HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`TESTIM safely and effectively. See full prescribing information for
`TESTIM.
`TESTIM® (testosterone gel) for topical use, CIII
`Initial U.S. Approval: 1953
`WARNING: SECONDARY EXPOSURE TO TESTOSTERONE
`See full prescribing information for complete boxed warning
` Virilization has been reported in children who were secondarily
`exposed to testosterone gel (5.2, 6.2)
` Children should avoid contact with unwashed or unclothed
`application sites in men using testosterone gel (2.2, 5.2)
` Healthcare providers should advise patients to strictly adhere to
`recommended instructions for use (2.2, 5.2, 17)
`
`----------------------------INDICATIONS AND USAGE-------------------------
`Testim® is an androgen indicated for testosterone replacement therapy in
`
`males for conditions associated with a deficiency or absence of endogenous
`
`testosterone:
`
` Primary Hypogonadism (Congenital or Acquired) (1)
`
` Hypogonadotropic Hypogonadism (1)
`
`Limitations of Use:
` Safety and efficacy of Testim in males less than 18 years old have not
`been established (8.4)
` Topical testosterone products may have different doses, strengths, or
`application instructions that may result in different systemic exposure (1,
`12.3)
`
`---------------------- DOSAGE AND ADMINISTRATION---------------------
` Recommended starting dose for adult males: 50 mg of testosterone (one
`tube) applied topically once daily (2.1)
` Apply to clean, dry, intact skin of the shoulders and/or upper arms. Do
`NOT apply Testim to the genitals or abdomen. (2.1, 2.2)
` If morning pre-dose serum testosterone concentration is below normal
`range, increase dose to 100 mg. (2.1)
` Pre-dose serum testosterone concentration should be assessed
`periodically. (2.1)
` Patients should wash hands with soap and water immediately after
`applying Testim and cover application site(s) with clothing after gel has
`dried. Wash the application site thoroughly with soap and water prior to
`any situation where skin-to-skin contact of the application site with
`another person is anticipated. (2.2)
` Testim is not interchangeable with other topical testosterone products.
`(2.1)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: SECONDARY EXPOSURE TO TESTOSTERONE
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Dosing and Dose Adjustment
`2.2 Administration Instructions
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Worsening of Benign Prostatic Hyperplasia (BPH) and Potential
`Risk of Prostate Cancer
`5.2 Potential for Secondary Exposure to Testosterone
`5.3 Polycythemia
`5.4 Use in Women
`5.5 Potential for Adverse Effects on Spermatogenesis
`5.6 Hepatic Adverse Effects
`5.7 Edema
`5.8 Gynecomastia
`5.9 Sleep Apnea
`5.10 Lipids
`5.11 Hypercalcemia
`5.12 Decreased Thyroxine-binding Globulin
`5.13 Flammability
`6 ADVERSE REACTIONS
`6.1 Clinical Studies Experience
`6.2 Postmarketing Experience
`
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`-----------------------DOSAGE FORMS AND STRENGTHS--------------------
` Topical Gel: 50 mg of testosterone in a unit-dose tube (3)
`
`-------------------------------CONTRAINDICATIONS-----------------------------
` Men with known carcinoma of the breast or known or suspected
`carcinoma of the prostate (4, 5.1)
` Pregnant or breastfeeding women. Testosterone may cause fetal harm (4,
`8.1, 8.3)
`
`-------------------------WARNINGS AND PRECAUTIONS---------------------­
` Monitor patients with benign prostatic hyperplasia (BPH) for worsening
`of signs and symptoms of BPH. (5.1)
` Avoid unintentional exposure of women or children to Testim. Secondary
`exposure to testosterone can produce signs of virilization. Testim should
`be discontinued until the cause of virilization is identified. (5.2)
` Exogenous administration of androgens may lead to azoospermia. (5.5)
` Edema, with or without congestive heart failure, may be a complication in
`patients with preexisting cardiac, renal, or hepatic disease. (5.7, 6.2)
` Sleep apnea may occur in those with risk factors (5.9)
` Monitor prostate specific antigen (PSA), hematocrit, and lipid
`concentrations periodically. (5.1, 5.3, 5.10)
` Testim is flammable until dry. (5.13)
`
`------------------------------ADVERSE REACTIONS-----------------------------
