NDC 43598-304 Testosterone

Testosterone

NDC Product Code 43598-304

NDC 43598-304-88

Package Description: 1 BOTTLE, PUMP in 1 CARTON > 88 g in 1 BOTTLE, PUMP

NDC Product Information

Testosterone with NDC 43598-304 is a a human prescription drug product labeled by Dr. Reddy's Laboratories, Inc.. The generic name of Testosterone is testosterone. The product's dosage form is gel, metered and is administered via transdermal form.

Labeler Name: Dr. Reddy's Laboratories, Inc.

Dosage Form: Gel, Metered - A gel preparation, with metered dose valves, which allow for the delivery of a uniform quantity of gel upon each activation.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

DEA Schedule: Schedule III (CIII) Substances What is the Drug Enforcement Administration (DEA) CIII Schedule?
The controlled substances in the CIII schedule have an abuse potential and dependence liability less than those in schedules CI and CII, and have an accepted medical use in the United States. Schedule CIII controlled substances include preparations containing limited quantities of certain narcotic drugs, and other nonnarcotic drugs such as: derivatives of barbituric acid, except those that are listed in another schedule, glutethimide (Doriden), methyprylon (Noludar), nalorphine, benzphetamine, chlorphentermine, clortermine, and phendimetrazine.


Testosterone Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • TESTOSTERONE 1.62 mg/g

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • CARBOMER HOMOPOLYMER TYPE C (UNII: 4Q93RCW27E)
  • ALCOHOL (UNII: 3K9958V90M)
  • ISOPROPYL MYRISTATE (UNII: 0RE8K4LNJS)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)
  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Transdermal - Administration through the dermal layer of the skin to the systemic circulation by diffusion.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Androgen - [EPC] (Established Pharmacologic Class)
  • Androgen Receptor Agonists - [MoA] (Mechanism of Action)
  • Androstanes - [CS]

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Dr. Reddy's Laboratories, Inc.
Labeler Code: 43598
FDA Application Number: ANDA208620 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 04-12-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Testosterone Product Label Images

Testosterone Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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)].

1 Indications And Usage

  • Testosterone gel 1.62% is an androgen 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 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): idiopathic 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.Limitations of use: Safety and efficacy of testosterone gel 1.62% in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established. Safety and efficacy of testosterone gel 1.62% in males less than 18 years old have not been established [seeUse in Specific Populations (8.4)]. Topical testosterone products may have different doses, strengths, or application instructions that may result in different systemic exposure [seeIndications and Usage (1),andClinical Pharmacology (12.3)].

2 Dosage And Administration

Dosage and Administration for testosterone gel 1.62% differs from testosterone gel 1%. For dosage and administration of testosterone gel 1% refer to its full prescribing information. (2)Prior to initiating testosterone gel 1.62%, 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 testosterone gel 1.62% is 40.5 mg of testosterone (2 pump actuations) applied topically once daily in the morning to the shoulders and upper arms. The dose can be adjusted between a minimum of 20.25 mg of testosterone (1 pump actuation) and a maximum of 81 mg of testosterone (4 pump actuations). To ensure proper dosing, the dose should be titrated based on the pre-dose morning serum testosterone concentration from a single blood draw at approximately 14 days and 28 days after starting treatment or following dose adjustment. In addition, serum testosterone concentration should be assessed periodically thereafter. Table 1 describes the dose adjustments required at each titration step.Table 1: Dose Adjustment CriteriaPre-Dose Morning Total Serum Testosterone ConcentrationDose TitrationGreater than 750 ng/dL Decrease daily dose by 20.25 mg (1 pump actuation) Equal to or greater than 350 and equal to or less than 750 ng/dL No change: continue on current dose Less than 350 ng/dL Increase daily dose by 20.25 mg (1 pump actuation) The application site and dose of testosterone gel 1.62% are not interchangeable with other topical testosterone products.

