Androgel has been related to the side effect of Abdominal discomfort. If you are taking Androgel and have experienced Abdominal discomfort this information may be of use to you.
IMPORTANT NOTE: The following information is intended to supplement, not substitute for, the expertise and judgment of your physician, pharmacist or other healthcare professional. It should not be construed to indicate that use of the drug is safe, appropriate, or effective for you. Consult your healthcare professional before using this drug.
AndroGel® (testosterone gel) 1% for topical use CIII
ANDROGEL
-
testosterone gel Solvay Pharmaceuticals, Inc.
----------
AndroGel® (testosterone gel) 1% for topical use CIII
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ANDROGEL
safely and effectively. See full prescribing information for ANDROGEL.
ANDROGEL
(testosterone)
gel for
transdermal
use - CIII Initial U.S. Approval:
1953
INDICATIONS AND USAGE
AndroGel is an androgen indicated for replacement therapy in males for conditions associated with a deficiency or absence
of endogenous testosterone :
Primary Hypogonadism (Congenital or Acquired) (1.1)
Hypogonadotropic Hypogonadism (Congenital or Acquired) (1.1)
DOSAGE AND ADMINISTRATION
Recommended starting dose: 5 g for adult males, applied topically once daily (2.1)
Apply to clean, dry, intact skin of shoulders and upper arms and/or abdomen. Do NOT apply AndroGel to the genitals (2.1)
Dose adjustment for adult males: If serum testosterone level is below the normal range, adjust dose from 5 g to 7.5 g and
from 7.5 g to 10 g (2.3)
DOSAGE FORMS AND STRENGTHS
AndroGel (testosterone gel) 1% for topical use is available as:
2 x 75 g pumps (each pump dispenses 60 metered 1.25 g doses) (3)
Most common adverse reactions (incidence ≥ 5%) are acne, application site reaction, abnormal lab tests, and prostatic disorders.
(6)
To report SUSPECTED ADVERSE REACTIONS, contact Solvay Pharmaceuticals, Inc. at
1-800-241-1643
or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
DRUG INTERACTIONS
Androgens may decrease blood glucose, and therefore insulin requirement in diabetic patients (7.1)
Use of testosterone with ACTH or corticosteroids may result in increased fluid retention. Use with caution, particularly in
patients with cardiac, renal, or hepatic disease (7.2)
Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of INR and prothrombin time is recommended
(7.3)
USE IN SPECIFIC POPULATIONS
Pregnancy: AndroGel may cause teratogenic effects. AndroGel should not be used in pregnant women (4, 8.1)
Safety and efficacy of AndroGel in males < 18 years old has not been established. (8.4)
There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing AndroGel to
determine whether efficacy in those > 65 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. (8.5)
No formal studies were conducted involving patients with renal or hepatic insufficiencies (8.6)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling
AndroGel, an androgen, 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 (FSH, LH) above the normal range.
Hypogonadotropic Hypogonadism (Congenital or Acquired) - idiopathic 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.
2 DOSAGE AND ADMINISTRATION
2.1 General Dosing
The recommended starting dose of AndroGel is 5 g once daily (preferably in the morning) to clean, dry, intact skin of the
shoulders and upper arms and/or abdomen. AndroGel must not be applied to the genitals. AndroGel is supplied as either a pump
or in individual packets. After applying the gel, the application site should be allowed to dry for a few minutes prior to
dressing. Avoid fire, flames or smoking until the gel has dried since alcohol based products, including AndroGel, are flammable.
Hands should be washed with soap and water after AndroGel has been applied. [see Warnings and Precautions (5.2, 5.10)].
2.2 Administration
Multi-Dose Pump
Patients should be instructed to prime the pump before using it for the first time by fully depressing the pump mechanism
(actuation) 3 times and discard this portion of the product to assure precise dose delivery. After the priming procedure,
patients should completely depress the pump one time (actuation) for every 1.25 g (AndroGel Pump) of product required to achieve
the daily prescribed dosage. The product may be delivered directly into the palm of the hand and then applied to the desired
application sites, either one pump actuation at a time or upon completion of all pump actuations required for the daily dose.
