Important limitations of use — Safety and efficacy of AXIRON in males <18 years old have not been established [see Use in Specific Populations (8.4)].

2.1 Dosing and Dose Adjustment

The recommended starting dose of AXIRON (testosterone) topical solution is 60 mg of testosterone (2 pump actuations) applied once daily.

To ensure proper dosing, serum testosterone concentrations should be measured after initiation of therapy to ensure that the desired concentrations (300 ng/dL-1050 ng/dL) are achieved. The AXIRON dose can be adjusted based on the serum testosterone concentration from a single blood draw 2 – 8 hours after applying AXIRON and at least 14 days after starting treatment or following dose adjustment.

If the measured serum testosterone concentration is below 300 ng/dL, the daily testosterone dose may be increased from 60 mg (2 pump actuations) to 90 mg (3 pump actuations) or from 90 mg to 120 mg (4 pump actuations). If the serum testosterone concentration exceeds 1050 ng/dL, the daily testosterone dose should be decreased from 60 mg (2 pump actuations) to 30 mg (1 pump actuation) as instructed by a physician. If the serum testosterone concentration consistently exceeds 1050 ng/dL at the lowest daily dose of 30 mg (1 pump actuation), AXIRON therapy should be discontinued.

The application site and dose of AXIRON are not interchangeable with other topical testosterone products.

2.2 Administration Instructions

AXIRON is applied to the axilla, preferably at the same time each morning, to clean, dry, intact skin. Do not apply AXIRON to other parts of the body including to the scrotum, penis, abdomen, shoulders or upper arms. After applying the solution, the application site should be allowed to dry completely prior to dressing. Avoid fire, flames or smoking until the solution has dried since alcohol based products, including AXIRON, are flammable.

AXIRON is applied to the axilla using an applicator. When using AXIRON for the first time, patients should be instructed to prime the pump by depressing the pump three (3) times, discard any product dispensed directly into a basin, sink, or toilet and then wash the liquid away thoroughly. This priming should be done only prior to the first use of each pump. After priming, patients should completely depress the pump one time (one pump actuation) to dispense 30 mg of testosterone. To dispense the solution, position the nozzle over the applicator cup and carefully depress the pump fully once. Ensure that the liquid is directed into the cup. The cup should be filled with no more than 30 mg (1 pump actuation) of testosterone. Dosing that requires greater than one pump actuation must be applied in increments of 30 mg as is shown in Table 1.

Keeping the applicator upright, patients should place it up into the axilla and wipe steadily down and up into the axilla. If the solution drips or runs, it can be wiped back up with the applicator cup. The solution should not be rubbed into the skin with fingers or hand. The process is then repeated with application of 30 mg of testosterone (1 pump actuation) to the other axilla to achieve a total of 60 mg of testosterone applied. For patients prescribed the 90 mg dose of testosterone, the procedure is the same, but three applications are required. To dose 120 mg of testosterone, four applications are required alternating left and right for each application as shown in Table 1. When repeat application to the same axilla is required, the axilla should be allowed to dry completely before more AXIRON is applied.

After use, the applicator should be rinsed under room temperature, running water and then patted dry with a tissue. The applicator and cap are then replaced on the bottle for storage.

When deodorants or antiperspirants are used as part of a regular program for personal hygiene, they should not interfere with the efficacy of AXIRON in treating hypogonadism. If patients use an antiperspirant or deodorant (stick or roll-on) then it should be applied prior to the application of AXIRON to avoid contamination of the stick or roll-on product.

Patients should be advised to avoid swimming or washing the application site until two hours following application of AXIRON [see Clinical Pharmacology (12.3)].

To reduce the likelihood of interpersonal transfer of testosterone, the application site should always be washed prior to any skin-to-skin contact regardless of the length of time since application. [See Warnings and Precautions (5.2)].

Hands should be washed thoroughly with soap and water after AXIRON has been applied [see Warnings and Precautions (5.2)].

