( 5.1)
• Avoid unintentional exposure of women or children to testosterone gel. Secondary exposure to testosterone can produce signs of virilization. Testosterone gel should be discontinued until the cause of virilization is identified. ( 5.2)
• Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), have been reported in patients using testosterone products. Evaluate patients with signs or symptoms consistent with DVT or PE. ( 5.4)
• Some postmarketing studies have shown an increased risk of myocardial infarction and stroke associated with use of testosterone replacement therapy. ( 5.5)
• Exogenous administration of androgens may lead to azoospermia. ( 5.8)
• Edema, with or without congestive heart failure, may be a complication in patients with preexisting cardiac, renal, or hepatic disease. ( 5.10)
• Sleep apnea may occur in those with risk factors. ( 5.12)
• Monitor prostate specific antigen (PSA), hematocrit, and lipid concentrations periodically. ( 5.1, 5.3, 5.13)
• Testosterone gel is flammable until dry. ( 5.16)

There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products, such as testosterone gel. Evaluate patients who report signs and 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 testosterone gel and initiate appropriate workup and management [see Adverse Reactions (6.2)] .

Prior to initiating testosterone gel, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these serum testosterone concentrations are below the normal range.

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, which elevate blood levels for prolonged periods, has produced multiple hepatic adenomas. Testosterone gel is not known to produce these adverse effects. Nonetheless, patients should be instructed to report any signs or symptoms of hepatic dysfunction (e.g., jaundice). If these occur, promptly discontinue testosterone gel while the cause is evaluated.

Testosterone gel is a clear to translucent hydroalcoholic topical gel for topical use available in unit-dose tubes, unit-dose packets, and multiple-dose metered pumps. Each tube or packet provides 50 mg testosterone in 5 g of gel. One pump actuation delivers 12.5 mg testosterone in 1.25 g of gel (4 actuations = 50 mg testosterone).

The following adverse reactions have been identified during post-approval use of testosterone gel products. 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.

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.

In a controlled clinical study, 304 patients were treated with testosterone gel 50 mg or 100 mg or placebo gel for up to 90 days. Two hundred-five (205) patients received testosterone gel 50 mg or 100 mg daily and 99 patients received placebo. Subjects could be counted in both testosterone gel treatment groups if they received both 50 mg and 100 mg at different points in the study and experienced an adverse reaction at both dose levels. Adverse reactions reported by ≥1% of the testosterone gel patients and greater than placebo are listed in Table 3.

The following adverse reactions occurred in fewer than 1% of patients but were greater in testosterone gel groups compared to the placebo group: activated partial thromboplastin time prolonged, blood creatinine increased, prothrombin time prolonged, appetite increased, sensitive nipples, and acne.

In this clinical trial of testosterone gel, six patients had adverse events that led to their discontinuation. These events included: depression with suicidal ideation, urinary tract infection, mood swings and hypertension. No testosterone gel patients discontinued due to skin reaction. In one foreign Phase 3 trial, one subject discontinued due to a skin-related adverse event.

In the pivotal U.S. and European Phase 3 trials combined, at the 50 mg dosage strength, the percentage of subjects reporting clinically notable increases in hematocrit or hemoglobin were similar to placebo. However, in the 100 mg dose group, 2.3% and 2.8% of patients had a clinically notable increase in hemoglobin (≥ 19 g/dL) or hematocrit (≥ 58%), respectively, compared to 1.0% and 1.5% of patients in the placebo group, respectively.

In the combined U.S. and European open label extension studies, approximately 140 patients received testosterone gel for at least 6 months. The results from these studies are consistent with those reported for the U.S. controlled clinical trial.

Geriatric Patients: There are insufficient long-term safety data to assess the potential risks of cardiovascular disease and prostate cancer. ( 8.5)

The recommended starting dose of testosterone gel is 50 mg of testosterone (one tube, one packet, or 4 pump actuations) applied topically once daily at approximately the same time each day to clean, dry intact skin of the shoulders and/or upper arms.

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

Testosterone gel was evaluated in a randomized multicenter, multi-dose, active and placebo controlled 90-day study in 406 adult males with morning testosterone levels ≤300 ng/dL. The study was double-blind for the doses of testosterone gel and placebo, but open label for the non-scrotal testosterone transdermal system. During the first 60 days, patients were evenly randomized to testosterone gel 50 mg, testosterone gel 100 mg, placebo gel, or testosterone transdermal system. At Day 60, patients receiving testosterone gel were maintained at the same dose, or were titrated up or down within their treatment group, based on 24-hour averaged serum testosterone concentration levels obtained on Day 30.