Alternatively, the product can be applied directly to the application sites. Application directly to the sites may prevent
loss of product that may occur during transfer from the palm of the hand onto the application sites. Table 1 has specific dosing guidelines for adult males when the 75 g AndroGel Pump is used.
Table 1: Specific Dosing Guidelines for Using the Adult Multi-Dose Pump
Prescribed Daily Dose
Number of Pump Actuations in 75 g Pump
5 g
4 (once daily)
7.5 g
6 (once daily)
10 g
8 (once daily)
Packets
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.
2.3 Dose Adjustment and Patient Assessments
To ensure proper dosing, serum testosterone levels should be measured at intervals and replaced to serum testosterone levels
in the normal range. If the serum testosterone concentration is below the normal range, the daily AndroGel dose may be increased
from 5 g to 7.5 g and from 7.5 g to 10 g for adult males as instructed by the physician. If the serum testosterone concentration
exceeds the normal range, the daily AndroGel dose may be decreased. If the serum testosterone concentration consistently exceeds
the normal range at a daily dose of 5 g, AndroGel therapy should be discontinued.
The following is general advice for treating and monitoring adult patients on AndroGel. No specific recommendations can be
made.
Prescribers should be aware that testosterone is contraindicated in men with known or suspected prostate cancer. Therefore,
evaluation for prostate cancer prior to initiation of AndroGel therapy is appropriate [see Contraindications (4)].
Based on results from controlled studies, serum PSA may rise when taking AndroGel. Therefore, periodic assessment of serum
PSA is recommended in patients taking AndroGel [see Adverse Reactions (6.1)].
Based on results from controlled studies, worsening of BPH may occur in patients taking AndroGel [see Adverse Reactions (6.1)]. Therefore, periodic assessments for signs and symptoms of BPH are recommended in patients taking AndroGel.
Hematocrit, serum lipid profile, and liver function test should be monitored in patients taking AndroGel [see Warnings and Precautions (5.9)].
3 DOSAGE FORMS AND STRENGTHS
AndroGel (testosterone gel) 1% for topical use is available in either unit-dose packets or multiple-dose pumps. The 75 g (60
metered-dose) pump delivers 1.25 g of product when the pump mechanism is fully depressed once.
AndroGel is available in the following three package containers:
2 x 75 g pumps (each pump dispenses 60 metered 1.25 g doses)
2.5 g packet
5 g packet
4 CONTRAINDICATIONS
AndroGel should not be used in any of the following patients:
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)].
Women who are or may become pregnant, or who are breastfeeding. AndroGel can cause fetal harm when administered to a pregnant
woman. AndroGel may cause serious adverse reactions in nursing infants. Exposure of a female fetus or nursing infant to androgens
may result in varying degrees of virilization. Pregnant women or those who may become pregnant need to be aware of the potential
for transfer of testosterone from men treated with AndroGel [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.3)].
Men with known hypersensitivity to any of its ingredients, including alcohol and soy products.
5 WARNINGS AND PRECAUTIONS
5.1 Worsening of 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.
Patients treated with androgens may be at increased risk for prostate cancer. Evaluation of the patient for prostate cancer
prior to initiating and during treatment with androgens is appropriate [see Warnings and Precaution (5.9), Adverse Reactions (6.1), and Nonclinical Toxicology (13.1)].
Increases in serum PSA from baseline values were seen in approximately 18% of individuals in an open label study of 162 hypogonadal
men treated with AndroGel for up to 42 months. Most of these increases were seen within the first year of therapy [see Contraindications (4), Warnings and Precautions (5.9), Adverse Reactions (6), and Nonclinical Toxicology (13.1)].
5.2 Potential for Testosterone Transfer to Others
Transfer of testosterone to others (including women and children) can occur when vigorous skin-to-skin contact is made with
the application site [see Clinical Studies (14.3)]. The following precautions are recommended to minimize potential transfer of testosterone from AndroGel-treated skin to another
person:
Patients should wash their hands immediately with soap and water after application of AndroGel.
Patients should cover the application site(s) with clothing after the gel has dried (e.g., a shirt).
In the event that unwashed or unclothed skin to which AndroGel has been applied does come 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.
In vitro studies show that residual testosterone is removed from the skin surface by washing with soap and water.