`Most common adverse reactions (incidence ≥ 2% of the Testim patients and
`greater than placebo) are application site reaction and increased hematocrit
`(6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Auxilium
`Pharmaceuticals, Inc. at 1-877-663-0412 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`------------------------------DRUG INTERACTIONS-------------------------------
` Androgens may decrease blood glucose and therefore may decrease
`insulin requirements in diabetic patients. (7.1)
` Changes in anticoagulant activity may be seen with androgens. More
`frequent monitoring of International Normalized Ratio (INR) and
`prothrombin time is recommended in patients taking warfarin. (7.2)
` Use of testosterone with corticosteroids may result in increased fluid
`retention. Use with caution, particularly in patients with cardiac, renal, or
`hepatic disease. (7.3)
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`Geriatric Patients: There are insufficient long-term safety data to assess the
`potential risks of cardiovascular disease and prostate cancer. (8.5)
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 08/2013
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`9 DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`9.2 Abuse
`9.3 Dependence
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Clinical Trials in Adult Hypogonadal Males
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1 Men with Known or Suspected Carcinoma of the Breast or
`Prostate
`17.2 Potential for Secondary Exposure to Testosterone and Steps to
`1
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`7 DRUG INTERACTIONS
`7.1
`Insulin
`7.2 Oral Anticoagulants
`7.3 Corticosteroids
`
`Prevent Secondary Exposure
`17.3 Potential Adverse Reactions with Androgens
`17.4 Patients Should Be Advised of the Following Instructions for Use
`*Sections or subsections omitted from the full prescribing information are not
`listed.
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`FULL PRESCRIBING INFORMATION
`
`
`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)].
`
`INDICATIONS AND USAGE
`1
`Testim® is indicated for testosterone 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 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 Testim in males less than 18 years old have not been established
`[see Use in Specific Populations (8.4)].
` Topical testosterone products may have different doses, strengths, or application
`
`instructions that may result in different systemic exposure [see Dosage and
`
`Administration (2) and Clinical Pharmacology (12.3)].
`
`
`DOSAGE AND ADMINISTRATION
`2
`Dosing and Dose Adjustment
`2.1
`The recommended starting dose of Testim® is 50 mg of testosterone (one tube) applied once
`daily (preferably in the morning) to clean, dry intact skin of the shoulders and/or upper arms.
`Dose Adjustment
`To ensure proper dosing, serum testosterone concentrations should be measured. Morning, pre-
`dose serum testosterone concentrations should be measured approximately 14 days after
`initiation of therapy to ensure proper serum testosterone concentrations are achieved. If the
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`serum testosterone concentration is below the normal range (300 ng/dL to 1,000 ng/dL), the daily
`Testim dose may be increased from 50 mg testosterone (one tube) to 100 mg testosterone (two
`tubes) once daily.
`The maximum recommended dose of Testim is 100 mg once daily.
`The application site and dose of Testim are not interchangeable with other topical testosterone
`products.
`2.2
`Administration Instructions
`Upon opening the tube the entire contents should be squeezed into the palm of the hand and
`immediately applied to the shoulders and/or upper arms (area of application should be limited to
`the area that will be covered by the patient’s short sleeve T-shirt (see figure below). Do not apply
`Testim to the genitals or to the abdomen.
`
`Application sites should be allowed to dry for a few minutes prior to dressing. Hands should be
`washed thoroughly with soap and water after Testim has been applied. Avoid fire, flame or
`smoking during the application of Testim until the Testim has dried [see Warnings and
`Precautions (5.2, 5.13)].
