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CLINICAL PHARMACOLOGY Testosterone The TESTODERM (testosterone (transdermal)) ® products deliver physiologic amounts of testosterone, the primary endogenous androgenic hormone. Endogenous testosterone serum concentrations in normal males follow a circadian pattern. Daily morning application of any of the TESTODERM (testosterone (transdermal)) ® products results in a serum testosterone profile that approximates the natural endogenous pattern of normal men. General Androgen Effects Endogenous androgens, including testosterone and dihydrotesterone (DHT), are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement, vocal chord thickening, alterations in body musculature, and fat distribution. DHT is 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. Symptoms associated with male hypogonadism include impotence and decreased sexual desire, fatigue and loss of energy, mood depression, and regression of secondary sexual characteristics. Drugs in the androgen class also cause retention of nitrogen, sodium, potassium, phosphorus, and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when there is sufficient intake of calories and protein. Androgens are responsible for the growth spurt of adolescence and for the eventual termination of linear growth brought about by fusion of the epiphyseal growth centers. In children, exogenous androgens accelerate linear growth rates but may cause a disproportionate advancement in bone maturation. Use over long periods may result in fusion of the epiphyseal growth centers and termination of the growth process. Androgens have been reported to stimulate the production of red blood cells by enhancing the production of erythropoietin. During exogenous administration of androgens, endogenous testosterone release may be inhibited through feedback inhibition of pituitary luteinizing hormone (LH). At large does of exogenous androgens, spermatogenesis may also be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH). There is a lack of substantial evidence that androgens are effective in accelerating fracture healing or in shortening post-surgical convalescence. Pharmacokinetics Absorption Daily morning application of any of the TESTODERM (testosterone (transdermal)) ® products approximates the natural endogenous pattern of serum testosterone of normal males. Following application, testosterone is continuously absorbed during the 24-hour dosing period. The serum testosterone concentration rises to a maximum at 2 to 4 hours and return toward baseline within approximately 2 hours after system removal. The testosterone levels achieved with TESTODERM (testosterone (transdermal)) ® products generally are within the range for normal men. Patients vary in their ability to absorb testosterone transdermally (see Clinical Studies). TESTODERM (testosterone (transdermal)) ® TTS For TESTODERM (testosterone (transdermal)) ® TTS three skin sites (arm, back, and upper buttocks), representing recommended application sites, are interchangeable based on equivalent testosterone AUC (0-27) (area under serum concentration curve) values. In clinical trials, 94% of patients on TESTODERM (testosterone (transdermal)) TTS treatment achieved maximum and average serum testosterone concentrations (Cmax and Cavg, respectively) within the normal range; the average Cmax and Cavg serum testosterone concentrations were 531 ng/dL and 366 ng/dL, respectively. Within-subject coefficient of variation in testosterone Cavg for subjects on TESTODERM (testosterone (transdermal)) TTS therapy was 17%. The typical steady state serum testosterone concentration pattern achieved with a nominal testosterone dose of 5 mg/day from TESTODERM (testosterone (transdermal)) TTS is shown in Figure 1. Figure 1. Serum concentrations of testosterone (mean ± SD) during pretreatment baseline or while wearing a TESTODERM (testosterone (transdermal)) TTS system on the upper buttocks (n=32). Systems were applied at 0 hours (8 AM) and removed 24 hours later. Normal range serum testosterone concentrations are reached during the first day of dosing. There is no accumulation of testosterone following repeated application of TESTODERM (testosterone (transdermal)) TTS. Two TESTODERM (testosterone (transdermal)) TTS systems deliver a testosterone dose which is twice that delivered by a single system. There is no first-pass skin metabolism of testosterone to DHT when applied to arm, back or upper buttocks skin sites as recommended. TESTODERM (testosterone (transdermal)) Scrotal skin is at least five times more permeable to testosterone than other skin sites. TESTODERM (testosterone (transdermal)) or TESTODERM (testosterone (transdermal)) WITH ADHESIVE will not produce adequate serum testosterone concentrations if applied to non-scrotal skin. Hypogonadal men using TESTODERM (testosterone (transdermal)) therapy have trough serum testosterone concentrations that are about 15% of peak levels. Serum levels reach a plateau at 3 to 4 weeks. TESTODERM (testosterone (transdermal)) WITH ADHESIVE Data from a pharmacokinetic trial in 50 normal male subjects show that TESTODERM (testosterone (transdermal)) WITH ADHESIVE applied to scrotal skin is equivalent to TESTODERM (testosterone (transdermal)) with respect to rate (Cmax) and extent (AUC) of testosterone delivery. Distribution Circulating testosterone is chiefly bound in the serum to sex hormone-binding globulin (SHBG) and albumin. The albumin-bound fraction of testosterone