Of 192 hypogonadal men who were appropriately titrated with testosterone gel and who had sufficient data for analysis, 74% achieved an average serum testosterone level within the normal range (300 to 1,000 ng/dL) on treatment Day 90.

Table 4 summarizes the mean testosterone concentrations on Day 30 for patients receiving testosterone gel 50 mg or 100 mg.

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

NDC 0832-1120-05

Testosterone Gel

50 mg testosterone per tube

Each unit-dose tube

contains 5 grams of gel.

CIII

For topical use only.

Topical testosterone products may have different doses, strengths,

or application instructions that may result in different systemic exposure.

To be applied to the shoulders and upper arms.

PHARMACIST: Dispense the Medication Guide provided separately

to each patient.

Contains 30 Unit-dose Tubes

Rx only

UPSHER-SMITH

• Virilization has been reported in children who were secondarily exposed to testosterone gel [see Warnings and Precautions (5.2)and Adverse Reactions (6.2)] .
• Children should avoid contact with unwashed or unclothed application sites in men using testosterone gel [see Dosage and Administration (2.2)and Warnings and Precautions (5.2)] .
• Healthcare providers should advise patients to strictly adhere to recommended instructions for use [see Dosage and Administration (2.2), Warnings and Precautions (5.2)and Patient Counseling Information (17)] .

NDC 0832-1121-42

Testosterone Gel

12.5 mg of testosterone

per pump actuation*

*Each actuation delivers

1.25 grams of gel.

Multi-dose pump capable of

dispensing 60 metered

pump actuations.

CIII

For topical use only.

Topical testosterone products may have different

doses, strengths, or application instructions that

may result in different systemic exposure.

To be applied to the shoulders and upper arms.

PHARMACIST: Dispense the Medication Guide

provided separately to each patient.

2 canisters containing 88 grams each

Rx only

UPSHER-SMITH

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 testosterone gel [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.

With large doses of exogenous androgens, including testosterone gel, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) which could possibly lead to adverse effects on semen parameters including sperm count.

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.

• Men 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)].

Dose Adjustment

To ensure proper dosing, serum testosterone concentrations should be measured. Morning, pre-dose serum testosterone concentrations should be measured approximately 14 days after initiation of therapy to ensure proper serum testosterone concentrations are achieved. If the serum testosterone concentration is below the normal range (300 ng/dL to 1,000 ng/dL), the daily testosterone gel dose may be increased from 50 mg testosterone (one tube, one packet, or 4 pump actuations) to 100 mg of testosterone (two tubes, two packets, or 8 pump actuations) once daily.

The maximum recommended dose of testosterone gel is 100 mg once daily.

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.

Androgens, including testosterone gel, 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. In addition to discontinuation of the drug, diuretic therapy may be required.

Changes in the serum lipid profile may occur. Monitor the lipid profile periodically, particularly after starting testosterone therapy and after any dose increases.

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 necessitate a decrease in the dose of anti-diabetic medication.

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.]

There were no reports of overdose in the testosterone gel clinical trials. There is a single report in the literature of acute overdosage after injection of testosterone enanthate. This subject had serum testosterone concentrations of up to 11,400 ng/dL, which were implicated in a cerebrovascular accident.

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

Testosterone gel, for topical use is a clear to translucent hydroalcoholic topical gel containing testosterone, an androgen. Testosterone gel provides continuous transdermal delivery of testosterone for 24 hours, following a single application to intact, clean, dry skin of the shoulders and/or upper arms.

Testosterone gel is available in unit-dose tubes, unit-dose packets, and a metered-dose pump. One 5-g or two 5-g tubes/packets of testosterone gel contains 50 mg or 100 mg of testosterone, respectively. One pump actuation dispenses 1.25 g of gel, which contains 12.5 mg of testosterone. Four pump actuations or eight pump actuations contain 50 mg or 100 mg of testosterone, respectively. Each metered-dose pump container is capable of dispensing 60 pump actuations.

The active pharmacological ingredient in testosterone gel is testosterone. Testosterone USP is a white to practically white crystalline powder chemically described as 17-β hydroxyandrost-4-en-3-one. The structural formula is shown in the following figure:

Inactive ingredients in testosterone gel are carbomer copolymer Type B, carbomer homopolymer Type C, diisopropyl adipate, ethyl alcohol, glycerin, methyl laurate, oleyl alcohol, polyethylene glycol, propylene glycol, purified water, and tromethamine.

