Label: ANDROGEL- testosterone gel
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- Packager: AbbVie Inc.
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: CIII
- Marketing Status: New Drug Application
Updated May 22, 2019
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- BOXED WARNING(What is this?)
WARNING: SECONDARY EXPOSURE TO TESTOSTERONE
- 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)].
- HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use AndroGel 1% safely and effectively. See full prescribing information for AndroGel 1%.
AndroGel ® (testosterone gel) 1% for topical use CIII
Initial U.S. Approval: 1953
WARNING: SECONDARY EXPOSURE TO TESTOSTERONE
See full prescribing information for complete boxed warning.
- Virilization has been reported in children who were secondarily exposed to testosterone gel. (5.2, 6.2)
- Children should avoid contact with unwashed or unclothed application sites in men using testosterone gel. (2.2, 5.2)
- Healthcare providers should advise patients to strictly adhere to recommended instructions for use. (2.2, 5.2, 17)
INDICATIONS AND USAGE
AndroGel 1% is indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone:
- Primary hypogonadism (congenital or acquired). (1)
- Hypogonadotropic hypogonadism (congenital or acquired). (1)
Limitations of use:
- Safety and efficacy of AndroGel 1% in men with “age-related hypogonadism” have not been established. (1)
- Safety and efficacy of AndroGel 1% in males less than 18 years old have not been established. (8.4)
- Topical testosterone products may have different doses, strengths or application instructions that may result in different systemic exposure. (1, 12.3)
DOSAGE AND ADMINISTRATION
- Dosage and Administration for AndroGel 1% differs from AndroGel 1.62 %. For dosage and administration of AndroGel 1.62% refer to its full prescribing information. (2)
- Prior to initiating AndroGel 1%., confirm the diagnosis of hypogonadism by ensuring that serum testosterone has been measured in the morning on at least two separate days and that these concentrations are below the normal range (2).
- Starting dose of AndroGel 1% is 50 mg of testosterone (two 25 mg packets or one 50 mg packet), applied once daily in the morning. (2.1)
- Apply to clean, dry, intact skin of shoulders and upper arms and/or abdomen. Do NOT apply AndroGel 1% to any other parts of the body including the genitals, chest, armpits (axillae), knees, or back. (2.2)
- Dose adjustment: AndroGel 1% can be dose adjusted using 50 mg, 75 mg, or 100 mg of testosterone on the basis of total serum testosterone concentration. The dose should be titrated based on the serum testosterone concentration. Additionally, serum testosterone concentration should be assessed periodically. (2.1)
- Patients should wash hands immediately with soap and water after applying AndroGel 1% and cover the application site(s) with clothing after the gel has dried. Wash the application site thoroughly with soap and water prior to any situation where skin-to-skin contact of the application site with another person is anticipated. (2.2)
DOSAGE FORMS AND STRENGTHS
WARNINGS AND PRECAUTIONS
- 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 AndroGel 1%. Secondary exposure to testosterone can produce signs of virilization. AndroGel 1% 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 (CHF), may be a complication in patients with preexisting cardiac, renal, or hepatic disease. (5.10, 6.2)
- Sleep apnea may occur in those with risk factors. (5.12)
- Monitor serum testosterone, prostate specific antigen (PSA), hemoglobin, hematocrit, liver function tests, and lipid concentrations periodically. (5.1, 5.3, 5.9, 5.13)
- AndroGel 1% is flammable until dry. (5.16)
Most common adverse reactions (incidence ≥ 5%) are acne, application site reaction, abnormal lab tests, and prostatic disorders. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 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 INR and prothrombin time is recommended. (7.2)
- Use of testosterone with adrenocorticotrophic hormone (ACTH) or corticosteroids may result in increased fluid retention. Use with caution, particularly in patients with cardiac, renal, or hepatic disease. (7.3)
USE IN SPECIFIC POPULATIONS
There are insufficient long-term safety data in geriatric patients using AndroGel 1% to assess the potential risks of cardiovascular disease and prostate cancer. (8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
- FULL PRESCRIBING INFORMATION: CONTENTS*
- Sections or subsections omitted from the full prescribing information are not listed.
- 1 INDICATIONS AND USAGE
- Primary hypogonadism (congenital or acquired): testicular failure due to conditions such as 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 concentrations 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 concentrations, but have gonadotropins in the normal or low range.