easily dissociates from albumin and is presumed to be bioactive. The portion of testosterone bound to SHBG is not considered biologically active. The amount of SHBG in the serum and the total testosterone level will determine the distribution of bioactive and nonbioactive androgen. SHBG-binding capacity is high in prepubertal children, declines during puberty and adulthood, and increases again during the later decades of life. Metabolism There is considerable variation in the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes. Testosterone is a substrate for conversion to an active metabolite, dihydrotestosterone (DHT). Testosterone is metabolized to various 17-keto steroids through two different pathways, and the major active metabolites are estradiol and DHT. Concentrations of estradiol in normal men are 1.0 to 5.0 ng/dL. DHT concentrations in normal male serum are 30 to 85 ng/dL. DHT binds with greater affinity to SHBG than does testosterone. In many tissues the activity of testosterone appears to depend on reduction to DHT, which binds to cytosol receptor proteins. The steroid-receptor complex is transported to the nucleus where it initiates transcription and cellular changes related to androgen action. In reproductive tissues, DHT is further metabolized to 3-alpha and 3-beta androstanediol. Composite results of all studies with TESTODERM (testosterone (transdermal)) show elevated DHT concentrations and a change in the ratio of testosterone to DHT (T/DHT) during treatment. The range in this ratio was 0.7 - 12.5, as compared with a ratio of 3.6 - 15.2 in normal untreated men. The long-term effects of the change in this ratio are not known. The T/DHT ratio during TESTODERM (testosterone (transdermal)) TTS treatment was not statistically significantly different from placebo treatment. Excretion About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. Special Populations Geriatric In clinical trials with TESTODERM (testosterone (transdermal)) TTS, Cavg testosterone concentrations were not different between men aged 65 and older and younger adult males. Race There is insufficient information available from trials with the TESTODERM (testosterone (transdermal)) products to compare testosterone pharmacokinetics in different racial groups. Renal Insufficiency There is no experience with the use of the TESTODERM (testosterone (transdermal)) products in patients with renal insufficiency. Hepatic Insufficiency There is no experience with the use of the TESTODERM (testosterone (transdermal)) products in patients with hepatic insufficiency. Drug-Drug Interactions See PRECAUTIONS: Drug Interactions. Clinical Studies TESTODERM (testosterone (transdermal)) TTS Of 32 hypogonadal men receiving daily application of a single TESTODERM (testosterone (transdermal)) TTS system, 94% achieved normal serum concentrations of testosterone as determined by Cmax and Cavg (200-1000 ng/dL). Mean free testosterone, estradiol, and dihydrotestosterone concentrations were also in the normal range after application of TESTODERM (testosterone (transdermal)) TTS. TESTODERM (testosterone (transdermal)) and TESTODERM (testosterone (transdermal)) WITH ADHESIVE After at least 3 weeks of TESTODERM (testosterone (transdermal)) therapy when steady-state is obtained, 30 hypogonadal men treated with 6 mg/d systems for 22 hours daily achieved mean maximum serum testosterone concentrations of 593 ng/dL at 2 to 4 hours post application. Sixty percent of the patients achieved individual maximal testosterone concentrations >500 ng/dL. The mean 24 hour steady-state AUC (area under the curve) value was 9132 ng/dL. The mean DHT serum concentrations ranged from 134 to 162 ng/dL. Normal levels of testosterone have been maintained in patients who have worn the systems for up to six years. DHT levels also remain stable. The increase in serum testosterone concentration is proportional to the size of the system. The variability of total testosterone concentrations among patients receiving TESTODERM (testosterone (transdermal)) treatment was 35% to 49%. The coefficient of variation of total testosterone concentrations within individual patients was 30% to 41%. This variability is comparable to the values reported in the literature for both normal and hypogonadal men. In two 12-week clinical studies in 72 hypogonadal men, TESTODERM (testosterone (transdermal)) therapy produced positive effects on mood and sexual behavior. By five weeks, 45 patients not previously treated with TESTODERM (testosterone (transdermal)) showed statistically significant increases in sexual activity. Compared to baseline, mean sexual events per week increased for sexual intercourse (0.3 to 0.8), orgasm (0.4 to 1.2), waking erections (1.0 to 3.5), and spontaneous erections (0.4 to 2.8). Changes in nonfasting serum lipid concentrations were observed during TESTODERM (testosterone (transdermal)) therapy. By three months total cholesterol and high-density lipoprotein cholesterol decreased an average of 8% and 13%, respectively. High-density lipoprotein cholesterol remained stable thereafter. Total cholesterol continued to decrease through two years. At the end of two years, the total cholesterol/high-density lipoprotein cholesterol ratio was not different from pretreatment values. Estradiol levels increased to the normal range with treatment. Sporadic elevations of estradiol above the normal range for men were observed in 3 of 72 patients and these were not associated with feminizing side effects.