Women and children should avoid skin contact with AndroGel application sites in males. Changes in body hair distribution,
significant increase in acne, or other signs of virilization should be brought to the attention of a physician. AndroGel may
cause fetal harm in a pregnant woman due to virilization of a female fetus [see Use in Specific Populations (8.1)].
5.3 Use in Women
Due to lack of controlled evaluations in women and potential virilizing effects, AndroGel is not indicated for use in women
[see Use in Specific Populations (8.1, 8.3)].
5.4 Potential for Adverse Effects on Spermatogenesis
At large doses of exogenous androgens, 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.
5.5 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 is not known to produce these adverse effects.
There are rare reports of hepatocellular carcinoma in patients receiving long-term oral therapy with androgens in high doses.
Withdrawal of the drugs did not lead to regression of the tumors in all cases.
5.6 Edema
Drugs in the androgen class 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)].
5.7 Gynecomastia
Gynecomastia may develop and may persist in patients being treated with androgens, including AndroGel, for hypogonadism.
5.8 Sleep Apnea
The treatment of hypogonadal men with testosterone products may potentiate sleep apnea in some patients, especially those
with risk factors such as obesity or chronic lung diseases [see Adverse Reactions (6.2)].
5.9 Laboratory Tests
Increases in hematocrit, reflective of increases in red blood cell mass, may require lowering or discontinuation of testosterone.
Increase in red blood cell mass may increase the risk for a thromboembolic event.
Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy.
Androgens may decrease levels of thyroxin-binding globulin, resulting in decreased total T4 serum levels and increased resin
uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.
Androgens 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.
5.10 Flammable until Dry
Alcohol Based Products including AndroGel are flammable; therefore avoid fire, flame or smoking until the gel has dried.
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.
Clinical Trials in Hypogonadal Men
Table 2 shows the incidence of all adverse events judged by the investigator to be at least possibly related to treatment with AndroGel
and reported by >1% of patients in a 180 Day, Phase 3 study.
Table 2: Adverse Events Possibly, Probably or Definitely Related to Use of AndroGel in the 180-Day Controlled Clinical Trial
*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.
Adverse Event
Dose of AndroGel
5 g
7.5 g
10 g
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%
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.
In this 180 day clinical trial, skin reactions at the site of application were reported with AndroGel, but none was severe
enough to require treatment or discontinuation of drug.
Six patients (4%) in this trial had adverse events that led to discontinuation of AndroGel. These events included: cerebral
hemorrhage, convulsion (neither of which were considered related to AndroGel administration), depression, sadness, memory
loss, elevated prostate specific antigen, and hypertension No AndroGel patient discontinued due to skin reactions.
In a separate uncontrolled pharmacokinetic study of 10 patients, two had adverse events associated with AndroGel; 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 and reported by > 1% of patients is shown in Table 3.
Table 3: Adverse Events Possibly, Probably or Definitely Related to Use of AndroGel in the 3 Year, Flexible Dose, Extension
Study
+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.
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
Two patients reported serious adverse events considered possibly related to treatment: deep vein thrombosis (DVT) and prostate
disorder requiring a transurethral resection of the prostate (TURP).
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).
Increases in Serum PSA Observed in Clinical Trials of Hypogonadal Men
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 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. 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.
Hypogonadal Men
Table 4 includes adverse reactions that have been identified postmarketing.
Table 4: Adverse Drug Reactions from Postmarketing Experience of AndroGel by MedDRA System Organ Class
Blood and the lymphatic system disorders:
Elevated Hgb, Hct (polycythemia)
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 GCTP, bilirubin)
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 requirements.
7.2 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.
7.3 Oral Anticoagulants
Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of INR and prothrombin time are recommended
in patients taking anticoagulants, especially at the initiation and termination of androgen therapy.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category X: AndroGel is contraindicated during pregnancy or in women who may become pregnant. It is teratogenic
and may cause fetal harm [see Contraindications (4)]. 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, AndroGel is contraindicated in nursing women because
of the potential for serious adverse reactions in nursing infants [see Contraindications (4)].
Testosterone and other androgens may adversely affect lactation.
8.4 Pediatric Use
Safety and efficacy of AndroGel in males < 18 years old has not been established. 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 AndroGel 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.
8.6 Renal or Hepatic Impairment
No formal studies were conducted involving patients with renal or hepatic insufficiencies.