2.2 Administration Instructions

  • Testosterone gel 1.62% should be applied to clean, dry, intact skin of the upper arms and shoulders. Do not apply testosterone gel 1.62% to any other parts of the body, including the abdomen, genitals, chest, armpits (axillae), or knees [see Clinical Pharmacology (12.3)]. Area of application should be limited to the area that will be covered by the patient's short sleeve t-shirt. Patients should be instructed to use the palm of the hand to apply testosterone gel 1.62% and spread across the maximum surface area as directed in Table 2 (for pump) and in Figure 1.Table 2: Application Sites for Testosterone Gel 1.62%, PumpTotal Dose of TestosteroneTotal Pump ActuationsPump Actuations Per Upper Arm and Shoulder  Upper Arm and Shoulder #1Upper Arm and Shoulder #220.25 mg 1 1 040.5 mg 2 1 160.75 mg 3 2 181 mg 4 2 2The prescribed daily dose of testosterone gel 1.62% should be applied to the right and left upper arms and shoulders as shown in the shaded areas in Figure 1.Figure 1. Application Sites for Testosterone Gel 1.62%Once the application site is dry, the site should be covered with clothing [see Clinical Pharmacology (12.3)]. Wash hands thoroughly with soap and water. Avoid fire, flames or smoking until the gel has dried since alcohol based products, including testosterone gel 1.62%, are flammable.The patient should avoid swimming or showering or washing the administration site for a minimum of 2 hours after application [see Clinical Pharmacology (12.3)]. To obtain a full first dose, it is necessary to prime the canister pump. To do so, with the canister in the upright position, slowly and fully depress the actuator three times. Safely discard the gel from the first three actuations. It is only necessary to prime the pump before the first dose. After the priming procedure, fully depress the actuator once for every 20.25 mg of testosterone gel 1.62%. Testosterone gel 1.62% should be delivered directly into the palm of the hand and then applied to the application sites. Strict adherence to the following precautions is advised in order to minimize the potential for secondary exposure to testosterone from testosterone gel 1.62%-treated skin: Children and women should avoid contact with unwashed or unclothed application site(s) of men using testosterone gel 1.62%. Testosterone gel 1.62% should only be applied to the upper arms and shoulders. The area of application should be limited to the area that will be covered by a short sleeve t-shirt. Patients should wash their hands with soap and water immediately after applying testosterone gel 1.62%. Patients should cover the application site(s) with clothing (e.g., a t-shirt) after the gel has dried. Prior to situations in which direct skin-to-skin contact is anticipated, patients should wash the application site(s) thoroughly with soap and water to remove any testosterone residue. In the event that unwashed or unclothed skin to which testosterone gel 1.62% 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

  • Testosterone gel 1.62% for topical use only, is available as follows:A metered-dose pump. Each pump actuation delivers 20.25 mg of testosterone in 1.25 g of gel.

4 Contraindications

  • Testosterone gel 1.62% is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Testosterone gel 1.62% is contraindicated in women who are or may become pregnant, or who are breastfeeding. Testosterone gel 1.62% may cause fetal harm when administered to a pregnant woman. Testosterone gel 1.62% may cause serious adverse reactions in nursing infants. Exposure of a 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 testosterone gel 1.62%. If a pregnant woman is exposed to testosterone gel 1.62%, she should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.3)].

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. Evaluation of patients for prostate cancer prior to initiating and during treatment with androgens is appropriate [seeContraindications (4)].

5.2 Potential For Secondary Exposure To Testosterone

Cases of secondary exposure resulting in virilization of children have been reported in postmarketing surveillance of testosterone gel products. Signs and symptoms have included enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases, these signs and symptoms regressed with removal of the exposure to testosterone gel. In a few cases, however, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronological age. The risk of transfer was increased in some of these cases by not adhering to precautions for the appropriate use of the topical testosterone product. Children and women should avoid contact with unwashed or unclothed application sites in men using testosterone gel 1.62% [seeDosage 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.