CLINICAL PHARMACOLOGY Mechanism Of Action Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis and scrotum; the development of male hair distribution, such as facial, pubic, chest and axillary hair; laryngeal enlargement, vocal chord thickening, alterations in body musculature and fat distribution. Testosterone and DHT are necessary for the normal development of secondary sex characteristics. Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter's syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH). Pharmacodynamics No pharmacodynamic studies were conducted using Striant. Pharmacokinetics Absorption When applied to the buccal mucosa, Striant releases testosterone, allowing for absorption of testosterone through gum and cheek surfaces that are in contact with the buccal system. Since venous drainage from the mouth is to the superior vena cava, trans-buccal delivery of testosterone circumvents first-pass (hepatic) metabolism. Following the initial application of Striant, the serum testosterone concentration rises to a maximum within 10-12 hours. The mean maximum (Cmax) and mean average serum total testosterone concentrations for the 12 hour dosing period (Cavg(0-12)) are within the normal physiologic range. Striant is intended for twice daily dosing. Serum concentrations of testosterone reach steady-state levels after the second dose of twice daily Striant dosing. Following removal of Striant, the serum testosterone concentration decreases to a level below the normal range within 2-4 hours. Figure 2: Mean (SD) total testosterone concentration-time curves on Day 7 (after 7 days of Striant treatment, n=29) Although no specific food effect study was conducted, Phase 3 study results showed that consumption of food and beverage did not significantly affect the absorption of testosterone from Striant. The effects of toothbrushing, mouth washing, chewing gum and alcoholic beverages on the use and absorption of Striant were not investigated in controlled studies. However, Phase 3 clinical studies permitted patients to do these activities indicating the use of Striant was not significantly affected by these activities. Distribution Circulating testosterone is chiefly bound in the serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins. Metabolism Testosterone is metabolized to various 17-keto steroids through two different pathways, and the major active metabolites are estradiol and dihydrotestosterone (DHT). Mean DHT concentrations increased in parallel with testosterone concentrations during Striant treatment. After 24 hours of treatment, mean (SD) DHT serum concentrations was approximately 80 (50) ng/dL. The mean steady-state T/DHT ratio during treatment with Striant ranged approximately 9-12. Excretion There is considerable variation in the half-life of testosterone as reported in the literature, ranging from ten to 100 minutes. About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. Geriatrics In patients 65 years of age and older, the total testosterone Cavg(0-24) value was higher by 13% compared to patients < 65 years of age. In addition, the total T to DHT area-under-the curve ratio was lower in the older population compared to the younger population by 16%. These differences may not be clinically significant. Clinical Studies Clinical Trials In Adult Hypogonadal Males Striant was evaluated in a multicenter, open-label Phase 3 trial in 98 hypogonadal men. In this study, 30 mg of Striant was administered buccally twice daily for 12 weeks. The mean age was 53.6 years (range 20 to 75 years). Overall, 69% of patients were Caucasian, 9% were African-American, 15% were Hispanic, 4% were Asian, and 2% were of another ethnic origin. At baseline, 10% of patients reported current use of tobacco and 42% drank alcohol. Of 82 patients who completed the trial and had sufficient data for full analysis, 86.6% had mean serum testosterone concentration (Cavg(0-24)) values within the physiologic range (300-1050 ng/dL). The mean (±SD) time-averaged steady-state daily testosterone concentration (Cavg(0-24)) at Day 84 was 520 (±205) ng/dL compared with a mean of 149 (±99) ng/dL at Baseline. The mean (±SD) maximum testosterone concentration (Cmax) at Day 84 was 970 (±442) ng/dL. At Day 84, the mean percentage of time over the 24-hour sampling period that total testosterone concentrations remained within the normal range of 300-1050 ng/dL was 76%. Figure 3 shows the mean total testosterone serum concentration versus time curves on Day 84 (after 12 weeks of Striant treatment). Figure 3: Mean (SD) total testosterone concentration-time curves on Day 84 (after 12 weeks of Striant treatment, n=82) Mean DHT concentrations increased in parallel with testosterone concentrations, with the total testosterone/DHT ratio (9-12) indicating no alteration in metabolism of testosterone to DHT in testosterone deficient men treated with Striant. During continuous treatment there was no accumulation of testosterone, and mean total testosterone, free testosterone, and DHT were maintained within their physiologic ranges.