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
AndroGel contains testosterone, a Schedule III controlled substance as defined by the Anabolic Steroids Control Act.
Oral ingestion of AndroGel will not result in clinically significant serum testosterone concentrations due to extensive first-pass
metabolism.
10 OVERDOSAGE
There is one report of acute overdosage with use of an approved injectable testosterone product: this subject had serum testosterone
levels of up to 11,400 ng/dL with a cerebrovascular accident. Treatment of overdosage would consist of discontinuation of
AndroGel together with appropriate symptomatic and supportive care.
11 DESCRIPTION
AndroGel (testosterone gel) 1% is a clear, colorless hydroalcoholic gel containing 1% testosterone. Topical administration
of AndroGel 5 g, 7.5 g, or 10 g contains 50 mg, 75 mg, or 100 mg of testosterone, respectively, is to be applied daily to
the skin's surface. Approximately 10% of the applied testosterone dose is absorbed across skin of average permeability during
a 24-hour period.
The active pharmacologic ingredient in AndroGel is testosterone. Testosterone USP is a white to practically white crystalline
powder chemically described as 17-beta hydroxyandrost-4-en-3-one. The structural formula is:
Inactive ingredients in AndroGel are carbomer 980, ethanol 67.0%, isopropyl myristate, purified water, and sodium hydroxide.
These ingredients are not pharmacologically active.
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 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).
12.3 Pharmacokinetics
Adult Males
Absorption
AndroGel delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate
normal levels (298 – 1043 ng/dL) seen in healthy men. AndroGel 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 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. Therefore, 5 g and 10 g of AndroGel systemically
deliver approximately 5 mg and 10 mg of testosterone, respectively. In a study with 10 g of AndroGel, 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 level 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, 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 (<300 ng/dL) maintained on 5 g or 10
g of AndroGel for 30 days. The average (± SD) daily testosterone concentration produced by AndroGel 10 g on Day 30 was 792
(± 294) ng/dL and by AndroGel 5 g 566 (± 262) ng/dL.
Figure 1: Mean (± SD) Steady-State Serum Testosterone Concentrations on Day 30 in Patients Applying AndroGel Once Daily
When AndroGel treatment is discontinued after achieving steady state, serum testosterone levels remain in the normal range
for 24 to 48 hours but return to their pretreatment levels by the fifth day after the last application.
Distribution
Circulating testosterone is primarily bound in the serum to sex hormone-binding globulin (SHBG) and albumin. Approximately
40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins.
Metabolism
There is considerable variation in the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes.
Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone
are estradiol and DHT.
DHT concentrations increased in parallel with testosterone concentrations during AndroGel treatment. After 180 days of treatment
in adult males, mean DHT concentrations were within the normal range with 5 g AndroGel and were about 7% above the normal
range after a 10 g dose. The mean steady-state DHT/T ratio during 180 days of AndroGel treatment remained within normal limits
and ranged from 0.23 to 0.29 (5 g/day) and from 0.27 to 0.33 (10 g/day).
Excretion
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.
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 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 5 g daily, 78 patients to AndroGel 10 g daily, and 76 patients to a non-scrotal testosterone transdermal system.
The study was double-blind for dose of AndroGel but open-label for active control. Patients who were originally randomized
to AndroGel and who had single-sample serum testosterone levels above or below the normal range on Day 60 were titrated to
7.5 g daily on Day 91. During the Extended Treatment Period (Days 91-180), 51 patients continued on AndroGel 5 g daily, 52
patients continued on AndroGel 10 g daily, 41 patients continued on a non-scrotal testosterone transdermal system (5 mg daily),
and 40 patients received AndroGel 7.5 g daily. Upon completion of the initial study, 163 enrolled and 162 patients received
treatment in an open-label extension study of AndroGel 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 5 g and 10 g. In patients continuing on AndroGel 5 g and 10 g, these mean testosterone
levels 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 for 30, 90 and 180 days. Testosterone
concentrations were maintained as long as the patient continued to properly apply the prescribed AndroGel treatment.
Figure 2: Mean Steady-State Testosterone Concentrations in Patients with Once-Daily AndroGel Therapy
Table 5 summarizes the mean testosterone concentrations on Treatment Day 180 for patients receiving 5 g, 7.5 g, or 10 g of AndroGel.