Strict adherence to the following precautions is advised in order to minimize the potential for secondary exposure to testosterone from AXIRON treated skin:

• Children and women should avoid contact with the unclothed or unwashed application sites on the skin of men using AXIRON.
• Patients should wash their hands immediately with soap and water after application of AXIRON.
• Patients should cover the application site(s) with clothing (e.g., a T-shirt) after the solution has dried.
• Prior to any situation in which direct skin-to-skin contact is anticipated, patients should wash the application site thoroughly with soap and water to remove any testosterone residue.
• In the event that unwashed or unclothed skin to which AXIRON has been applied comes in direct 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.

While interpersonal testosterone transfer can occur with a T-shirt on, it has been shown that transfer can be substantially reduced by wearing a T-shirt and the majority of residual testosterone is removed from the skin surface by washing with soap and water.

5.1 Worsening of Benign Prostatic Hyperplasia and Potential Risk of Prostate Cancer

• Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH.
• Patients treated with Androgens may be at increased risk for prostate cancer. Evaluate patients for prostate cancer prior to initiating treatment. It would be appropriate to reevaluate patients 3 to 6 months after initiation of treatment, and then in accordance with prostate cancer screening practices. [See Contraindications (4)].

5.2 Potential for Secondary Exposure to Testosterone

Cases of secondary exposure to testosterone in children and women have been reported with topical testosterone products applied to the abdomen or upper arms, including cases of secondary exposure resulting in virilization of children. 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. 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 AXIRON [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 should also be brought to the attention of a physician. Testosterone therapy should be promptly discontinued at least until the cause of virilization has been identified. [See Dosage and Administration (2.2)].

5.3 Polycythemia

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

5.4 Use in Women

Due to lack of controlled studies in women and potential virilizing effects, AXIRON is not indicated for use in women [see Contraindications (4) and Use in Specific Populations (8.1, 8.3)].

5.5 Potential for Adverse Effects on Spermatogenesis

At large doses of exogenous androgens, including AXIRON, 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.

5.6 Hepatic Adverse Effects

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

5.7 Edema

Androgens, including AXIRON, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease [see Adverse Reactions (6)].

5.8 Gynecomastia

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

5.9 Sleep Apnea

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

5.10 Lipids

Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy.

5.11 Hypercalcemia

Androgens, including AXIRON, 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.

5.12 Decreased Thyroxine-binding Globulin

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

5.13 Flammability

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

6.1 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.

7.1 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, insulin requirement.

7.2 Oral anticoagulants

Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of INR and prothrombin time is recommended in patients taking anticoagulants, especially at the initiation and termination of androgen therapy.

7.3 Corticosteroids

The concurrent use of testosterone with ACTH or corticosteroids may result in increased fluid retention and should be monitored cautiously, particularly in patients with cardiac, renal or hepatic disease.

8.1 Pregnancy

Pregnancy Category X [see Contraindications (4)] — AXIRON is contraindicated during pregnancy or in women who may become pregnant. Testosterone is teratogenic and may cause fetal harm. Exposure of a female fetus to androgens may result in varying degrees of virilization. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

8.3 Nursing Mothers

Although it is not known how much testosterone transfers into human milk, AXIRON is contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants. Testosterone and other androgens may adversely affect lactation. [See Contraindications (4)].

8.4 Pediatric Use

Safety and efficacy of AXIRON has not been established in males <18 years of age. Improper use may result in acceleration of bone age and premature closure of epiphyses.

8.5 Geriatric Use

There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing AXIRON to determine whether efficacy in those over 65 years of age differs from younger patients. Of the 155 patients enrolled in the pivotal clinical study utilizing AXIRON, 21 were over 65 years of age. Additionally, there were insufficient long-term safety data in these patients utilizing AXIRON to assess a potential incremental risk of cardiovascular disease and prostate cancer.

8.6 Renal Impairment

No formal studies were conducted involving patients with renal impairment.

8.7 Hepatic Impairment

No formal studies were conducted involving patients with hepatic impairment.

8.8 Use in Men with Body Mass Index (BMI) >35 kg/m2

Safety and efficacy of AXIRON in males with BMI >35 kg/m2 has not been established.

9.1 Controlled Substance

AXIRON contains testosterone, a Schedule III controlled substance as defined by the Anabolic Steroids Control Act.