DESCRIPTION TESTODERM (testosterone transdermal) ®TTS, TESTODERM (testosterone transdermal) ® and TESTODERM (testosterone transdermal) ® WITH ADHESVIE Testosterone Transdermal Systems (referred to collectively as the TESTODERM (testosterone transdermal) ® products) are designed to release controlled amounts of testosterone, the primary circulating endogenous androgen, continuously upon application to the arm, back or upper buttocks (TESTODERM (testosterone transdermal) ®TTS) or scrotal skin (TESTODERM (testosterone transdermal) ® and TESTODERM (testosterone transdermal) ® WITH ADHESVIE). The TESTODERM (testosterone transdermal) ® products are described below. Product Dose (mg/day) Size (cm2) Application Site Testoderm (testosterone transdermal) ® TTS 5 60 Arm, Back, Upper Buttocks Testoderm®* 5 60 Scrotum Testoderm®* 4 40 Scrotum Testoderm (testosterone transdermal) ® with Adhesive 6 60 Scrotum * The composition of the two sizes per unit area is identical. The active component of each of the systems is testosterone. Testosterone USP is a white or creamy-white crystalline powder or crystals chemically described as 17-beta hydroxyandrost-4-en-3-one. The remaining components of the systems are pharmacologically inactive. TESTODERM (testosterone transdermal) ® TTS is composed of the following layers: a flexible backing of polyester/ethylene-vinyl acetate copolymer film, a drug reservoir of testosterone USP and 1.2 mL alcohol USP gelled with hydroxypropyl cellulose, and an ethylene-vinyl acetate copolymer membrane coated with a layer of a polyisobutylene adhesive formulation that controls the rate of release of testosterone from the system. A protective liner of silicone-coated polyester covers the adhesive surface. The liner must be removed before application. TESTODERM (testosterone transdermal) ® is composed of two layers: a soft flexible backing of polyester and a testosterone-containing film of ethylene-vinyl acetate copolymer that contacts the skin surface and modulates the availability of the steroid. A protective liner of fluorocarbon diacrylate or silicone-coated polyester covers the drug film. The liner must be removed before application. TESTODERM (testosterone transdermal) ® WITH ADHESVIE is composed of three layers: a soft flexible backing of polyester and a testosterone-containing film of ethylene-vinyl acetate copolymer. The surface of the drug film is partially covered by the third layer: thin and narrow adhesive stripes composed of polyisobutylene and colloidal silicon dioxide. A protective liner of fluorocarbon diacrylate covers the adhesive stripes and the adhesive-free area of the drug film. The liner must be removed before application. The active component of the systems is testosterone. The remaining components of the systems are pharmacologically inactive.

Find Lowest Prices on Striant (testosterone buccal system) Mucoadhesive DESCRIPTION Striant (testosterone buccal system) mucoadhesive is for buccal administration only. It contains testosterone, an androgen. Striant is designed to adhere to the gum or inner cheek. It provides a controlled and sustained release of testosterone through the buccal mucosa as the buccal system gradually hydrates. Application of Striant twice a day, in the morning and in the evening, provides continuous systemic delivery of testosterone. Striant is a white to off-white colored, monoconvex, tablet-like, mucoadhesive buccal system. Striant adheres to the gum tissue above the incisors, with the flat surface facing the cheek mucosa. The active ingredient in Striant is testosterone (see Figure 1). Each buccal system contains 30 mg of testosterone. Testosterone USP is practically white crystalline powder chemically described as 17-beta hydroxyandrost-4-en-3one. Figure 1: Chemical Structure of Testosterone Other pharmacologically inactive ingredients in Striant are anhydrous lactose NF, carbomer 934P, hypromellose USP, magnesium stearate NF, lactose monohydrate NF, polycarbophil USP, colloidal silicon dioxide NF, starch NF and talc USP.