- Safety and efficacy of AndroGel 1% in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established.
- Safety and efficacy of AndroGel 1% 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 (1, 12.3).
- 2 DOSAGE AND ADMINISTRATION
Dosage and Administration for AndroGel 1% differs from AndroGel 1.62%. For dosage and administration of AndroGel 1.62% refer to its full prescribing information. (2)
Prior to initiating AndroGel 1%, 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.
2.1 Dosing and Dose Adjustment
The recommended starting dose of AndroGel 1% is 50 mg of testosterone (two 25 mg packets or one 50 mg packet), applied topically once daily in the morning to the shoulders and upper arms and/or abdomen area (preferably at the same time every day).
To ensure proper dosing, serum testosterone concentrations should be measured at intervals. If the serum testosterone concentration is below the normal range, the daily AndroGel 1% dose may be increased from 50 mg to 75 mg and from 75 mg to 100 mg for adult males as instructed by the physician. If the serum testosterone concentration exceeds the normal range, the daily AndroGel 1% dose may be decreased. If the serum testosterone concentration consistently exceeds the normal range at a daily dose of 50 mg, AndroGel 1% therapy should be discontinued. In addition, serum testosterone concentrations should be assessed periodically.
2.2 Administration Instructions
AndroGel 1% should be applied to clean, dry, healthy, intact skin of the right and left upper arms/shoulders and/or right and left abdomen. Area of application should be limited to the area that will be covered by the patient’s short sleeve T-shirt. Do not apply AndroGel 1% to any other part of the body including the genitals, chest, armpits (axillae), knees, or back. AndroGel 1% should be evenly distributed between the right and left upper arms/shoulders or both sides of the abdomen.
After applying the gel, the application site should be allowed to dry prior to dressing. Hands should be washed thoroughly with soap and water after application. Avoid fire, flames or smoking until the gel has dried since alcohol based products, including AndroGel 1%, are flammable.
The entire contents should be squeezed into the palm of the hand and immediately applied to the application sites. Alternately, patients may squeeze a portion of the gel from the packet into the palm of the hand and apply to application sites. Repeat until entire contents have been applied.
- Children and women should avoid contact with unwashed or unclothed application site(s) of men using AndroGel 1%.
- Patients should wash hands with soap and water immediately after application of AndroGel 1%.
- Patients should cover the application site(s) with clothing (e.g., a T-shirt) after the gel has dried.
- Prior to 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 AndroGel 1% 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.
- 3 DOSAGE FORMS AND STRENGTHS
- A unit dose packet containing 25 mg of testosterone provided in 2.5 g of gel.
- A unit dose packet containing 50 mg of testosterone provided in 5 g of gel.
- 4 CONTRAINDICATIONS
- AndroGel 1% is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate [see Warnings and Precautions (5.1), Adverse Reactions (6.1), and Nonclinical Toxicology (13.1)].
- AndroGel 1% is contraindicated in women who are pregnant. AndroGel 1% 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%. If a pregnant woman is exposed to AndroGel 1%, she should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1)].
- 5 WARNINGS AND PRECAUTIONS
5.1 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)].
5.2 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.
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.
5.4 Venous Thromboembolism
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 AndroGel 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)].
5.5 Cardiovascular Risk
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.
5.6 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.
5.7 Use in Women
5.8 Potential for Adverse Effects on Spermatogenesis
With large doses of exogenous androgens, including AndroGel 1%, 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.
5.9 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% is not known to cause these adverse effects.
Androgens, including AndroGel 1%, 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)].
5.12 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 [see Adverse Reactions (6.2)].
Androgens, including AndroGel 1%, 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.
5.15 Decreased Thyroxine-binding Globulin
Androgens, including AndroGel 1%, 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.
- 6 ADVERSE REACTIONS
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.
Table 1 shows the incidence of all adverse events judged by the investigator to be at least possibly related to treatment with AndroGel 1% and reported by >1% of patients in a 180 Day, Phase 3 study.