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.

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.

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

Testosterone gel is supplied in unit-dose tubes in cartons of 30 and unit-dose packets in cartons of 30. Each tube or packet contains 50 mg testosterone in 5 g of gel.

Testosterone gel is also supplied in a metered-dose pump that delivers 12.5 mg of testosterone per complete pump actuation. Each 88 g metered-dose pump is capable of dispensing 75 g of gel or 60-metered pump actuations. Each pump actuation delivers 1.25 g of gel. The metered-dose pump is supplied in cartons of 2.

Testosterone gel is available as follows:

Gynecomastia occasionally develops and occasionally persists in patients being treated for hypogonadism [see Adverse Reactions (6.1)] .

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

The safety and efficacy of testosterone gel in pediatric patients less than 18 years old have not been established. Improper use may result in acceleration of bone age and premature closure of epiphyses.

There is insufficient long-term safety data in geriatric patients to assess the potentially increased risks of cardiovascular disease and prostate cancer [see Warnings and Precautions (5.1)] .

Androgens, including testosterone gel, 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.

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

• Most common adverse reactions (incidence ≥ 2% of the testosterone gel patients and greater than placebo) are application site reactions and increased hematocrit. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact UPSHER-SMITH LABORATORIES, LLC at 1-855-899-9180 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• Androgens may decrease blood glucose and therefore may decrease insulin requirements in diabetic patients. ( 7.1)
• Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of International Normalized Ratio (INR) and prothrombin time is recommended in patients taking warfarin. ( 7.2)
• Use of testosterone with corticosteroids may result in increased fluid retention. Use with caution, particularly in patients with cardiac, renal or hepatic disease. ( 7.3)

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

No studies were conducted in patients with renal impairment.

Read this Instructions for Use for testosterone gel 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 Testosterone gel:

Testosterone gel comes in tubes, packets, or in a pump.

• Before applying testosterone gel, make sure that your shoulders and upper arms are clean, dry, and there is no broken skin.
• The application sites for testosterone gel are the shoulders and the upper arms that will be covered by a short sleeve t-shirt (See Figure A). Do notapply testosterone gel to any other parts of your body such as your penis, scrotum, or stomach area (abdomen).

If you are using testosterone gel tubes:

• Remove the cap from the tube and use the top of the cap to puncture the metal seal on the top of the tube.
• Squeeze from the bottom of the tube to the top.
• Squeeze all of the testosterone gel out of the tube into the palm of your hand.
• Testosterone gel is to be applied only to the areas of your shoulders and upper arms that will be covered by a short sleeve t-shirt.
• Apply testosterone gel to the application site. Rub the gel onto your skin for several seconds.
• Testosterone gel is flammable until dry. Let testosterone gel dry before smoking or going near an open flame.
• Let the application site dry for a few minutes before putting on a t-shirt.
• Wash your hands with soap and water right away after applying testosterone gel.
• Put the cap back on the tube.
• Avoid showering, swimming, or bathing for at least 2 hours after you apply testosterone gel.

If you are using testosterone gel packets:

• Tear open the packet completely at the notch on the top edge. Squeeze from the bottom of the packet to the top.
• Squeeze all of the testosterone gel out of the packet into the palm of your hand. Apply testosterone gel to the application site. Rub the gel onto your skin for several seconds.
• Let the application site dry for a few minutes before putting on a t-shirt.
• Wash your hands with soap and water right awayafter applying testosterone gel .

If you are using the testosterone gel pump:

• Before using a new bottle of testosterone gel for the first time, you will need to prime the pump. To prime the testosterone gel pump, remove the cap and slowly push the pump all the way down 3 times.
• Do not use any testosterone gel that came out while priming. Wash it down the sink to avoid accidental exposure to others. Your testosterone gel pump is now ready to use.
• Remove the cap from the pump. Then position the nozzle over the palm of your hand and slowly push the pump all the way down. Your healthcare provider will tell you the number of times to press the pump for each dose.
• Apply testosterone gel to the application site. Rub the gel onto your skin for several seconds.
• Let the application site dry for a few minutes before putting on a t-shirt.
• Wash your hands with soap and water right away.
• Put the cap back on the pump.

How should I store testosterone gel?