INDICATIONS Striant 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 (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) above the normal range. Hypogonadotropic hypogonadism (congenital or acquired) –Gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency, or pituitary hypothalamic injury from tumors, trauma, or radiation. These patients have low serum testosterone levels but have gonadotropins in the normal or low range. Limitations of use Safety and efficacy of Striant in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established. Safety and efficacy of Striant in males less than 18 years old have not been established [see Use in Specific Populations]. DOSAGE AND ADMINISTRATION Prior to initiating, Striant 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. Dosage Information The recommended dosage for Striant is the application of one buccal system (30 mg) to the gum region twice daily; morning and evening (about 12 hours apart). To ensure proper dosing, serum testosterone concentrations should be measured. Morning, pre-dose serum testosterone concentrations should be measured at 4 to 12 weeks after initiation of therapy to ensure proper serum testosterone concentrations are achieved. Striant therapy should be discontinued if serum testosterone concentrations are consistently outside of the normal range (300 to 1050 ng/dL) despite the use of one buccal system applied twice daily. Administration Instructions Striant should be placed in a comfortable position just above the incisor tooth (on either side of the mouth). With each application, Striant should be rotated to alternate sides of the mouth. Upon opening the packet, the rounded side surface of the buccal system should be placed against the gum and held firmly in place with a finger over the lip and against the product for 30 seconds to ensure adhesion. Striant is designed to stay in position until removed. If the buccal system fails to properly adhere to the gum or should fall off during the 12-hour dosing interval, the old buccal system should be removed and a new one applied. If the buccal system falls out of position within the first 8 hours of dosing, replace with a new system and continue for a total of 12 hours from the placement of the first system. If the system falls out of position after 8 hours of dosing, a new buccal system should be applied and it may remain in place for 12 hours then continue with the next regularly scheduled dosing. Patients should take care to avoid dislodging the buccal system. Patients should check to see if Striant is in place following consumption of food or alcoholic/non-alcoholic beverages. Striant should not be chewed or swallowed. To remove Striant, gently slide it downwards from the gum toward the tooth to avoid scratching the gum. The Striant buccal system should be removed before routine morning and evening oral care is performed, followed by application of a new buccal system. HOW SUPPLIED Dosage Forms And Strengths Each Striant buccal system contains 30 mg of testosterone. It is white to off-white colored with a flat edge on one side and a convex surface on the other. Striant is debossed on its flat side, as shown below: A Storage And Handling Striant (testosterone buccal system) mucoadhesive is supplied in transparent blister packs containing 10 doses. It is white to off-white colored with a flat edge on one side and a convex surface on the other. Striant is debossed on its flat side, as shown below: A Each Striant buccal system contains 30 mg of testosterone and is supplied as follows: NDC Number Package Size 52244-030-60 6 blister packs, 10 buccal systems per blister pack, 30 mg of testosterone per buccal system Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature]. Protect from heat and moisture. Damaged blister packages should not be used. Discard used Striant buccal systems in household trash in a manner that prevents accidental application or ingestion by children or pets. Manufactured by: Mipharm S.p.A, Milan, Italy Manufactured for: Actient Pharmaceuticals LLC, Chesterbrook, PA 19087. Revised: May 2015

PATIENT INFORMATION STRIANT® (STRI' ant) (testosterone buccal system) mucoadhesive Read this Patient Information before you start using Striant and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is Striant? Striant is prescription medicine that contains testosterone. Striant is used to treat adult males who have low or no testosterone due to certain medical conditions. Your healthcare provider will test your blood for testosterone before you start and while you are using Striant. It is not known if Striant is safe or effective to treat men who have low testosterone due to aging. It is not known if Striant is safe and effective in children younger than 18 years old. Improper use of testosterone may affect bone growth in children. Striant is a controlled substance (CIII) because it contains testosterone that can be a target for people who abuse prescription medicines. Keep your Striant in a safe place to protect it. Never give your Striant to anyone else, even if they have the same symptoms you have. Selling or giving away this medicine may harm others and it is against the law. Striant is not meant for use by women. Who should not use Striant? Do not use Striant if you: are a man who has breast cancer have or might have prostate cancer are pregnant or may become pregnant or are breastfeeding. Striant may harm your unborn or breastfeeding baby. Talk to your healthcare provider before using this medicine if you have any of the above conditions. What should I tell my healthcare provider before using Striant? Before you use Striant, tell your healthcare provider if you: have breast cancer have or might have prostate cancer have problems urinating due to an enlarged prostate have heart problems have kidney or liver problems have problems breathing while you sleep (sleep apnea) have diabetes have any other medical conditions Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Using Striant with other medicines can affect each other. Especially tell your healthcare provider if you take: insulin medicines that decrease blood clotting corticosteroids Know the medicines you take. Ask your healthcare provider or pharmacist for a list of all your medicines if you are not sure. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I use Striant? Apply Striant exactly as your healthcare provider tells you to. Striant is applied 1 time in the morning (after your routine oral care) and 1 time in the evening (about 12 hours apart). Change (rotate) your application site to the other side of your mouth with each application. Striant should stay on the application site until you take it off. If your Striant becomes loose or falls off, throw it away and put on a new one. Check to make sure that Striant is still in place after you brush your teeth, use mouthwash, or have anything to eat or drink. Do not chew or swallow Striant. Remove Striant by gently sliding it to the front or back of your mouth to loosen it. Then slide it downwards from your gum to your tooth. This will avoid scratching the gum. Applying Striant: Striant is to be applied to your upper gum, just above either the left or right incisor tooth. The incisor is the tooth just to the right or left of your 2 front teeth. Remove your Striant from the package. Tear off 1 Striant. Start at the corner tab and peel off paper backing (See Figure A). Figure A Push Striant through the foil from the front (See Figure B). Figure B Check Striant. Striant is curved on one side and flat on the other side. The flat side has the letter “A” marked on it (See Figure C). Figure C Apply Striant. Place the flat side of the Striant on your fingertip (See Figure D). Figure D Gently place the curved side of Striant against your upper gum, then push Striant up as high as it will go on your gum (See Figure E). The flat side of Striant should be facing your cheek. Figure E Hold Striant in place for 30 seconds. Using your finger, push down on the outside of your upper lip over the application site for 30 seconds (See Figure F). This will help Striant to stick to the application site. Figure F What are the possible side effects of Striant? Striant can cause serious side effects including: Gum problems. Striant can cause severe gum irritation. You should check your gums often and tell your healthcare provider right away if you notice any signs of gum problems. If you already have an enlargement of your prostate gland, your signs and symptoms may get worse while using Striant. This can include: increased urination at night trouble starting your urine stream having to pass urine many times during the day having an urge that you have to go to the bathroom right away having a urine accident being unable to pass urine or weak urine flow Possible increased risk of prostate cancer. Your healthcare provider should check you for prostate cancer or other prostate problems before you start and while you use Striant. Blood clots in the legs or lungs. Signs and symptoms of a blood clot in your leg can include leg pain, swelling or redness. Signs and symptoms of a blood clot in your lungs can include difficulty breathing or chest pain. Possible increased risk of heart attack or stroke. In large doses Striant may lower your sperm count. Swelling of your ankles, feet or body, with or without heart failure Enlarged or painful breasts Problems breathing while you sleep (sleep apnea). Tell your healthcare provider right away if you have any of the serious side effects listed above. The most common side effects of Striant include: a change in how food tastes to you or an unusual or bitter taste in your mouth gum pain, tenderness, or swelling headache Other side effects include more erections than are normal for you or erections that last a long time. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Striant. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Striant? Keep Striant at room temperature between 68°F to 77°F (20°C to 25°C). Keep Striant dry and away from heat. Do not use a damaged blister package. If your Striant blister package is damaged, throw it away and get a new one. Safely throw away your used Striant in the household trash. Keep Striant and all medicines out of the reach of children and pets. General information about the safe and effective use of Striant. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Striant for a condition for which it was not prescribed. Do not give Striant to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about Striant. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Striant that is written for health professionals. For more information go to www.striant.com or call 1-877-663-0412. What are the ingredients in Striant? Active Ingredient: testosterone Inactive Ingredients: anhydrous lactose NF, carbomer 934P, hypromellose USP, magnesium stearate NF, lactose monohydrate NF, polycarbophil USP, colloidal silicon dioxide NF, starch NF, and talc USP.

OVERDOSE There is one report of acute overdosage by injection of testosterone enanthate: testosterone levels of up to 11,400 ng/dL were implicated in a cerebrovascular accident. CONTRAINDICATIONS Androgens are contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate. The TESTODERM (testosterone (transdermal)) products are not indicated for use in women, have not been evaluated in women, and must not be used in women. Testosterone may cause fetal harm. The TESTODERM (testosterone (transdermal)) products should not be used in patients with known hypersensitivity to any components of the respective systems, e.g., ethanol (alcohol USP is a component of TESTODERM (testosterone (transdermal)) TTS).

SIDE EFFECTS Adverse events are reported in this section by product. Adverse events reported during use of a given product may occur in patients who are treated with any TESTODERM (testosterone (transdermal)) product. Adverse Events with TESTODERM (testosterone (transdermal)) TTS In clinical studies of 457 participants (116 hypogonadal males and 341 healthy adult males) treated for up to 6 weeks with TESTODERM (testosterone (transdermal)) TTS, the most commonly reported adverse events were application site reactions of transient itching (12%) and moderate or severe erythema (3%). Adverse events reported by less than 1% of TESTODERM (testosterone (transdermal)) TTS users in clinical trials that were of probable or unknown relationship to drug were: Body as a Whole: abdominal pain, back pain, infection; Cardiovascular System: congestive heart failure, hypertension, tachycardia; Digestive System: diarrhea, nausea; Metabolic and Nutritional System: hyperglycemia, hyperlipemia, hyponatremia; Musculoskeletal System: arthralgia; Nervous System: nervousness, depression, dizziness, dry mouth, insomnia, decreased libido, personality disorder, CNS stimulation; Respiratory System: bronchitis; Skin System: application site reactions--papules/pustules, edema, vesicles, pain, other--, acne, alopecia, hirsutism; Urogenital System: abnormal ejaculation, breast pain, dysuria, urinary tract infection, and impaired urination. Topical Reactions Of 457 study participants, 3 men (1%) discontinued prematurely because of application site reactions. There were no clinically significant differences in skin tolerability in younger (