`In order to prevent transfer to another person, wear clothing to cover the application sites. If
`direct skin-to-skin contact with another person is anticipated, the application sites must be
`washed thoroughly with soap and water [see Warnings and Precautions (5.2) and Clinical
`Pharmacology (12.3)].
`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)].
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`Strict adherence to the following precautions is advised in order to minimize the potential
`for secondary exposure to testosterone from Testim-treated skin:
`
` Children and women should avoid contact with unwashed or unclothed application
`site(s) of men using Testim.
` Testim 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 Testim.
` 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 Testim 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.
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`Testim® (testosterone gel) for topical use is available in a unit-dose tube. Each tube contains
`50 mg testosterone in 5 g of gel.
`4
` CONTRAINDICATIONS
`
` Testim is contraindicated in men with carcinoma of the breast or known or suspected
`carcinoma of the prostate [see Warnings and Precautions (5.1)].
` Testim is contraindicated in women who are or may become pregnant, or who are
`breastfeeding. Testim may cause fetal harm when administered to a pregnant woman.
`Testim 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 Testim. If a pregnant woman is exposed to Testim,
`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)].
`
`WARNINGS AND PRECAUTIONS
`5
`5.1 Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate
`Cancer
`
` Patients with BPH treated with androgens are at an increased risk for worsening of signs
`and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms.
` Patients treated with androgens may be at increased risk for prostate cancer. Evaluate
`patients for prostate cancer prior to initiating and during treatment with androgens [see
`Contraindications (4)].
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`Potential for Secondary Exposure to Testosterone
`5.2
`Cases of secondary exposure resulting in virilization of children have been reported in
`postmarketing surveillance. Signs and symptoms have included enlargement of the penis or
`clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and
`advanced bone age. In most cases, these signs and symptoms regressed with removal of the
`exposure to testosterone gel. In a few cases, however, enlarged genitalia did not fully return to
`age-appropriate normal size, and bone age remained modestly greater than chronological age.
`The risk of transfer was increased in some of these cases by not adhering to precautions for the
`appropriate use of the topical testosterone product. Children and women should avoid contact
`with unwashed or unclothed application sites in men using Testim [see Dosage and
`Administration (2.2), Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].
`Inappropriate changes in genital size or development of pubic hair or libido in children, or
`changes in body hair distribution, significant increase in acne, or other signs of virilization in
`adult women should be brought to the attention of a physician and the possibility of secondary
`exposure to testosterone gel should also be brought to the attention of a physician. Testosterone
`gel should be promptly discontinued until the cause of virilization has been identified.
`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
`Use in Women
`Due to lack of controlled evaluations in women and potential virilizing effects, Testim is not
`indicated for use in women [see Contraindications (4) and Use in Specific Populations (8.1,
`8.3)].
`Potential for Adverse Effects on Spermatogenesis
`5.5
`With large doses of exogenous androgens, including Testim, spermatogenesis may be suppressed
`through feedback inhibition of pituitary follicle-stimulating hormone (FSH) which could
`possibly lead to adverse effects on semen parameters including sperm count.
`5.6 Hepatic Adverse Effects
`Prolonged use of high doses of orally active 17-alpha-alkyl androgens (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, which elevates
`blood levels for prolonged periods, has produced multiple hepatic adenomas. Testim is not
`known to cause these adverse effects. Nonetheless, patients should be instructed to report any
`signs or symptoms of hepatic dysfunction (e.g., jaundice). If these occur, promptly discontinue
`Testim while the cause is evaluated.
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`Edema
`5.7
`Androgens, including Testim, 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. In addition to discontinuation of the drug, diuretic therapy may
`be required.
`5.8 Gynecomastia
`Gynecomastia occasionally develops and occasionally persists in patients being treated for
`hypogonadism [see Adverse Reactions (6.1)].
`5.9
`Sleep Apnea
`The treatment of hypogonadal men with testosterone may potentiate sleep apnea in some
`patients, especially those with risk factors such as obesity or chronic lung diseases.