• Store testosterone gel at room temperature between 68° to 77°F (20° to 25°C).
• Safely throw away used testosterone gel containers in the household trash. Be careful to prevent accidental exposure of children or pets.
• Keep testosterone gel away from fire.

Keep testosterone gel and all medicines out of the reach of children.

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

Revised 5/2020

No specific pharmacodynamic studies were conducted using testosterone gel.

In a single-dose, replicate crossover clinical study evaluating 58 hypogonadal males, the serum testosterone exposures (AUC _0-24and AUC _0-t) and maximum testosterone concentration (C _max) following a topical administration of 100 mg testosterone administration as a 2 × 5 g testosterone gel tubes (applied to the shoulders/upper arms) were bioequivalent to those following a topical administration of an approved testosterone gel product.

No studies were conducted in patients with hepatic impairment.

Testosterone gel is indicated for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone:

• Primary hypogonadism (congenital or acquired): testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter's syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone levels and gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) above the normal range.
• Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum levels but have gonadotropins in the normal or low range.

Limitations of Use:

• Safety and efficacy of testosterone gel in men with "age-related hypogonadism" (also referred to as "late-onset hypogonadism") have not been established.
• Safety and efficacy of testosterone gel in males less than 18 years old have not been established [see Use in Specific Populations (8.4)] .
• Topical testosterone products may have different doses, strengths, or application instructions that may result in different systemic exposure [see Dosage and Administration (2)and Clinical Pharmacology (12.3)] .

Long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of testosterone replacement therapy in men. To date, epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of major adverse cardiovascular events (MACE), such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the use of testosterone compared to non-use. Some studies, but not all, have reported an increased risk of MACE in association with use of testosterone replacement therapy in men. Patients should be informed of this possible risk when deciding whether to use or to continue to use testosterone gel.

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 warfarin, especially at the initiation and termination of androgen therapy.

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 the 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.

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).

Testosterone gel contains testosterone, a Schedule III controlled substance in the Controlled Substances Act.

Used testosterone gel tubes, packets or pumps should be discarded in household trash in a manner that prevents accidental exposure of women, children, or pets [see Boxed Warningand Warnings and Precautions (5.2)] . Contents are flammable [see Warnings and Precautions (5.16)] .

• Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH. ( 5.1)
• Avoid unintentional exposure of women or children to testosterone gel. Secondary exposure to testosterone can produce signs of virilization. Testosterone gel should be discontinued until the cause of virilization is identified. ( 5.2)
• Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), have been reported in patients using testosterone products. Evaluate patients with signs or symptoms consistent with DVT or PE. ( 5.4)
• Some postmarketing studies have shown an increased risk of myocardial infarction and stroke associated with use of testosterone replacement therapy. ( 5.5)
• Exogenous administration of androgens may lead to azoospermia. ( 5.8)
• Edema, with or without congestive heart failure, may be a complication in patients with preexisting cardiac, renal, or hepatic disease. ( 5.10)
• Sleep apnea may occur in those with risk factors. ( 5.12)
• Monitor prostate specific antigen (PSA), hematocrit, and lipid concentrations periodically. ( 5.1, 5.3, 5.13)
• Testosterone gel is flammable until dry. ( 5.16)

There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products, such as testosterone gel. Evaluate patients who report signs and 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 testosterone gel and initiate appropriate workup and management [see Adverse Reactions (6.2)] .

Prior to initiating testosterone gel, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these serum testosterone concentrations are below the normal range.

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, which elevate blood levels for prolonged periods, has produced multiple hepatic adenomas. Testosterone gel is not known to produce these adverse effects. Nonetheless, patients should be instructed to report any signs or symptoms of hepatic dysfunction (e.g., jaundice). If these occur, promptly discontinue testosterone gel while the cause is evaluated.

Testosterone gel is a clear to translucent hydroalcoholic topical gel for topical use available in unit-dose tubes, unit-dose packets, and multiple-dose metered pumps. Each tube or packet provides 50 mg testosterone in 5 g of gel. One pump actuation delivers 12.5 mg testosterone in 1.25 g of gel (4 actuations = 50 mg testosterone).

The following adverse reactions have been identified during post-approval use of testosterone gel products. 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.

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.

In a controlled clinical study, 304 patients were treated with testosterone gel 50 mg or 100 mg or placebo gel for up to 90 days. Two hundred-five (205) patients received testosterone gel 50 mg or 100 mg daily and 99 patients received placebo. Subjects could be counted in both testosterone gel treatment groups if they received both 50 mg and 100 mg at different points in the study and experienced an adverse reaction at both dose levels. Adverse reactions reported by ≥1% of the testosterone gel patients and greater than placebo are listed in Table 3.