WARNINGS 1. 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 testosterone enanthate, which elevates blood levels for prolonged periods, has produced multiple hepatic adenomas. Testosterone is not known to produce these adverse effects. 2. Geriatric patients treated with androgens may be at an increased risk for the development of prostatic hyperplasia and prostatic carcinoma. 3. Geriatric patients and other patients with clinical or demographic characteristics that are recognized to be associated with an increased risk of prostate cancer should be evaluated for the presence of prostate cancer prior to initiation of testosterone replacement therapy. In men receiving testosterone replacement therapy, surveillance for prostate cancer should be consistent with current practices for eugonadal men (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility and Laboratory Tests). 4. 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. Gynecomastia frequently develops and occasionally persists in patients being treated for hypogonadism. 6. There are literature reports that the treatment of hypogonadal men with testosterone esters may potentiate sleep apnea in some patients,1,2 especially those with risk factors such as obesity or chronic lung diseases.3,4,5 PRECAUTIONS General The physician should instruct patients to report any of the following: Too frequent or persistent erections of the penis. Any nausea, vomiting, changes in skin color, or ankle swelling. Breathing disturbances, including those associated with sleep. Virilization of female partners has been reported with use of a topical testosterone solution. Percutaneous creams leave as much as 90 mg residual testosterone on the skin. The results from one study indicated that, after removal of a TESTODERM (testosterone (transdermal)) system, the potential for transfer of testosterone to a sexual partner was 6 mc g, 1/45th the daily endogenous testosterone production by the female body. TESTODERM (testosterone (transdermal)) TTS, unlike TESTODERM (testosterone (transdermal)) and TESTODERM (testosterone (transdermal)) WITH ADHESIVE, has an occlusive backing that prevents the partner from coming in contact with the active material in the system. If a TESTODERM (testosterone (transdermal)) TTS system is inadvertently transferred to a female partner, it should be removed immediately and the contacted skin washed. Changes in body hair distribution or significant increase in acne of the female partner should be brought to the attention of a physician. Information for Patients An information brochure containing instructions for the use of TESTODERM (testosterone (transdermal)) TTS is available. A separate instruction booklet is available for TESTODERM (testosterone (transdermal)) and TESTODERM (testosterone (transdermal)) WITH ADHESIVE. These booklets contain important information and instructions on how to properly use and dispose of the TESTODERM (testosterone (transdermal)) products. Patients should be encouraged to ask questions of the physician and pharmacist. Advise patients of the following: TESTODERM (testosterone (transdermal)) TTS should not be applied to the scrotum. TESTODERM (testosterone (transdermal)) and TESTODERM (testosterone (transdermal)) WITH ADHESIVE are designed for application to scrotal skin only. The TESTODERM (testosterone (transdermal)) products should be applied once daily to dry, clean skin. If the TESTODERM (testosterone (transdermal)) product has come off after it has been worn for more than 12 hours and it cannot be reapplied, the patient may wait until the next routine application time to apply a new system. Laboratory Tests Hemoglobin and hematocrit levels should be checked periodically (to detect polycythemia) in patients on long-term androgen therapy. Liver function, prostatic specific antigen, cholesterol, and high-density lipoprotein should be checked periodically. To ensure proper dosing, serum testosterone concentrations may be measured (see DOSAGE AND ADMINISTRATION ). Drug Interactions Anticoagulants: C-17 substituted derivatives of testosterone, such as methandrostenolone, have been reported to decrease the anticoagulant requirements of patients receiving oral anticoagulants. Patients receiving oral anticoagulant therapy require close monitoring, especially when androgens are started or stopped. Oxyphenbutazone: Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone. Insulin: In diabetic patients, the metabolic effects of androgens may decrease blood glucose and therefore, insulin requirements. Propranolol: In a published pharmacokinetic study of an injectable testosterone product, administration of testosterone cypionate led to an increased clearance of propranolol in the majority of men tested.6 Corticosteroids: The concurrent administration of testosterone with ACTH or corticosteroids may enhance edema formation; thus these drugs should be administered cautiously, particularly in patients with cardiac or hepatic disease.7 Drug/Laboratory Test Interactions 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. Carcinogenesis, Mutagenesis, Impairment of Fertility Animal Data: 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. Human Data: There are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in high doses. Withdrawal of the drugs did not lead to regression of the tumors in all cases. Geriatric patients treated with androgens may be at an increased risk for the development of prostatic hyperplasia and prostatic carcinoma. Geriatric patients and other patients with clinical or demographic characteristics that are recognized to be associated with an increased risk of prostate cancer should be evaluated for the presence of prostate cancer prior to initiation of testosterone replacement therapy. In men receiving testosterone replacement therapy, surveillance for prostate cancer should be consistent with current practices for eugonadal men. Pregnancy Category X (see CONTRAINDICATIONS): Teratogenic Effects: The TESTODERM (testosterone (transdermal)) products are not indicated for women and must not be used in women. Nursing Mothers The TESTODERM (testosterone (transdermal)) products are not indicated for women and must not be used in women. Pediatric Use Safety and efficacy of the TESTODERM (testosterone (transdermal)) products in pediatric patients has not been established.