Table 1: Adverse Events Possibly, Probably or Definitely Related to Use of AndroGel 1% in the 180-Day Controlled Clinical Trial Adverse Event Dose of AndroGel 1% 50 mg 75 mg 100 mg N = 77 N = 40 N = 78 Acne 1% 3% 8% Alopecia 1% 0% 1% Application Site Reaction 5% 3% 4% Asthenia 0% 3% 1% Depression 1% 0% 1% Emotional Lability 0% 3% 3% Gynecomastia 1% 0% 3% Headache 4% 3% 0% Hypertension 3% 0% 3% Lab Test Abnormal* 6% 5% 3% Libido Decreased 0% 3% 1% Nervousness 0% 3% 1% Pain Breast 1% 3% 1% Prostate Disorder** 3% 3% 5% Testis Disorder*** 3% 0% 0% *Lab test abnormal occurred in nine patients with one or more of the following events reported: elevated hemoglobin or hematocrit, hyperlipidemia, elevated triglycerides, hypokalemia, decreased HDL, elevated glucose, elevated creatinine, elevated total bilirubin. **Prostate disorders included five patients with enlarged prostate, one with BPH, and one with elevated PSA results. ***Testis disorders were reported in two patients: one with left varicocele and one with slight sensitivity of left testis.
Other less common adverse reactions, reported in fewer than 1% of patients included: amnesia, anxiety, discolored hair, dizziness, dry skin, hirsutism, hostility, impaired urination, paresthesia, penis disorder, peripheral edema, sweating, and vasodilation.
Six patients (4%) in this trial had adverse events that led to discontinuation of AndroGel 1%. These events included: cerebral hemorrhage, convulsion (neither of which were considered related to AndroGel 1% administration), depression, sadness, memory loss, elevated prostate specific antigen, and hypertension. No AndroGel 1% patient discontinued due to skin reactions.
In a separate uncontrolled pharmacokinetic study of 10 patients, two had adverse events associated with AndroGel 1%; these were asthenia and depression in one patient and increased libido and hyperkinesia in the other.
In a 3 year, flexible dose, extension study, the incidence of all adverse events judged by the investigator to be at least possibly related to treatment with AndroGel 1% and reported by > 1% of patients is shown in Table 2.
Table 2: Adverse Events Possibly, Probably or Definitely Related to Use of AndroGel 1% in the 3 Year, Flexible Dose, Extension Study Adverse Event Percent of Subjects (N = 162) Lab Test Abnormal+ 9.3 Skin dry 1.9 Application Site Reaction 5.6 Acne 3.1 Pruritus 1.9 Enlarged Prostate 11.7 Carcinoma of Prostate 1.2 Urinary Symptoms* 3.7 Testis Disorder** 1.9 Gynecomastia 2.5 Anemia 2.5 +Lab test abnormal occurred in 15 patients with one or more of the following events reported: elevated AST, elevated ALT, elevated testosterone, elevated hemoglobin or hematocrit, elevated cholesterol, elevated cholesterol/LDL ratio, elevated triglycerides, elevated HDL, elevated serum creatinine. *Urinary symptoms included nocturia, urinary hesitancy, urinary incontinence, urinary retention, urinary urgency and weak urinary stream. **Testis disorders included three patients. There were two with a non-palpable testis and one with slight right testicular tenderness.
Discontinuation for adverse events in this study included: two patients with application site reactions, one with kidney failure, and five with prostate disorders (including increase in serum PSA in 4 patients, and increase in PSA with prostate enlargement in a fifth patient).
During the initial 6-month study, the mean change in PSA values had a statistically significant increase of 0.26 ng/mL. Serum PSA was measured every 6 months thereafter in the 162 hypogonadal men on AndroGel 1% in the 3-year extension study. There was no additional statistically significant increase observed in mean PSA from 6 months through 36 months. However, there were increases in serum PSA observed in approximately 18% of individual patients. The overall mean change from baseline in serum PSA values for the entire group from month 6 to 36 was 0.11 ng/mL.
Twenty-nine patients (18%) met the per-protocol criterion for increase in serum PSA, defined as >2X the baseline or any single serum PSA >6 ng/mL. Most of these (25/29) met this criterion by at least doubling of their PSA from baseline. In most cases where PSA at least doubled (22/25), the maximum serum PSA value was still <2 ng/mL. The first occurrence of a pre-specified, post-baseline increase in serum PSA was seen at or prior to Month 12 in most of the patients who met this criterion (23 of 29; 79%).