The 7.5 g dose produced mean concentrations intermediate to those produced by 5 g and 10 g of AndroGel.
Table 5: Mean (± SD) Steady-State Serum Testosterone Concentrations During Therapy (Day 180)
5 g
7.5 g
10 g
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 and who had sufficient data for analysis, 87% achieved
an average serum testosterone level within the normal range on Treatment Day 180.
In patients treated with AndroGel, 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.
AndroGel 5 g/day and 10 g/day resulted in significant increases over time in total body mass and total body lean mass, while
total body fat mass and the percent body fat decreased significantly. These changes were maintained for 180 days of treatment
during the original study. Changes in the 7.5 g dose group were similar. Bone mineral density in both hip and spine increased
significantly from Baseline to Day 180 with 10 g AndroGel.
AndroGel treatment at 5 g/day and 10 g/day for 90 days produced significant improvement in libido (measured by sexual motivation,
sexual activity and enjoyment of sexual activity as assessed by patient responses to a questionnaire). The degree of penile
erection as subjectively estimated by the patients, increased with AndroGel treatment, as did the subjective score for “satisfactory
duration of erection.” AndroGel treatment at 5 g/day and 10 g/day produced positive effects on mood and fatigue. Similar changes
were seen after 180 days of treatment and in the group treated with the 7.5 g dose. DHT concentrations increased in parallel
with testosterone concentrations at AndroGel doses of 5 g/day and 10 g/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 5 or 10 g/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 treatment. In men with hypergonadotropic hypogonadism, serum levels of LH and FSH fell in a dose- and time-dependent
manner during treatment with AndroGel.
14.2 Phototoxicity in Humans
The phototoxic potential of AndroGel 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.
14.3 Testosterone Transfer from Male Patients to Female Partners
The potential for dermal testosterone transfer following AndroGel use was evaluated in a clinical study between males dosed
with AndroGel and their untreated female partners. Two (2) to 12 hours after AndroGel (10 g) application 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 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.
16 HOW SUPPLIED/STORAGE AND HANDLING
AndroGel is supplied in non-aerosol, metered-dose pumps. The pump is composed of plastic and stainless steel and an LDPE/aluminum
foil inner liner encased in rigid plastic with a polypropylene cap. Each 88 g AndroGel Pump in the twin package is capable
of dispensing 75 g or 60 metered 1.25 g doses.
AndroGel is also supplied in unit-dose aluminum foil packets in cartons of 30. Each packet of 2.5 g or 5 g gel contains 25
mg or 50 mg testosterone, respectively.
NDC Number
Package Size
0051-8488-88
2 x 75 g pumps (each pump dispenses 60 metered 1.25 g doses)
0051-8425-30
30 packets (2.5 g per packet)
0051-8450-30
30 packets (5 g per packet)
Keep AndroGel out of the reach of children.
Storage
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Disposal
Used AndroGel pumps or used AndroGel packets should be discarded in household trash in a manner that prevents accidental application
or ingestion by children or pets.
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 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.
17.2 Instructions for Use of AndroGel
Patients should be informed to apply AndroGel once daily (preferably in the morning) to clean, dry skin of the shoulders and
upper arms and/or abdomen. To prevent transfer of AndroGel to others, patient should wash their hands after application and
cover the application site with clothing.
Advise patients that AndroGel is an alcohol based product and is flammable, therefore avoid fire, flame or smoking until the
gel has dried.
Counsel patients on the importance of adhering to all recommended monitoring by their healthcare professional.
Advise patients to report any changes in their state of health, such as changes in urinary habits, breathing, sleep, and mood.
17.3 FDA-Approved Patient Labeling
AndroGel (testosterone gel) 1% CIII is available packaged with 2 x 75 g pumps (each pump dispenses 60 metered 1.25 g doses)
or in a box of 30 packets with 2.5g or 5g gel.
This is a summary of the important information about AndroGel. For details, talk to your healthcare professional and refer
to the package insert.
1. What Disease or Condition Does AndroGel Treat?
Your healthcare provider has prescribed this medication because your body does not produce enough testosterone. The medical
term for this condition is hypogonadism.