5.3 Polycythemia

Increases in hematocrit, reflective of increases in red blood cell mass, may require lowering or discontinuation of testosterone. Check hematocrit prior to initiating 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 testosterone gel 1.62%. 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 testosterone gel 1.62% and initiate appropriate workup and management [seeAdverse 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. Patients should be informed of this possible risk when deciding whether to use or to continue to use testosterone gel 1.62%.

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

Due to the lack of controlled evaluations in women and potential virilizing effects, testosterone gel 1.62% is not indicated for use in women [see Contraindications (4) and Use in Specific Populations (8.1, 8.3)].

5.8 Potential For Adverse Effects On Spermatogenesis

With large doses of exogenous androgens, including testosterone gel 1.62%, spermatogenesis may be suppressed through feedback inhibition of pituitary FSH possibly leading 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. Testosterone gel 1.62% is not known to cause these adverse effects.

5.10 Edema

Androgens, including testosterone gel 1.62%, 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 [seeAdverse Reactions ( 6.2 )].

5.11 Gynecomastia

Gynecomastia may develop and persist in patients being treated with androgens, including testosterone gel 1.62%, for hypogonadism.

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.

5.13 Lipids

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

5.14 Hypercalcemia

Androgens, including testosterone gel 1.62 %, 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 testosterone gel 1.62%, 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.