Four patients met this criterion by having a serum PSA >6 ng/mL and in these, maximum serum PSA values were 6.2 ng/mL, 6.6 ng/mL, 6.7 ng/mL, and 10.7 ng/mL. In two of these patients, prostate cancer was detected on biopsy. The first patient’s PSA levels were 4.7 ng/mL and 6.2 ng/mL at baseline and at Month 6/Final, respectively. The second patient’s PSA levels were 4.2 ng/mL, 5.2 ng/mL, 5.8 ng/mL, and 6.6 ng/mL at baseline, Month 6, Month 12, and Final, respectively.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of AndroGel 1%. 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 3).
Table 3: Adverse Drug Reactions from Postmarketing Experience of AndroGel 1% by MedDRA System Organ Class Blood and the lymphatic system disorders: Elevated Hgb, Hct (polycythemia) Cardiovascular disorders: Myocardial infarction, stroke Endocrine disorders: Hirsutism Gastrointestinal disorders: Nausea General disorders and administration site reactions: Asthenia, edema, malaise Genitourinary disorders: Impaired urination Hepatobiliary disorders: Abnormal liver function tests (e.g. transaminases, elevated GGTP, bilirubin) Investigations: Elevated PSA, electrolyte changes (nitrogen, calcium, potassium, phosphorus, sodium), changes in serum lipids (hyperlipidemia, elevated triglycerides, decreased HDL), impaired glucose tolerance, fluctuating testosterone concentrations, weight increase Neoplasms benign, malignant and unspecified (cysts and polyps): Prostate cancer Nervous system: Headache, dizziness, sleep apnea, insomnia Psychiatric disorders: Depression, emotional lability, decreased libido, nervousness, hostility, amnesia, anxiety Reproductive system and breast disorders: Gynecomastia, mastodynia, prostatic enlargement, testicular atrophy, oligospermia, priapism (frequent or prolonged erections) Respiratory disorders: Dyspnea Skin and subcutaneous tissue disorders: Acne, alopecia, application site reaction (pruritus, dry skin, erythema, rash, discolored hair, paresthesia), sweating Vascular disorders: Hypertension, vasodilation (hot flushes), venous thromboembolism
Cases of secondary exposure to testosterone resulting in virilization of children have been reported in postmarket surveillance. 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)].
- 7 DRUG INTERACTIONS
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.
7.2 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.
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.
- 8 USE IN SPECIFIC POPULATIONS
AndroGel 1% is contraindicated in pregnant women. Testosterone is teratogenic and may cause fetal harm when administered to a pregnant woman based on data from animal studies and its mechanism of action [see Contraindications (4) and Clinical Pharmacology (12.1)]. Exposure of a female fetus to androgens may result in varying degrees of virilization. In animal developmental studies, exposure to testosterone in utero resulted in hormonal and behavioral changes in offspring and structural impairments of reproductive tissues in female and male offspring. These studies did not meet current standards for nonclinical development toxicity studies.
In developmental studies conducted in rats, rabbits, pigs, sheep and rhesus monkeys, pregnant animals received intramuscular injection of testosterone during the period of organogenesis. Testosterone treatment at doses that were comparable to those used for testosterone replacement therapy resulted in structural impairments in both female and male offspring. Structural impairments observed in females included increased ano-genital distance, phallus development, empty scrotum, no external vagina, intrauterine growth retardation, reduced ovarian reserve, and increased ovarian follicular recruitment. Structural impairments seen in male offspring included increased testicular weight, larger seminal tubular lumen diameter, and higher frequency of occluded tubule lumen. Increased pituitary weight was seen in both sexes.
Testosterone exposure in utero also resulted in hormonal and behavioral changes in offspring. Hypertension was observed in pregnant female rats and their offspring exposed to doses approximately twice those used fortestosterone replacement therapy.
8.3 Females and Males of Reproductive Potential
During treatment with large doses of exogenous androgens, including AndroGel 1%, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis [see Warnings and Precautions (5.8)]. Reduced fertility is observed in some men taking testosterone replacement therapy. Testicular atrophy, subfertility, and infertility have also been reported in men who abuse anabolic androgenic steroids [see Drug Abuse and Dependence (9.2)]. With either type of use, the impact on fertility may be irreversible.
8.4 Pediatric Use
8.5 Geriatric Use
There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing AndroGel 1% to determine whether efficacy in those over 65 years of age differs from younger subjects. Additionally, there is insufficient long-term safety data in geriatric patients to assess the potential risks of cardiovascular disease and prostate cancer.
- 9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
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.