`5.10 Lipids
`Changes in the serum lipid profile may occur. Monitor the lipid profile periodically, particularly
`after starting testosterone therapy and after dose increases.
`5.11 Hypercalcemia
`Androgens, including Testim, should be used with caution in cancer patients at risk of
`hypercalcemia (and associated hypercalciuria). Regular monitoring of serum calcium
`concentrations is recommended in these patients.
`5.12 Decreased Thyroxine-binding Globulin
`Androgens, including Testim, may decrease concentrations of thyroxine-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.
`5.13 Flammability
`Alcohol-based products, including Testim, are flammable; therefore, patients should be
`advised to avoid fire, flame or smoking until the Testim has dried.
`6
`ADVERSE REACTIONS
`6.1
`Clinical Studies 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.
`In a controlled clinical study, 304 patients were treated with Testim® 50 mg or 100 mg or
`placebo gel for up to 90 days. Two hundred-five (205) patients received Testim 50 mg or 100 mg
`daily and 99 patients received placebo. Subjects could be counted in both Testim treatment
`groups if they received both 50 mg and 100 mg at different points in the study and experienced
`an adverse reaction at both dose levels. Adverse reactions reported by 1% of the Testim patients
`and greater than placebo are listed in Table 1.
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`Table 1: Incidence of Adverse Reactions (Reported by 1% of the
`Testim Patients and Greater than Placebo) in the Controlled Clinical
`Trial Through 90 Days
`Testim
`50 mg
`(n=103)
`2%
`1%
`1%
`1%
`1%
`
`Testim
`100 mg
`(n=149)
`4%
`1%
`0%
`1%
`2%
`
`Placebo
`
`(n=99)
`3%
`0%
`0%
`0%
`0%
`
`Event
`
`Application Site Reactions
`Blood Pressure Increased
`Gynecomastia
`Headache
`Hematocrit/hemoglobin
`Increased
`Hot Flushes
`Insomnia
`Mood Swings
`Smell Disorder
`Spontaneous Penile
`Erection
`Taste Disorder
`
`1%
`1%
`1%
`1%
`1%
`
`1%
`
`0%
`0%
`0%
`0%
`0%
`
`1%
`
`0%
`0%
`0%
`0%
`0%
`
`0%
`
`The following adverse reactions occurred in fewer than 1% of patients but were greater in Testim
`groups compared to the placebo group: activated partial thromboplastin time prolonged, blood
`creatinine increased, prothrombin time prolonged, appetite increased, sensitive nipples, and acne.
`In this clinical trial of Testim, six patients had adverse reactions that led to their discontinuation.
`These events included: depression with suicidal ideation, urinary tract infection, mood swings
`and hypertension. No Testim patients discontinued due to skin reaction. In one foreign Phase 3
`trial, one subject discontinued due to a skin-related adverse reaction.
`In the pivotal U.S. and European Phase 3 trials combined, at the 50 mg dosage strength, the
`percentage of subjects reporting clinically notable increases in hematocrit or hemoglobin were
`similar to placebo. However, in the 100 mg dose group, 2.3% and 2.8% of patients had a
`clinically notable increase in hemoglobin ( 19 g/dL) or hematocrit ( 58%), respectively,
`compared to 1.0% and 1.5% of patients in the placebo group, respectively.
`In the combined US and European open label extension studies, approximately 140 patients
`received Testim for at least 6 months. The results from these studies are consistent with those
`reported for the US controlled clinical trial.
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`Postmarketing Experience
`6.2
`The following adverse reactions have been identified during post-approval use of testosterone gel
`products. 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.