5.16 Flammability

Alcohol based products, including testosterone gel 1.62%, are flammable; therefore, patients should be advised to avoid fire, flame or smoking until the testosterone gel 1.62% has dried.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Testosterone gel 1.62% was evaluated in a two-phase, 364-day, controlled clinical study. The first phase was a multi-center, randomized, double-blind, parallel-group, placebo-controlled period of 182 days, in which 234 hypogonadal men were treated with testosterone gel 1.62% and 40 received placebo. Patients could continue in an open-label, non-comparative, maintenance period for an additional 182 days[see Clinical Studies (14.1)].The most common adverse reaction reported in the double-blind period was increased prostate specific antigen (PSA) reported in 26 testosterone gel 1.62%-treated patients (11.1%). In 17 patients, increased PSA was considered an adverse event by meeting one of the two pre-specified criteria for abnormal PSA values, defined as (1) average serum PSA >4 ng/mL based on two separate determinations, or (2) an average change from baseline in serum PSA of greater than 0.75 ng/mL on two determinations. During the 182-day, double-blind period of the clinical trial, the mean change in serum PSA value was 0.14 ng/mL for patients receiving testosterone gel 1.62% and -0.12 ng/mL for the patients in the placebo group. During the double-blind period, seven patients had a PSA value >4 ng/mL, four of these seven patients had PSA less than or equal to 4 ng/mL upon repeat testing. The other three patients did not undergo repeat PSA testing. During the 182-day, open-label period of the study, the mean change in serum PSA values was 0.10 ng/mL for both patients continuing on active therapy and patients transitioning onto active from placebo. During the open-label period, three patients had a serum PSA value > 4 ng/mL, two of whom had a serum PSA less than or equal to 4 ng/mL upon repeated testing. The other patient did not undergo repeat PSA testing. Among previous placebo patients, 3 of 28 (10.7%), had increased PSA as an adverse event in the open-label period. Table 4 shows adverse reactions reported by >2% of patients in the 182-day, double-blind period of the testosterone gel 1.62% clinical trial and more frequent in the testosterone gel 1.62% treated group versus placebo.Table 4: Adverse Reactions Reported in >2% of Patients in the 182-Day, Double-Blind Period of Testosterone Gel 1.62% Clinical Trial Number (%) of PatientsAdverse Reaction Testosterone gel 1.62% N=234 Placebo N= 40 PSA increased* 26 (11.1%) 0% Emotional lability** 6 (2.6%) 0% Hypertension 5 (2.1%) 0% Hematocrit or hemoglobin increased 5 (2.1%) 0% Contact dermatitis*** 5 (2.1%) 0% *PSA increased includes: PSA values that met pre-specified criteria for abnormal PSA values (an average change from baseline > 0.75 ng/mL and/or an average PSA value >4 ng/mL based on two measurements) as well as those reported as adverse events. **Emotional lability includes: mood swings, affective disorder, impatience, anger, and aggression. ***Contact dermatitis includes: 4 patients with dermatitis at non-application sites. Other adverse reactions occurring in less than or equal to 2% of testosterone gel 1.62%-treated patients and more frequently than placebo included: frequent urination, and hyperlipidemia. In the open-label period of the study (N=191), the most commonly reported adverse reaction (experienced by greater than 2% of patients) was increased PSA (n=13; 6.2%) and sinusitis. Other adverse reactions reported by less than or equal to 2% of patients included increased hemoglobin or hematocrit, hypertension, acne, libido decreased, insomnia, and benign prostatic hypertrophy. During the 182-day, double-blind period of the clinical trial, 25 testosterone gel 1.62%-treated patients (10.7%) discontinued treatment because of adverse reactions. These adverse reactions included 17 patients with PSA increased and 1 report each of: hematocrit increased, blood pressure increased, frequent urination, diarrhea, fatigue, pituitary tumor, dizziness, skin erythema and skin nodule (same patient – neither at application site), vasovagal syncope, and diabetes mellitus. During the 182-day, open-label period, 9 patients discontinued treatment because of adverse reactions. These adverse reactions included 6 reports of PSA increased, 2 of hematocrit increased, and 1 each of triglycerides increased and prostate cancer. Application Site ReactionsIn the 182-day double-blind period of the study, application site reactions were reported in two (2/234; 0.9%) patients receiving testosterone gel 1.62%, both of which resolved. Neither of these patients discontinued the study due to application site adverse reactions. In the open-label period of the study, application site reactions were reported in three (3/219; 1.4%) additional patients that were treated with testosterone gel 1.62%. None of these subjects were discontinued from the study due to application site reactions.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of testosterone gel 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 5). Table 5: Adverse Reactions from Post Approval Experience of Testosterone Gel 1% by System Organ ClassSystem Organ Class Adverse Reaction Blood and lymphatic system disorders: Elevated hemoglobin or hematocrit, polycythemia, anemia Cardiovascular disorders: Myocardial infarction, stroke  Endocrine disorders: Hirsutism Gastrointestinal disorders: Nausea General disorders: Asthenia, edema, malaise Genitourinary disorders: Impaired urination* Hepatobiliary disorders: Abnormal liver function tests Investigations: Lab test abnormal**, elevated PSA, electrolyte changes (nitrogen, calcium, potassium [includes hypokalemia], phosphorus, sodium), impaired glucose tolerance, hyperlipidemia, HDL, fluctuating testosterone levels, weight increase Neoplasms: Prostate cancer Nervous system disorders: Dizziness, headache, insomnia, sleep apnea Psychiatric disorders: Amnesia, anxiety, depression, hostility, emotional lability, decreased libido, nervousness Reproductive system and breast disorders: Gynecomastia, mastodynia, oligospermia, priapism (frequent or prolonged erections), prostate enlargement, BPH, testis disorder*** Respiratory disorders: Dyspnea Skin and subcutaneous tissue disorders: Acne, alopecia, application site reaction (discolored hair, dry skin, erythema, paresthesia, pruritus, rash), skin dry, pruritus, sweating Vascular disorders: Hypertension, vasodilation (hot flushes), venous thromboembolism* Impaired urination includesnocturia, urinary hesitancy, urinary incontinence, urinary retention, urinary urgency and weak urinary stream**Lab test abnormal includeselevated AST, elevated ALT, elevated testosterone, elevated hemoglobin or hematocrit, elevated cholesterol, elevated cholesterol/LDL ratio, elevated triglycerides, or elevated serum creatinine***Testis disorder includesatrophy or non-palpable testis, varicocele, testis sensitivity or tendernessSecondary Exposure to Testosterone in ChildrenCases of secondary exposure to testosterone resulting in virilization of children have been reported in postmarketing surveillance of testosterone gel products. 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)].