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 additional adverse reactions have been reported in women: hirsutism, virilization, deepening of voice, clitoral enlargement, breast atrophy, male-pattern baldness, and menstrual irregularities.
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.
- 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.
- 10 OVERDOSAGE
There is one report of acute overdosage with use of an approved injectable testosterone product: this subject had serum testosterone concentrations of up to 11,400 ng/dL with a cerebrovascular accident.Close
- 11 DESCRIPTION
The active pharmacologic ingredient in AndroGel 1% is testosterone, an androgen. Testosterone USP is a white to practically white crystalline powder chemically described as 17-beta hydroxyandrost-4-en-3-one. The structural formula is:
- 12 CLINICAL PHARMACOLOGY
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 chord thickening, 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).
AndroGel 1% delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate normal concentrations (298 - 1043 ng/dL) seen in healthy men. AndroGel 1% provides continuous transdermal delivery of testosterone for 24 hours following a single application to intact, clean, dry skin of the shoulders, upper arms and/or abdomen.
AndroGel 1% is a hydroalcoholic formulation that dries quickly when applied to the skin surface. The skin serves as a reservoir for the sustained release of testosterone into the systemic circulation. Approximately 10% of the testosterone dose applied on the skin surface from AndroGel is absorbed into systemic circulation. In a study with AndroGel 1% 100 mg , all patients showed an increase in serum testosterone within 30 minutes, and eight of nine patients had a serum testosterone concentration within normal range by 4 hours after the initial application. Absorption of testosterone into the blood continues for the entire 24-hour dosing interval. Serum concentrations approximate the steady-state concentration by the end of the first 24 hours and are at steady state by the second or third day of dosing.
With single daily applications of AndroGel 1%, follow-up measurements 30, 90 and 180 days after starting treatment have confirmed that serum testosterone concentrations are generally maintained within the eugonadal range. Figure 1 summarizes the 24-hour pharmacokinetic profiles of testosterone for hypogonadal men (less than 300 ng/dL) maintained on AndroGel 1% 50 mg or 100 mg for 30 days. The average (± SD) daily testosterone concentration produced by AndroGel 1% 100 mg on Day 30 was 792 (± 294) ng/dL and by AndroGel 1% 50 mg 566 (± 262) ng/dL.
Figure 1: Mean (± SD) Steady-State Serum Testosterone Concentrations on Day 30 in Patients Applying AndroGel 1% Once Daily
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 bound to albumin and other proteins.
DHT concentrations increased in parallel with testosterone concentrations during AndroGel 1% treatment. The mean steady-state DHT/T ratio during 180 days of AndroGel treatment ranged from 0.23 to 0.29 (50 mg of AndroGel 1%/day) and from 0.27 to 0.33 (100 mg of AndroGel 1%/day).
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 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% treatment is discontinued after achieving steady state, serum testosterone concentrations remain in the normal range for 24 to 48 hours but return to their pretreatment concentrations by the fifth day after the last application.
The potential for dermal testosterone transfer following AndroGel 1% use was evaluated in a clinical study between males dosed with AndroGel 1% and their untreated female partners. Two (2) to 12 hours after application of 100 mg of testosterone administered as AndroGel 1% by the male subjects, the couples (N = 38 couples) engaged in daily, 15-minute sessions of vigorous skin-to-skin contact so that the female partners gained maximum exposure to the AndroGel 1% application sites. Under these study conditions, all unprotected female partners had a serum testosterone concentration >2 times the baseline value at some time during the study. When a shirt covered the application site(s), the transfer of testosterone from the males to the female partners was completely prevented.
- 13 NONCLINICAL TOXICOLOGY
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.
- 14 CLINICAL STUDIES
14.1 Clinical Trials in Adult Hypogonadal Males
AndroGel 1% was evaluated in a multi-center, randomized, parallel-group, active-controlled, 180-day trial in 227 hypogonadal men. The study was conducted in 2 phases. During the Initial Treatment Period (Days 1-90), 73 patients were randomized to AndroGel 1% 50 mg daily, 78 patients to AndroGel 1% 100 mg daily, and 76 patients to a non-scrotal testosterone transdermal system. The study was double-blind for dose of AndroGel 1% but open-label for active control. Patients who were originally randomized to AndroGel 1% and who had single-sample serum testosterone concentrations above or below the normal range on Day 60 were titrated to 75 mg daily on Day 91. During the Extended Treatment Period (Days 91-180), 51 patients continued on AndroGel 1% 50 mg daily, 52 patients continued on AndroGel 1% 100 mg daily, 41 patients continued on a non-scrotal testosterone transdermal system (5 mg daily), and 40 patients received AndroGel 1% 75 mg daily. Upon completion of the initial study, 163 enrolled and 162 patients received treatment in an open-label extension study of AndroGel 1% for an additional period of up to 3 years.