`Secondary Exposure to Testosterone in Children
`Cases 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 of
`the penis, development of pubic hair, increased erections and libido, aggressive behavior, and
`advanced bone age. In most cases with a reported outcome, these signs and symptoms were
`reported to have regressed with removal of the testosterone gel exposure. In a few cases,
`however, enlarged genitalia did not fully return to age-appropriate normal size, and bone age
`remained modestly greater than chronological age. In some of the cases, direct contact with the
`sites of application on the skin of men using testosterone gel was reported. In at least one
`reported case, the reporter considered the possibility of secondary exposure from items such as
`the testosterone gel user’s shirts and/or other fabric, such as towels and sheets [see Warnings and
`Precautions (5.2)].
`7
`DRUG INTERACTIONS
`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 necessitate a decrease in the dose of anti-diabetic medication.
`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 warfarin, especially at the initiation and termination of androgen therapy.
`7.3
`Corticosteroids
`The concurrent use of testosterone with corticosteroids may result in increased fluid retention
`and requires careful monitoring particularly in patients with cardiac, renal or hepatic disease.
`8
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`Pregnancy Category X [see Contraindications (4)]: Testim® is contraindicated in pregnant
`women or in women who may become pregnant. Testosterone is teratogenic and may cause fetal
`harm. Exposure of a fetus to androgens, such as testosterone, 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.
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`Nursing Mothers
`8.3
`Although it is not known how much testosterone transfers into human milk, Testim is
`contraindicated in nursing women because of the potential for serious adverse reactions in nursing
`infants [see Contraindications (4)].
`8.4
`Pediatric Use
`The safety and effectiveness of Testim in pediatric patients less than 18 years old have not been
`established. Improper use may result in acceleration of bone age and premature closure of epiphyses.
`8.5 Geriatric Use
`There is insufficient long-term safety data in geriatric patients to assess the potentially increased
`risks of cardiovascular disease and prostate cancer [see Warnings and Precautions (5.1)].
`8.6
`Renal Impairment
`No studies were conducted in patients with renal impairment.
`8.7 Hepatic Impairment
`No studies were conducted in patients with hepatic impairment.
`9
`DRUG ABUSE AND DEPENDENCE
`9.1
`Controlled Substance
`Testim® contains testosterone, a Schedule III controlled substance in the Controlled Substances
`Act.
`Abuse
`9.2
`Anabolic steroids, such as testosterone, are abused. Abuse is often associated with adverse
`physical and psychological effects.
`9.3
`Dependence
`Although drug dependence is not documented in individuals using therapeutic doses of anabolic
`steroids for approved indications, dependence is observed in some individuals abusing high
`doses of anabolic steroids. In general, anabolic steroid dependence is characterized by any three
`of the following:
`
` Taking more drug than intended
` Continued drug use despite medical and social problems
` Significant time spent in obtaining adequate amounts of drug
` Desire for anabolic steroids when supplies of the drugs are interrupted
` Difficulty in discontinuing use of the drug despite desires and attempts to do so
` Experience of a withdrawal syndrome upon discontinuation of anabolic steroid use
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`OVERDOSAGE
`10
`There were no reports of overdose in the Testim® clinical trials. There is a single report in the
`literature of acute overdosage after injection of testosterone enanthate. This subject had serum
`testosterone concentrations of up to 11,400 ng/dL, which were implicated in a cerebrovascular
`accident.
`Treatment of overdosage would consist of discontinuation of Testim, washing the application
`site with soap and water, and appropriate symptomatic and supportive care.
`11
`DESCRIPTION
`Testim® (testosterone gel) is a clear to translucent hydroalcoholic topical gel containing
`testosterone, an androgen. Testim provides continuous transdermal delivery of testosterone for
`24 hours, following a single application to intact, clean, dry skin of the shoulders and/or upper
`arms.
`One 5-g or two 5-g tubes of Testim contains 50 mg or 100 mg of testosterone, respectively, 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 pharmacological ingredient in Testim is testosterone. Testosterone USP is a white to
`practically white crystalline powder chemically described as 17- hydroxyandrost-4-en-3-one.
`The structural formula is shown in the following figure:
`
`MW: 288.42
`
`0 /2-
`
`H
`
`Testosterone
`
`Inactive ingredients in Testim are purified water, pentadecalactone, carbopol, acrylates,
`propylene glycol, glycerin, polyethylene glycol, ethanol (74%), and tromethamine.