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Gum-Related Adverse Reactions And Limited Long-Term Information On Oral Safety Gum-related adverse reactions, including severe gum irritation, were reported in clinical trials of Striant. Long-term clinical trial data on gum safety is available in only a limited number of patients (117 patients, 51 patients and 48 patients with at least 6 months, 1 year, and 2 years of exposure, respectively). It is recommended that patients regularly inspect their own gum region where Striant is applied. Any abnormal finding should be brought promptly to the attention of the patient's physician. In such circumstances, dental consultation may be appropriate. 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 and ADVERSE REACTIONS]. 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. 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 Striant. 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 Striant and initiate appropriate workup and management [see ADVERSE REACTIONS]. 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 Striant. Use In Women Due to lack of controlled evaluations in women and potential virilizing effects, Striant is not indicated for use in women. Potential For Adverse Effects On Spermatogenesis With large doses of exogenous androgens, including Striant, 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. 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 testosterone enanthate, which elevates blood levels for prolonged periods, has produced multiple hepatic adenomas. Testosterone is not known to produce 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 Striant while the cause is evaluated. Edema Androgens, including Striant, 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 [see ADVERSE REACTIONS]. Gynecomastia Gynecomastia may develop and persist in patients being treated with androgens, including Striant, for hypogonadism. 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. Lipids Changes in the serum lipid profile may occur. Monitor the lipid profile periodically, particularly after starting therapy. Hypercalcemia Androgens, including Striant, 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. Decreased Thyroxine-binding Globulin Androgens, including Striant, may decrease concentrations of thyroxine-binding globulins, resulting in decreased total T4 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. Patient Counseling Information See FDA-Approved Patient Labeling (PATIENT INFORMATION). Patients should be informed of the following: Men With Known Or Suspected Prostate Or Breast Cancer Men with known or suspected prostate or breast cancer should not use Striant [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. Gum-Related Adverse Reactions Gum-related adverse reactions, including severe gum irritation, were reported in clinical trials of Striant. Advise patients to regularly inspect the gum region where they apply Striant and to report any abnormality to their health care professional. Potential Adverse Reactions With Androgens Patients should be informed that treatment with androgens, such as Striant, may lead to adverse reactions that include: Changes in urinary habits such as increased urination at night, trouble starting their urine stream, passing urine many times during the day, having an urge that they have to go to the bathroom right away, having a urine accident, being unable to pass urine and having a 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 Patients Should Be Advised Of these Application Instructions Advise patients to carefully read the patient information accompanying each carton of Striant blister packaged tablets. Morning and evening oral care should be timed to coincide with removal of the residual old system and application of a new buccal system. Before morning and evening oral care, the residual Striant buccal system residual should be removed, then oral care should be performed. Following oral care, a new buccal system should be applied. Upon opening the packet, the rounded side surface of the buccal system should be placed against the gum and held firmly in place with a finger over the lip and against the product for 30 seconds to ensure adhesion. Striant should be placed in a comfortable position just above the incisor tooth (on either side of the mouth). With each application, Striant should be rotated to alternate sides of the mouth. Striant is designed to stay in position until removed. If the buccal system fails to properly adhere to the gum or falls off within the first 8 hours of dosing, replace with a new system and continue for a total of 12 hours for the placement of the first system. If the system falls out of position after 8 hours of dosing, a new buccal system should be applied and it may remain in place for 12 hours then continue with the next regularly scheduled dosing. Patients should take care to avoid dislodging the buccal system. Patients should check to see if Striant is in place following consumption of food or alcoholic/non-alcoholic beverages. Striant should not be chewed or swallowed. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenicity 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. Mutagenesis Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays. Impairment of Fertility 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. Use In Specific Populations Pregnancy Pregnancy Category X: Striant 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 a woman becomes pregnant while taking Striant, she should be apprised of the potential hazard to the fetus. Nursing Mothers Although it is not known how much testosterone transfers into human milk, Striant is contraindicated in nursing women because of the potential for virilization in nursing infants. Testosterone and other androgens may adversely affect lactation. Pediatric Use Safety and effectiveness of Striant in males less than 18 year of age have not been established. Improper use may result in acceleration of bone age and premature closure of the epiphyses. Geriatric Use Of the total number of subjects in clinical studies of Striant, 51 patients (17%) were 65 years of age and older. There is insufficient long-term safety data in geriatric patients to assess the potentially increased risks of cardiovascular disease and prostate cancer. Renal Impairment No studies were conducted in patients with renal impairment. Hepatic Impairment No studies were conducted in patients with hepatic impairment.