Mean peak, trough and average serum testosterone concentrations within the normal range (298-1043 ng/dL) were achieved on the first day of treatment with doses of 50 mg and 100 mg of AndroGel 1%. In patients continuing on AndroGel 1% 50 mg and 100 mg, these mean testosterone concentrations were maintained within the normal range for the 180-day duration of the original study. Figure 2 summarizes the 24-hour pharmacokinetic profiles of testosterone administered as AndroGel 1% for 30, 90 and 180 days. Testosterone concentrations were maintained as long as the patient continued to properly apply the prescribed AndroGel 1% treatment.
Figure 2: Mean Steady-State Testosterone Concentrations in Patients with Once-Daily AndroGel 1% Therapy
Table 4 summarizes the mean testosterone concentrations on Treatment Day 180 for patients receiving 50 mg, 75 mg, or 100 mg of AndroGel 1%. The 75 mg dose produced mean concentrations intermediate to those produced by 50 mg and 100 mg of AndroGel 1%.
Table 4: Mean (± SD) Steady-State Serum Testosterone Concentrations During Therapy (Day 180) 50 mg 75 mg 100 mg N = 44 N = 37 N = 48 Cavg 555 ± 225 601 ± 309 713 ± 209 Cmax 830 ± 347 901 ± 471 1083 ± 434 Cmin 371 ± 165 406 ± 220 485 ± 156
Of 129 hypogonadal men who were appropriately titrated with AndroGel 1% and who had sufficient data for analysis, 87% achieved an average serum testosterone concentration within the normal range on Treatment Day 180.
In patients treated with AndroGel 1%, there were no observed differences in the average daily serum testosterone concentrations at steady-state based on age, cause of hypogonadism, or body mass index.
DHT concentrations increased in parallel with testosterone concentrations at AndroGel 1% doses of 50 mg/day and 100 mg/day, but the DHT/T ratio stayed within the normal range, indicating enhanced availability of the major physiologically active androgen. Serum estradiol (E2) concentrations increased significantly within 30 days of starting treatment with AndroGel 1% 50 or 100 mg/day and remained elevated throughout the treatment period but remained within the normal range for eugonadal men. Serum levels of SHBG decreased very slightly (1 to 11%) during AndroGel 1% treatment. In men with hypergonadotropic hypogonadism, serum levels of LH and FSH fell in a dose- and time-dependent manner during treatment with AndroGel 1%.
14.2 Phototoxicity in Humans
The phototoxic potential of AndroGel 1% was evaluated in a double-blind, single-dose study in 27 subjects with photosensitive skin types. The Minimal Erythema Dose (MED) of ultraviolet radiation was determined for each subject. A single 24 (+1) hour application of duplicate patches containing test articles (placebo gel, testosterone gel, or saline) was made to naive skin sites on Day 1. On Day 2, each subject received five exposure times of ultraviolet radiation, each exposure being 25% greater than the previous one. Skin evaluations were made on Days 2 to 5. Exposure of test and control article application sites to ultraviolet light did not produce increased inflammation relative to non-irradiated sites, indicating no phototoxic effect.
- 16 HOW SUPPLIED/STORAGE AND HANDLING
NDC Number Package Size 0051-8425-30 30 packets (a unit dose packet containing 25 mg of testosterone provided in 2.5 g of gel) 0051-8450-30 30 packets (a unit dose packet containing 50 mg of testosterone provided in 5 g of gel)
- 17 PATIENT COUNSELING INFORMATION
17.1 Use in Men with Known or Suspected Prostate or Breast Cancer
17.2 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.
- 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% 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 testosterone gel in men [see Medication Guide]:
- Children and women should avoid contact with unwashed or unclothed application site(s) of men using testosterone gel
- Patients using AndroGel 1% should apply the product as directed and strictly adhere to the following:
- Wash hands with soap and water 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% 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)].
17.3 Potential Adverse Reactions with Androgens
- 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 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.