7.1 Insulin

Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, 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.

7.3 Corticosteroids

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.

8.1 Pregnancy

Pregnancy Category X [seeContraindications (4)]: Testosterone gel 1.62% is contraindicated during pregnancy or in women who may become pregnant. Testosterone is teratogenic and may cause fetal harm. Exposure of a 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 made aware of the potential hazard to the fetus.

8.3 Nursing Mothers

Although it is not known how much testosterone transfers into human milk, testosterone gel 1.62% is contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants. Testosterone and other androgens may adversely affect lactation [seeContraindications (4)].

8.4 Pediatric Use

The safety and effectiveness of testosterone gel 1.62% in pediatric patients less than 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 testosterone gel 1.62% to determine whether efficacy in those over 65 years of age differs from younger subjects. Of the 234 patients enrolled in the clinical trial utilizing testosterone gel 1.62%, 21 were over 65 years of age. Additionally, there is insufficient long-term safety data in geriatric patients to assess the potentially increased risks of cardiovascular disease and prostate cancer.Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of BPH.

8.6 Renal Impairment

No studies were conducted involving patients with renal impairment.

8.7 Hepatic Impairment

No studies were conducted in patients with hepatic impairment.

9.1 Controlled Substance

Testosterone gel 1.62% contains testosterone, a Schedule III controlled substance in the Controlled Substances Act.

9.2 Abuse

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.Abuse-Related Adverse Reactions 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 adverse reactions have also been reported in men: transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility. 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.The following adverse reactions have been reported in male and female adolescents: premature closure of bony epiphyses with termination of growth, and precocious puberty. 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.

9.3 Dependence

  • Behaviors Associated with AddictionContinued abuse of testosterone and other anabolic steroids, leading to addiction is characterized by the following behaviors: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 usePhysical 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.Drug dependence in individuals using approved doses of testosterone for approved indications has not been documented.

10 Overdosage

There is a single report of acute overdosage after parenteral administration of an approved testosterone product in the literature. This subject had serum testosterone concentrations of up to 11,400 ng/dL, which were implicated in a cerebrovascular accident. There were no reports of overdosage in the testosterone gel 1.62% clinical trial.Treatment of overdosage would consist of discontinuation of testosterone gel 1.62%, washing the application site with soap and water, and appropriate symptomatic and supportive care.

11 Description

Testosterone gel 1.62% for topical use is a clear, colorless to light yellow gel containing testosterone. Testosterone is an androgen. Testosterone gel 1.62% is available in a metered-dose pump.The active pharmacologic ingredient in testosterone gel 1.62% is testosterone. Testosterone USP is a white or slightly creamy white powder chemically described as 17-beta hydroxyandrost-4-en-3-one. The structural formula is:The inactive ingredients in testosterone gel 1.62% are: carbopol 980, ethyl alcohol, isopropyl myristate, purified water, and sodium hydroxide.

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; and 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).

12.2 Pharmacodynamics

No specific pharmacodynamic studies were conducted using testosterone gel 1.62%.

Absorption

Testosterone gel 1.62% delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate normal levels (300 – 1000 ng/dL) seen in healthy men. Testosterone gel 1.62% provides continuous transdermal delivery of testosterone for 24 hours following once daily application to clean, dry, intact skin of the shoulders and upper arms. Average serum testosterone concentrations over 24 hours (Cavg) observed when testosterone gel 1.62% was applied to the upper arms/shoulders were comparable to average serum testosterone concentrations (Cavg) when testosterone gel 1.62% was applied using a rotation method utilizing the abdomen and upper arms/shoulders. The rotation of abdomen and upper arms/shoulders was a method used in the pivotal clinical trial [seeClinical Studies (14.1)].Figure 2: Mean (±SD) Serum Total Testosterone Concentrations on Day 7 in Patients Following Testosterone Gel 1.62% Once-Daily Application of 81 mg of Testosterone (N=33) for 7 Days

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 loosely bound to albumin and other proteins.