2. How Should AndroGel (Pump or Packet) Be Applied?
It is important that you use AndroGel as prescribed by your healthcare professional. If you experience serious problems, contact
your healthcare professional. Your healthcare professional will tell you how much AndroGel to use each day.
Figure3: Site(s) of Gel Application
AndroGel should be applied once daily at the same time each day (preferably every morning) to clean, dry, healthy, intact skin of the shoulders, upper arms and/or abdomen. If you take a
bath or shower in the morning, use AndroGel after your bath or shower.
AndroGel should not be applied to the penis or scrotum, or to skin with open sores, wounds or irritation.
Wash your hands with soap and water immediately after application to reduce the chance that the medication will spread from your hands to other people.
Let AndroGel dry for a few minutes before you dress.
AndroGel is flammable until dry; allow the gel to dry before smoking or going near an open flame.
Wait 5 to 6 hours before showering or swimming. This will ensure that the greatest amount of AndroGel is absorbed into your system.
How to use the AndroGel pump?
It is important that you read and follow these directions on how to use the AndroGel Pump properly. Before using the pump
for the first time, you must prime the AndroGel pump by fully depressing the pump three times and discarding the gel. The
unused gel should be discarded in a manner to avoid accidental exposure or ingestion by household members or pets. Fully depress
the pump the appropriate number of times to deliver the daily dose prescribed by your healthcare provider. The product may
be delivered directly into the palm of your hand and then applied to the desired application sites, either one pump depression
at a time or upon completion of all pump depressions required for the daily dose.
How to use the AndroGel packets?
Open one AndroGel aluminum foil packet by folding the top edge at the perforation and tearing completely across the packet
along the perforation. Squeeze the contents into the palm of your hand. Squeeze from the bottom of the packet toward the top.
If you like, you may squeeze a portion of the gel from the packet into the palm of your hand and apply to application site(s).
Repeat until the entire contents of the packet have been applied.
3. What Should You Discuss With Your Healthcare Professional?
Before you start using AndroGel, tell your healthcare professional if you :
Have prostate cancer or breast cancer.
Have a known hypersensitivity to any of AndroGel's components, including individuals who are hypersensitive to testosterone
that is chemically synthesized from soy.
4. What Other Drugs Should Not Be Used Together With AndroGel?
Tell your healthcare provider about all of the medicines you take, including prescription and non-prescription medicines,
vitamins and herbal supplements. AndroGel can affect how your body handles other drugs. Changes in your dose or careful monitoring
may be needed if you are taking any of the following medications:
Insulin
Corticosteroids
Oral Anticoagulants
5. What Are The Side Effects And Risks?
Possible side effects of AndroGel to discuss with your healthcare professional include:
Most common: Skin irritation where gel is applied, breast development or tenderness, acne, prostate enlargement, changes in lab test results
and changes in urinary habits.
Contact your healthcare professional if you experience any of the following adverse reactions:
Too frequent or persistent erections of the penis.
Any nausea, vomiting, changes in skin color or ankle swelling.
Breathing disturbances, including those associated with sleep, or excessive daytime sleepiness.
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.
The major risks of AndroGel include:
Prostate Disorders: Patients treated with testosterone may be at an increased risk for prostate enlargement, and prostate cancer. Talk to your
healthcare provider for more information on risk factors and ways to monitor for prostate disorders.
Testosterone Transfer: Transfer of testosterone to others (including women and children) can occur when vigorous skin-to-skin contact is made with
the application site. AndroGel must not be used by women, and exposure to the active ingredient testosterone in pregnancy
can cause fetal harm. Notify your healthcare provider if your female partner develops changes in hair distribution, increases
in acne or other signs of masculinity.
6. How Should AndroGel Be Stored?
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep out of
the reach of children.
7. Is There Anything Else I Need To Know When Using AndroGel?
Your healthcare professional has prescribed AndroGel to meet your specific needs; never share your AndroGel with anyone. If
you have any questions or concerns about your AndroGel treatment, ask your healthcare provider or pharmacist.
Manufactured By: Laboratoires Besins International Montrouge, France For: Unimed Pharmaceuticals, LLC A Solvay Pharmaceuticals, Inc. Company Marietta, GA 30062-2224
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