17.4 Patients Should Be Advised of the Following Instructions for Use:
- Read the Medication Guide before starting AndroGel 1% therapy and to reread it each time the prescription is renewed
- AndroGel 1% 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% out of the reach of children
- AndroGel 1% 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% is prescribed to meet the patient’s specific needs; therefore, the patient should never share AndroGel 1% with anyone.
- Wait 5 hours before swimming or washing following application of AndroGel 1%. This will ensure that the greatest amount of AndroGel 1% is absorbed into their system.
- MEDICATION GUIDE
- INSTRUCTIONS FOR USE
Read this Instructions for Use for ANDROGEL 1% 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.
- Before applying ANDROGEL 1%, make sure that your shoulders, upper arms or stomach are clean, dry, and there is no broken skin.
- The application sites for ANDROGEL 1% are the shoulders, upper arms or stomach area (abdomen) that will be covered by a short sleeve t-shirt (see Figure A). Do not apply ANDROGEL 1% to any other parts of your body such as your penis, scrotum, chest, armpits (axillae), knees, or back.
- 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% out of the packet into the palm of your hand.
- Apply ANDROGEL 1% to the application site. You may also apply ANDROGEL 1% from the packet directly to the application site.
- Let the application areas dry completely before putting on a t-shirt.
- ANDROGEL 1% is flammable until dry. Let ANDROGEL 1% dry before smoking or going near an open flame.
- Wash your hands with soap and water right away after applying ANDROGEL 1%.
- Avoid showering, swimming, or bathing for at least 5 hours after you apply ANDROGEL 1%.
- Store ANDROGEL 1% at room temperature between 68ºF to 77ºF (20ºC to 25ºC).
- Safely throw away used ANDROGEL 1% in the household trash. Be careful to prevent accidental exposure of children or pets.
- Keep ANDROGEL 1% away from fire.
- PRINCIPAL DISPLAY PANEL
- INGREDIENTS AND APPEARANCE
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0051-8488 Route of Administration TRANSDERMAL DEA Schedule CIII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength testosterone (UNII: 3XMK78S47O) (testosterone - UNII:3XMK78S47O) testosterone 10 mg in 1 g Inactive Ingredients Ingredient Name Strength isopropyl myristate (UNII: 0RE8K4LNJS) water (UNII: 059QF0KO0R) sodium hydroxide (UNII: 55X04QC32I) carbomer homopolymer type C (UNII: 4Q93RCW27E) alcohol (UNII: 3K9958V90M) Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0051-8488-88 2 in 1 CARTON 03/14/2011 08/31/2015 1 NDC:0051-8488-33 75 g in 1 BOTTLE, PUMP; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021015 03/14/2011 08/31/2015 ANDROGEL
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0051-8425 Route of Administration TRANSDERMAL DEA Schedule CIII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength testosterone (UNII: 3XMK78S47O) (testosterone - UNII:3XMK78S47O) testosterone 10 mg in 1 g Inactive Ingredients Ingredient Name Strength alcohol (UNII: 3K9958V90M) isopropyl myristate (UNII: 0RE8K4LNJS) water (UNII: 059QF0KO0R) sodium hydroxide (UNII: 55X04QC32I) CARBOMER HOMOPOLYMER TYPE C (ALLYL PENTAERYTHRITOL CROSSLINKED) (UNII: 4Q93RCW27E) Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0051-8425-30 30 in 1 CARTON 03/14/2011 1 NDC:0051-8425-01 2.5 g in 1 PACKET; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021015 03/14/2011 ANDROGEL
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0051-8450 Route of Administration TRANSDERMAL DEA Schedule CIII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength testosterone (UNII: 3XMK78S47O) (testosterone - UNII:3XMK78S47O) testosterone 10 mg in 1 g Inactive Ingredients Ingredient Name Strength alcohol (UNII: 3K9958V90M) isopropyl myristate (UNII: 0RE8K4LNJS) water (UNII: 059QF0KO0R) sodium hydroxide (UNII: 55X04QC32I) CARBOMER HOMOPOLYMER TYPE C (ALLYL PENTAERYTHRITOL CROSSLINKED) (UNII: 4Q93RCW27E) Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0051-8450-30 30 in 1 CARTON 03/14/2011 1 NDC:0051-8450-01 5 g in 1 PACKET; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021015 03/14/2011 Labeler - AbbVie Inc. (078458370)