Metabolism

Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are estradiol and DHT.

Excretion

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 acid 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 testosterone gel 1.62% treatment is discontinued, serum testosterone concentrations return to approximately baseline concentrations within 48 to 72 hours after administration of the last dose. Potential for testosterone transfer The potential for testosterone transfer following administration of testosterone gel 1.62% when it was applied only to upper arms/shoulders was evaluated in two clinical studies of males dosed with testosterone gel 1.62% and their untreated female partners. In one study, 8 male subjects applied a single dose of testosterone gel 1.62% 81 mg to their shoulders and upper arms. Two (2) hours after application, female subjects rubbed their hands, wrists, arms, and shoulders to the application site of the male subjects for 15 minutes. Serum concentrations of testosterone were monitored in female subjects for 24 hours after contact occurred. After direct skin-to-skin contact with the site of application, mean testosterone Cavg and Cmax in female subjects increased by 280% and 267%, respectively, compared to mean baseline testosterone concentrations. In a second study evaluating transfer of testosterone, 12 male subjects applied a single dose of testosterone gel 1.62% 81 mg to their shoulders and upper arms. Two (2) hours after application, female subjects rubbed their hands, wrists, arms, and shoulders to the application site of the male subjects for 15 minutes while the site of application was covered by a t-shirt. When a t-shirt was used to cover the site of application, mean testosterone Cavg and Cmax in female subjects increased by 6% and 11%, respectively, compared to mean baseline testosterone concentrations.  A separate study was conducted to evaluate the potential for testosterone transfer from 16 males dosed with testosterone gel 1.62% 81 mg when it was applied to abdomen only for 7 days, a site of application not approved for testosterone gel 1.62%. Two (2) hours after application to the males on each day, the female subjects rubbed their abdomens for 15 minutes to the abdomen of the males. The males had covered the application area with a T-shirt. The mean testosterone Cavg and Cmax in female subjects on day 1 increased by 43% and 47%, respectively, compared to mean baseline testosterone concentrations. The mean testosterone Cavg and Cmax in female subjects on day 7 increased by 60% and 58%, respectively, compared to mean baseline testosterone concentrations. Effect of showering In a randomized, 3-way (3 treatment periods without washout period) crossover study in 24 hypogonadal men, the effect of showering on testosterone exposure was assessed after once daily application of testosterone gel 1.62% 81 mg to upper arms/shoulders for 7 days in each treatment period. On the 7th day of each treatment period, hypogonadal men took a shower with soap and water at either 2, 6, or 10 hours after drug application. The effect of showering at 2 or 6 hours post-dose on Day 7 resulted in 13% and 12% decreases in mean Cavg, respectively, compared to Day 6 when no shower was taken after drug application. Showering at 10 hours after drug application had no effect on bioavailability. The amount of testosterone remaining in the outer layers of the skin at the application site on the 7th day was assessed using a tape stripping procedure and was reduced by at least 80% after showering 2 to 10 hours post-dose compared to on the 6th day when no shower was taken after drug application.Effect of hand washingIn a randomized, open-label, single-dose, 2-way crossover study in 16 healthy male subjects, the effect of hand washing on the amount of residual testosterone on the hands was evaluated. Subjects used their hands to apply the maximum dose (81 mg testosterone) of testosterone gel 1.62% to their upper arms and shoulders. Within 1 minute of applying the gel, subjects either washed or did not wash their hands prior to study personnel wiping the subjects’ hands with ethanol dampened gauze pads. The gauze pads were then analyzed for residual testosterone content. A mean (SD) of 0.1 (0.04) mg of residual testosterone (0.12% of the actual applied dose of testosterone, and a 96% reduction compared to when hands were not washed) was recovered after washing hands with water and soap.Effect of sunscreen or moisturizing lotion on absorption of testosterone In a randomized, 3-way (3 treatment periods without washout period) crossover study in 18 hypogonadal males, the effect of applying a moisturizing lotion or a sunscreen on the absorption of testosterone was evaluated with the upper arms/shoulders as application sites. For 7 days, moisturizing lotion or sunscreen (SPF 50) was applied daily to the testosterone gel 1.62% application site 1 hour after the application of testosterone gel 1.62% 40.5 mg. Application of moisturizing lotion increased mean testosterone Cavg and Cmax by 14% and 17%, respectively, compared to testosterone gel 1.62% administered alone. Application of sunscreen increased mean testosterone Cavg and Cmax by 8% and 13%, respectively, compared to testosterone gel 1.62% applied alone.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Testosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical-uterine tumors which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats. Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays.The administration of exogenous testosterone has been reported to suppress spermatogenesis in the rat, dog and non-human primates, which was reversible on cessation of the treatment.