9.2 Abuse

Anabolic steroids, such as testosterone, are abused. Abuse is often associated with adverse physical and psychological effects.

9.3 Dependence

Although drug dependence is not documented in individuals using therapeutic doses of anabolic steroids for approved indications, dependence is observed in some individuals abusing high doses of anabolic steroids. In general, anabolic steroid dependence is characterized by any three of the following:

• Taking more drug than intended
• Continued drug use despite medical and social problems
• Significant time spent in obtaining adequate amounts of drug
• Desire for anabolic steroids when supplies of the drug are interrupted
• Difficulty in discontinuing use of the drug despite desires and attempts to do so
• Experience of withdrawal syndrome upon discontinuation of anabolic steroid use

12.1 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, alterations in body musculature and fat distribution. Testosterone and DHT are necessary for the normal development of secondary sex characteristics. Male hypogonadism results from insufficient secretion of testosterone and is characterized by low serum testosterone concentrations. Signs/symptoms associated with male hypogonadism include erectile dysfunction and decreased sexual desire, fatigue and loss of energy, mood depression, regression of secondary sexual characteristics and osteoporosis.

Male hypogonadism 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).

12.2 Pharmacodynamics

No specific pharmacodynamic studies were conducted using AXIRON.

12.3 Pharmacokinetics

Absorption — AXIRON delivers physiologic circulating testosterone that approximate normal concentration range (i.e., 300 - 1050 ng/dL) seen in healthy men following application to the axilla.

On the skin, the ethanol and isopropyl alcohol evaporate leaving testosterone and octisalate. The skin acts as a reservoir from which testosterone is released into the systemic circulation over time (see Figure 1). In general, steady-state serum concentrations are achieved by approximately 14 days of daily dosing.

Figure 1: Mean (±SD) Serum Testosterone Concentrations on Day 7 in Patients Following AXIRON Once-Daily Application of 30 mg, 60 mg, or 90 mg of Testosterone

When AXIRON treatment is discontinued after achieving steady-state, serum testosterone concentrations returned to their pretreatment concentrations by 7 – 10 days after the last application.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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. Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays. The administration of exogenous testosterone has been reported to suppress spermatogenesis in the rat, dog and non-human primates, which was reversible on cessation of the treatment.

14.1 Clinical Studies in Hypogonadal Men

AXIRON was evaluated in a multicenter, open label, 120-day trial that enrolled 155 hypogonadal men at 26 clinical research centers. The median age of subjects was 53 years with a range of 19 – 78 years. Of the 144 subjects whose race was recorded, 122 (84.7%) were Caucasian, 13 (9.0%) were Hispanic, 6 (4.2%) were African Americans, 1 (0.7%) was Asian and 2 (1.4%) had race recorded as “Other”.

Patients were instructed to apply AXIRON to unclothed, clean, dry, and unbroken skin. The solution was applied to the axillary area. Patients were not instructed to alter their normal grooming routine, e.g., shave under the arm.

During the initial AXIRON treatment period (Days 1-15) 143 patients were treated with 60 mg of testosterone daily. On Day 45 of the trial, patients were maintained at the same dose, or were titrated up or down, based on their 24 hour average serum testosterone concentration measured on Day 15. On Day 90 of the trial, patients were maintained at the same dose, or were titrated up or down, based on their 24 hour average serum testosterone concentration measured on Day 60.

On day 120, 75% of responding patients finished the study on the starting dose of 60 mg of testosterone, while 2% had been titrated to 30 mg, 17% had been titrated to 90 mg and 6% had been titrated to the 120 mg dose.

On day 60, 84.8% of subjects had total testosterone concentrations in the normal range. Of those who had sufficient data for analysis on day 120, 84.1%, had their average serum testosterone concentration in the normal range of 300 – 1050 ng/dL.

Table 3 summarizes the proportion of subjects having average testosterone concentrations within the normal range on Days 60 and 120.

Of the 135 patients who completed the 120 day treatment, 123 patients did so with no deviation from the protocol. By day 120, average serum testosterone concentration was within normal range for 67% of those who titrated down on the 30 mg dose, 89% of those on the 60 mg dose, 86% of those who titrated up to 90 mg and 70% of those who titrated up to the 120 mg dose. Table 4 below summarizes the testosterone concentration data in the patients who completed 120 days.

