Androgel (Testosterone) Gel [Rebel Distributors Corp.]

1.1 Testosterone Replacement TherapyAndroGel, 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.

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.

6.1 Clinical Trial ExperienceBecause 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___________ Dose of AndroGel ___ Adverse Event _____________________ ____________________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% * 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.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 greater than 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 StudyAdverse 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.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 greater than 2X the baseline or any single serum PSA greater than 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 less than 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 greater than 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 ExperienceThe 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 ClassBlood and the lymphatic system disorders:Elevated Hgb, Hct (polycythemia)Endocrine disorders:HirsutismGastrointestinal disorders:NauseaGeneral disorders and administration site reactions:Asthenia, edema, malaiseGenitourinary disorders:Impaired urinationHepatobiliary disorders:Abnormal liver function tests (e.g. transaminases, elevated GCTP, 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 levels, weight increaseNeoplasms benign, malignant and unspecified (cysts and polyps):Prostate cancerNervous system:Headache, dizziness, sleep apnea, insomniaPsychiatric disorders:Depression, emotional lability, decreased libido, nervousness, hostility, amnesia, anxietyReproductive system and breast disorders:Gynecomastia, mastodynia, prostatic enlargement, testicular atrophy, oligospermia, priapism (frequent or prolonged erections)Respiratory disorders:DyspneaSkin and subcutaneous tissue disorders:Acne, alopecia, application site reaction (pruritus, dry skin, erythema, rash, discolored hair, paresthesia), sweatingVascular disorders:Hypertension, vasodilation (hot flushes)

5.1 Worsening of BPH and Potential Risk of Prostate CancerPatients 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 OthersTransfer 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 WomenDue 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 SpermatogenesisAt 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 EffectsProlonged 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 EdemaDrugs 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 GynecomastiaGynecomastia may develop and may persist in patients being treated with androgens, including AndroGel, for hypogonadism.5.8 Sleep ApneaThe 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 TestsIncreases 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 DryAlcohol Based Products including AndroGel are flammable; therefore avoid fire, flame or smoking until the gel has dried.

2.1 General DosingThe 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 PumpPrescribed Daily DoseNumber of Pump Actuations in 75 g Pump5 g4 (once daily)7.5 g6 (once daily)10 g8 (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 AssessmentsTo 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)].

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

7.1 InsulinChanges 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 CorticosteroidsThe 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 AnticoagulantsChanges 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.