14.1 Clinical Trials In Hypogonadal Males

Testosterone gel 1.62% was evaluated in a multi-center, randomized, double-blind, parallel-group, placebo-controlled study (182-day double-blind period) in 274 hypogonadal men with body mass index (BMI) 18 to 40 kg/m2 and 18 to 80 years of age (mean age 53.8 years). The patients had an average serum testosterone concentration of <300 ng/dL, as determined by two morning samples collected on the same visit. Patients were Caucasian 83%, Black 13%, Asian or Native American 4%. 7.5% of patients were Hispanic. Patients were randomized to receive active treatment or placebo using a rotation method utilizing the abdomen and upper arms/shoulders for 182 days. All patients were started at a daily dose of 40.5 mg (two pump actuations) testosterone gel 1.62% or matching placebo on Day 1 of the study. Patients returned to the clinic on Day 14, Day 28, and Day 42 for predose serum total testosterone assessments. The patient's daily dose was titrated up or down in 20.25 mg increments if the predose serum testosterone value was outside the range of 350 to 750 ng/dL. The study included four active testosterone gel 1.62% doses: 20.25 mg, 40.5 mg, 60.75 mg, and 81 mg daily. The primary endpoint was the percentage of patients with Cavg within the normal range of 300 to 1000 ng/dL on Day 112. In patients treated with testosterone gel 1.62%, 81.6% (146/179) had Cavg within the normal range at Day 112. The secondary endpoint was the percentage of patients, with Cmax above three pre-determined limits. The percentages of patients with Cmax greater than 1500 ng/dL, and between 1800 and 2499 ng/dL on Day 112 were 11.2% and 5.5%, respectively. Two patients had a Cmax >2500 ng/dL on Day 112 (2510 ng/dL and 2550 ng/dL, respectively); neither of these 2 patients demonstrated an abnormal Cmax on prior or subsequent assessments at the same dose. Patients could agree to continue in an open-label, active treatment maintenance period of the study for an additional 182 days. Dose titrations on Days 14, 28, and 42 resulted in final doses of 20.25 mg – 81 mg on Day 112 as shown in Table 6.Table 6: Mean (SD) Testosterone Concentrations (Cavg and Cmax) by final dose on Days 112 and 364ParameterFinal Dose on Day 112 Placebo (n=27)  20.25 mg (n=12)40.5 mg (n=34) 60.75 mg (n=54) 81 mg (n=79) All Active (n=179) Cavg (ng/dL) 303 (135) 457 (275) 524 (228) 643 (285) 537 (240) 561 (259) Cmax (ng/dL) 450 (349) 663 (473) 798 (439) 958 (497) 813 (479) 845 (480) Final Dose on Day 364  20.25 mg (n=7) 40.5 mg (n=26) 60.75 mg (n=29) 81 mg (n=74) Continuing Active (n=136) Cavg (ng/dL)  386 (130) 474 (176) 513 (222) 432 (186) 455 (192) Cmax (ng/dL) 562 (187) 715 (306) 839 (568) 649 (329) 697 (389) Figure 3 summarizes the pharmacokinetic profile of total testosterone in patients completing 112 days of testosterone gel 1.62% treatment administered as a starting dose of 40.5 mg of testosterone (2 pump actuations) for the initial 14 days followed by possible titration according to the follow-up testosterone measurements.Figure 3: Mean (±SD) Steady-State Serum Total Testosterone Concentrations on Day 112  Efficacy was maintained in the group of men that received testosterone gel 1.62% for one full year. In that group, 78% (106/136) had average serum testosterone concentrations in the normal range at Day 364. Figure 4 summarizes the mean total testosterone profile for these patients on Day 364.Figure 4: Mean (±SD) Steady-State Serum Total Testosterone Concentrations on Day 364  The mean estradiol and DHT concentration profiles paralleled the changes observed in testosterone. The levels of LH and FSH decreased with testosterone treatment. The decreases in levels of LH and FSH are consistent with reports published in the literature of long-term treatment with testosterone.