The following adverse reactions occurred in fewer than 1% of patients but were greater in testosterone gel groups compared to the placebo group: activated partial thromboplastin time prolonged, blood creatinine increased, prothrombin time prolonged, appetite increased, sensitive nipples, and acne.

In this clinical trial of testosterone gel, six patients had adverse events that led to their discontinuation. These events included: depression with suicidal ideation, urinary tract infection, mood swings and hypertension. No testosterone gel patients discontinued due to skin reaction. In one foreign Phase 3 trial, one subject discontinued due to a skin-related adverse event.

In the pivotal U.S. and European Phase 3 trials combined, at the 50 mg dosage strength, the percentage of subjects reporting clinically notable increases in hematocrit or hemoglobin were similar to placebo. However, in the 100 mg dose group, 2.3% and 2.8% of patients had a clinically notable increase in hemoglobin (≥ 19 g/dL) or hematocrit (≥ 58%), respectively, compared to 1.0% and 1.5% of patients in the placebo group, respectively.

In the combined U.S. and European open label extension studies, approximately 140 patients received testosterone gel for at least 6 months. The results from these studies are consistent with those reported for the U.S. controlled clinical trial.

Geriatric Patients: There are insufficient long-term safety data to assess the potential risks of cardiovascular disease and prostate cancer. ( 8.5)

The recommended starting dose of testosterone gel is 50 mg of testosterone (one tube, one packet, or 4 pump actuations) applied topically once daily at approximately the same time each day to clean, dry intact skin of the shoulders and/or upper arms.

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

Testosterone gel was evaluated in a randomized multicenter, multi-dose, active and placebo controlled 90-day study in 406 adult males with morning testosterone levels ≤300 ng/dL. The study was double-blind for the doses of testosterone gel and placebo, but open label for the non-scrotal testosterone transdermal system. During the first 60 days, patients were evenly randomized to testosterone gel 50 mg, testosterone gel 100 mg, placebo gel, or testosterone transdermal system. At Day 60, patients receiving testosterone gel were maintained at the same dose, or were titrated up or down within their treatment group, based on 24-hour averaged serum testosterone concentration levels obtained on Day 30.

Of 192 hypogonadal men who were appropriately titrated with testosterone gel and who had sufficient data for analysis, 74% achieved an average serum testosterone level within the normal range (300 to 1,000 ng/dL) on treatment Day 90.

Table 4 summarizes the mean testosterone concentrations on Day 30 for patients receiving testosterone gel 50 mg or 100 mg.

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

NDC 0832-1120-05

Testosterone Gel

50 mg testosterone per tube

Each unit-dose tube

contains 5 grams of gel.

CIII

For topical use only.

Topical testosterone products may have different doses, strengths,

or application instructions that may result in different systemic exposure.

To be applied to the shoulders and upper arms.

PHARMACIST: Dispense the Medication Guide provided separately

to each patient.

Contains 30 Unit-dose Tubes

Rx only

UPSHER-SMITH

• Virilization has been reported in children who were secondarily exposed to testosterone gel [see Warnings and Precautions (5.2)and Adverse Reactions (6.2)] .
• Children should avoid contact with unwashed or unclothed application sites in men using testosterone gel [see Dosage and Administration (2.2)and Warnings and Precautions (5.2)] .
• Healthcare providers should advise patients to strictly adhere to recommended instructions for use [see Dosage and Administration (2.2), Warnings and Precautions (5.2)and Patient Counseling Information (17)] .

NDC 0832-1121-42

Testosterone Gel

12.5 mg of testosterone

per pump actuation*

*Each actuation delivers

1.25 grams of gel.

Multi-dose pump capable of

dispensing 60 metered

pump actuations.

CIII

For topical use only.

Topical testosterone products may have different

doses, strengths, or application instructions that

may result in different systemic exposure.

To be applied to the shoulders and upper arms.

PHARMACIST: Dispense the Medication Guide

provided separately to each patient.

2 canisters containing 88 grams each

Rx only

UPSHER-SMITH

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 testosterone gel [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.

With large doses of exogenous androgens, including testosterone gel, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) which could possibly lead to adverse effects on semen parameters including sperm count.

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.

• Men 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)].