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`CLINICAL PHARMACOLOGY
`12
`12.1 Mechanism of Action
`Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsible
`for the normal growth and development of the male sex organs and for maintenance of secondary
`sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles,
`penis and scrotum; the development of male hair distribution, such as facial, pubic, chest and
`axillary hair; laryngeal enlargement; vocal cord thickening; and 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 can present as primary hypogonadism caused by defects of the gonads, such
`as Klinefelter's Syndrome or Leydig cell aplasia, while secondary hypogonadism
`(hypogonadotropic 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 Testim.
`12.3 Pharmacokinetics
`Absorption
`Testim® (testosterone gel) delivers physiologic amounts of testosterone, producing circulating
`testosterone concentrations that approximate normal concentrations (e.g., 300 – 1000 ng/dL)
`seen in healthy men.
`The skin serves as a reservoir for the sustained release of testosterone into the systemic
`circulation. Approximately 10% of the testosterone applied on the skin surface is absorbed into
`the systemic circulation during a 24-hour period.
`Single Dose
`In single dose studies, when either Testim 50 mg or 100 mg was administered, absorption of
`testosterone into the blood continued for the entire 24 hour dosing period. Also, mean peak and
`average serum concentrations within the normal range were achieved within 24 hours.
`Multiple Dose
`With single daily applications of Testim 50 mg and 100 mg, follow-up measurements at 30 and
`90 days after starting treatment have confirmed that serum testosterone and DHT concentrations
`are generally maintained within the normal range.
`Figure 1 summarizes the 24-hour pharmacokinetic profile of testosterone for patients maintained
`on Testim 50 mg or Testim 100 mg for 30 days.
`
`Reference ID: 3365948
`
`12
`
`
`00012
`
`

`

`Figure 1
`Mean Steady-State Serum Testosterone (±SD) (ng/dL) Concentrations on Day 30 in Patients Applying Testim
`Once Daily
`
`1200
`
`~ 1000 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
`
`800
`
`! C
`J
`i I
`
`600
`
`400
`
`200
`
`O ' - - - r - - - - -~ - - -~ - - - -~ - - - -~ - - -~ - - -~
`12
`24
`0
`4
`8
`16
`20
`
`Hours
`
`T T T Teslim® 50 mg/day * * * Teslim® 100 mg/day
`The average daily testosterone concentration produced by Testim 100 mg at Day 30 was
`612 ( 286) ng/dL and by Testim 50 mg at Day 30 was 365 ( 187) ng/dL.
`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. The average daily DHT
`concentration produced by Testim 100 mg at Day 30 was 555 ( 293) pg/mL and by Testim
`50 mg at Day 30 was 346 ( 212) pg/mL.
`
`Reference ID: 3365948
`
`13
`
`
`00013
`
`

`

`Figure 2 summarizes the 24-hour pharmacokinetic profile of DHT for patients maintained on
`Testim 50 mg or Testim 100 mg for 30 days.
`Figure 2
`Mean Steady-State Serum Dihydrotestosterone (±SD) (pg/mL) Concentrations on Day 30 in Patients
`Applying Testim Once Daily
`
`TTT Testim®SO m,g/ day
`
`* ** T estim® 100 m,g/ day
`
`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.
`Potential for Testosterone Transfer from Male Patients to Female Partners
`The potential for dermal testosterone transfer following Testim use was evaluated in two clinical
`trials with males dosed with Testim and their untreated female partners.
`In the first trial, 30 couples were evenly randomized to five groups. In the first four groups, 100
`mg of Testim was applied to the male abdomen and the couples were then asked to rub
`abdomen-to-abdomen for 15 minutes at 1 hour, 4 hours, 8 hours or 12 hours after dose
`application, respectively. In these couples, serum testosterone concentrations in female partners
`increased from