16 How Supplied/Storage And Handling

Testosterone gel 1.62% is supplied in non-aerosol, metered-dose pumps that deliver 20.25 mg of testosterone per complete pump actuation. The pumps are composed of plastic and stainless steel and an LDPE/aluminum foil inner liner encased in rigid plastic with a polypropylene cap. Each 88 g metered-dose pump is capable of dispensing 75 g of gel or 60-metered pump actuations; each pump actuation dispenses 1.25 g of gel. NDC Number Package Size 43598-304-88 88 g pump (each pump dispenses 60 metered pump actuations with each pump actuation containing 20.25 mg of testosterone in 1.25 g of gel) Store at controlled room temperature 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Used testosterone gel 1.62% pumps should be discarded in household trash in a manner that prevents accidental application or ingestion by children or pets.

17 Patient Counseling Information And Medication Guide

See FDA-Approved Medication Guide Patients should be informed of the following:

17.1 Use In Men With Known Or Suspected Prostate Or Breast Cancer

Men with known or suspected prostate or breast cancer should not use testosterone gel 1.62% [seeContraindications (4)andWarnings and Precautions (5.1)].

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. Cases of secondary exposure to testosterone have been reported in children.Physicians should advise patients of the reported signs and symptoms of secondary exposure, which may include the following: 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.Testosterone gel 1.62% 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 1.62% in men [seeMedication Guide]:Children and women should avoid contact with unwashed or unclothed application site(s) of men using testosterone gel 1.62%.Patients using testosterone gel 1.62% should apply the product as directed and strictly adhere to the following:Wash hands with soap and water immediately 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 testosterone gel 1.62% 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 [seeDosage and Administration (2.2), Warnings and Precautions (5.2)and Clinical Pharmacology (12.3)].

17.3 Potential Adverse Reactions With Androgens

  • Patients should be informed that treatment with androgens may lead to adverse reactions which include: Changes in urinary habits such as increased urination at night, trouble starting the urine stream, passing urine many times during the day, having an urge 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 testosterone gel 1.62% therapy and to reread it each time the prescription is renewed.Testosterone gel 1.62% should be applied and used appropriately to maximize the benefits and to minimize the risk of secondary exposure in children and women. Keep testosterone gel 1.62% out of the reach of children. Testosterone gel 1.62% 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. Testosterone gel 1.62% is prescribed to meet the patient's specific needs; therefore, the patient should never share testosterone gel 1.62% with anyone. Wait 2 hours before swimming or washing following application of testosterone gel 1.62%. This will ensure that the greatest amount of testosterone gel 1.62% is absorbed into their system.Distributed by: Dr. Reddy’s Laboratories, Inc.Princeton, NJ - 08540.MADE IN CANADA Issued: 0119

* Please review the disclaimer below.

Previous Code
43598-303
Next Code
43598-305