Figure 2 summarizes the pharmacokinetic profiles of total testosterone in patients completing 120 days of AXIRON treatment administered as 60 mg of testosterone for the initial 15 days followed by possible titration according to follow-up testosterone measurements.

Figure 2: Mean (± SD) Steady-State Serum Testosterone Concentrations on Day 120 (30, 60, 90 or 120 mg testosterone) in Patients Who Completed 120 Days (N=135) of AXIRON Once-Daily Treatment

16.1 How Supplied

AXIRON (testosterone) topical solution is available as a metered-dose pump containing 110 mL of solution. The pump is capable of dispensing 90 mL of solution in 60 metered pump actuations. One pump actuation delivers 30 mg of testosterone in 1.5 mL of solution. Each metered-dose pump is supplied with an applicator. Neither the bottle nor the applicator cup contains latex.

NDC 54868-6406-0

16.2 Storage and Handling

Keep AXIRON out of reach of children.

Store at 25°C (77°F). Excursions are permitted to 15°C to 30°C (59°F to 86°F). See USP Controlled Room Temperature.

Used AXIRON bottles and applicators should be discarded in household trash in a manner that prevents accidental exposure of children or pets.

17.1 Use in Men with Known or Suspected Prostate or Breast Cancer

Men with known or suspected prostate or breast cancer should not use AXIRON. [See Contraindications (4) and Warnings and Precaution (5.1)].

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

Cases of secondary exposure to testosterone in children and women have been reported with topical testosterone products applied to the abdomen, shoulders or upper arms, including cases of secondary exposure resulting in virilization of children, with signs and symptoms including enlargement of the penis or clitoris, premature development of pubic hair, increased erections, aggressive behavior and advanced bone age. Inappropriate changes in genital size or premature development of pubic hair or libido in children, or changes in hair distribution, increase in acne, or other signs of testosterone effects in adult women should be brought to the attention of a physician and the possibility of secondary exposure to AXIRON also should be brought to the attention of a physician. AXIRON should be promptly discontinued at least until the cause of virilization is identified.

Strict adherence to the following precautions is advised in order to minimize the potential for secondary exposure to testosterone from AXIRON treated skin:

• AXIRON should only be applied to the axilla, not to any other part of the body.
• Children and women should avoid contact with the unwashed skin of the axilla or unclothed application sites of men where AXIRON has been applied.
• Patients should wash their hands immediately with soap and water after application of AXIRON.
• Patients should cover the axilla application site(s) with clothing (e.g., a shirt) after waiting 3 minutes for the solution to dry.
• Prior to any situation in which direct skin-to-skin contact of the axilla is anticipated, patients should wash the axilla to which AXIRON has been applied thoroughly with soap and water to remove any testosterone residue.
• In the event that unwashed or unclothed skin to which AXIRON has been applied comes in direct 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)].

17.3 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 your urine stream, passing urine many times during the day, having an urge that you have to go to the bathroom right away, having urine accident, being unable to pass urine and having a 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.

17.4 Patients Should be Advised of these Application Instructions

• The pump should be primed by depressing it 3 times prior to its first use. No priming is needed with subsequent uses of that pump.
• AXIRON should NOT be applied to the scrotum, penis, abdomen, shoulders or upper arms.
• With testosterone doses greater than 60 mg, which require two applications of AXIRON to the same axilla, the product should be allowed to dry after the first application before the second is applied.
• AXIRON should be applied once daily at approximately the same time each day. AXIRON should be applied to clean, dry skin.
• Patients may use an antiperspirant or deodorant spray before applying AXIRON. If patients use a stick or roll-on antiperspirant or deodorant, then it should be applied prior to application of AXIRON to avoid contamination of the stick or roll-on product.
• Avoid swimming or washing the application site until two hours following application of AXIRON [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].
• Avoid splashing in the eyes. In case of contact with eyes, flush thoroughly with water. If irritation persists, seek medical advice.

Distributed by:
Physicians Total Care, Inc.
Tulsa, OK    74146