ZOLADEX

ZOLADEX (goserelin implant) is a GnRH agonist. Goserelin acetate is chemically described as an acetate salt of [D-Ser(Bu t ) 6 ,Azgly 10 ]. Its chemical structure is pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t )-Leu-Arg-Pro-Azgly-NH 2 acetate [C 59 H 84 N 18 O 14· (C 2 H 4 O 2 ) x where x = 1 to 2.4]. Goserelin acetate is an off-white powder with a molecular weight of 1269 Daltons (free base). It is freely soluble in glacial acetic acid. It is soluble in water, 0.1M hydrochloric acid, 0.1M sodium hydroxide, dimethylformamide and dimethyl sulfoxide. Goserelin acetate is practically insoluble in acetone, chloroform and ether. ZOLADEX is supplied as a sterile, biodegradable product containing 3.8 mg goserelin acetate, equivalent to 3.6 mg of goserelin. ZOLADEX is designed for subcutaneous injection with continuous release over a 28-day period. Goserelin acetate, containing up to 12% goserelin-related substances, is dispersed in a matrix of D,L-lactic and glycolic acids copolymer (to a total implant weight of 18.0 mg, containing less than 2.5% total acetic acid) and presented as a sterile, white to cream colored 1-mm diameter cylinder, preloaded in a special single use syringe with a 16-gauge x 36 +/- 0.5 mm siliconized needle with protective needle sleeve (SafeSystem ® Syringe) in a sealed, light- and moisture-proof, aluminum foil laminate pouch containing a desiccant capsule. Studies of the D,L-lactic and glycolic acids copolymer have indicated that it is completely biodegradable and has no demonstrable antigenic potential.

ZOLADEX is a Gonadotropin Releasing Hormone (GnRH) agonist indicated for: Use in combination with flutamide for the management of locally confined carcinoma of the prostate ( 1.1 ) Palliative treatment of advanced carcinoma of the prostate ( 1.2 ) The management of endometriosis ( 1.3 ) Use as an endometrial-thinning agent prior to endometrial ablation for dysfunctional uterine bleeding ( 1.4 ) Use in the palliative treatment of advanced breast cancer in pre- and perimenopausal women ( 1.5 ) 1.1 Stage B2-C Prostatic Carcinoma ZOLADEX is indicated for use in combination with flutamide for the management of locally confined Stage T2b-T4 (Stage B2-C) carcinoma of the prostate. Treatment with ZOLADEX and flutamide should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy [see Dosage and Administration ( 2.1 ) and Clinical Studies ( 14.1 )]. 1.2 Prostatic Carcinoma ZOLADEX is indicated in the palliative treatment of advanced carcinoma of the prostate [see Dosage and Administration ( 2.2 ) and Clinical Studies ( 14.2 )]. 1.3 Endometriosis ZOLADEX is indicated for the management of endometriosis, including pain relief and reduction of endometriotic lesions for the duration of therapy. Experience with ZOLADEX for the management of endometriosis has been limited to women 18 years of age and older treated for 6 months [see Dosage and Administration ( 2.3 ) and Clinical Studies ( 14.3 )]. 1.4 Endometrial Thinning ZOLADEX is indicated for use as an endometrial-thinning agent prior to endometrial ablation for dysfunctional uterine bleeding [see Dosage and Administration ( 2.4 ) and Clinical Studies ( 14.4 )]. 1.5 Advanced Breast Cancer ZOLADEX is indicated for use in the palliative treatment of advanced breast cancer in pre- and perimenopausal women. The estrogen and progesterone receptor values may help to predict whether ZOLADEX therapy is likely to be beneficial [see Dosage and Administration ( 2.5 ), Clinical Pharmacology ( 12.1 ), and Clinical Studies ( 14.5 )]. The automatic safety feature of the syringe aids in the prevention of needlestick injury.

ZOLADEX, at a dose of 3.6 mg, should be administered subcutaneously every 28 days into the anterior abdominal wall below the navel line using an aseptic technique under the supervision of a physician [see Dosage and Administration ( 2.7 )]. While a delay of a few days is permissible, every effort should be made to adhere to the 28-day schedule. ZOLADEX 3.6 mg should be administered subcutaneously every 28 days ( 2.1 , 2.7 ) For the management of endometriosis, the recommended duration of administration is 6 months for women 18 years of age and older ( 2.3 ) 2.1 Stage B2-C Prostatic Carcinoma When ZOLADEX is given in combination with radiotherapy and flutamide for patients with Stage T2b-T4 (Stage B2-C) prostatic carcinoma, treatment should be started 8 weeks prior to initiating radiotherapy and should continue during radiation therapy. A treatment regimen using a ZOLADEX 3.6 mg depot 8 weeks before radiotherapy, followed in 28 days by the ZOLADEX 10.8 mg depot, can be administered. Alternatively, four injections of 3.6 mg depot can be administered at 28-day intervals, two depots preceding and two during radiotherapy. 2.2 Prostatic Carcinoma For the management of advanced prostate cancer, ZOLADEX is intended for long-term administration unless clinically inappropriate. 2.3 Endometriosis For the management of endometriosis, the recommended duration of administration is 6 months. Currently, there are no clinical data on the effect of treatment of benign gynecological conditions with ZOLADEX for periods in excess of 6 months. Retreatment cannot be recommended for the management of endometriosis since safety data for retreatment are not available. If the symptoms of endometriosis recur after a course of therapy, and further treatment with ZOLADEX is contemplated, consideration should be given to monitoring bone mineral density. Clinical studies suggest the addition of Hormone Replacement Therapy (estrogens and/or progestins) to ZOLADEX is effective in reducing the bone mineral loss which occurs with ZOLADEX alone without compromising the efficacy of ZOLADEX in relieving the symptoms of endometriosis. The addition of Hormone Replacement Therapy may also reduce the occurrence of vasomotor symptoms and vaginal dryness associated with hypoestrogenism. The optimal drugs, dose and duration of treatment has not been established. 2.4 Endometrial Thinning For use as an endometrial-thinning agent prior to endometrial ablation, the dosing recommendation is one or two depots (with each depot given four weeks apart). When one depot is administered, surgery should be performed at four weeks. When two depots are administered, surgery should be performed within two to four weeks following administration of the second depot. 2.5 Breast Cancer For the management of advanced breast cancer, ZOLADEX is intended for long-term administration unless clinically inappropriate. 2.6 Renal or Hepatic Impairment No dosage adjustment is necessary for patients with renal or hepatic impairment. 2.7 Administration Technique The proper method of administration of ZOLADEX is described in the instructions that follow. Put the patient in a comfortable position with the upper part of the body slightly raised. Prepare an area of the anterior abdominal wall below the navel line with an alcohol swab. NOTE: Caution should be taken while injecting ZOLADEX into the anterior abdominal wall due to the proximity of underlying inferior epigastric artery and its branches. Examine the foil pouch and syringe for damage. Remove the syringe from the opened foil pouch and hold the syringe at a slight angle to the light. Check that at least part of the ZOLADEX implant is visible. NOTE: do not remove the syringe by the plunger. Grasp the red plastic safety tab and pull away from the syringe, and discard. Remove needle cover. Unlike liquid injections, there is no need to remove air bubbles as attempts to do so may displace the ZOLADEX implant. Holding the syringe around the protective sleeve, using an aseptic technique, pinch the skin of the patient's anterior abdominal wall below the navel line. With the bevel of the needle facing up, insert the needle at a 30 to 45 degree angle to the skin in one continuous deliberate motion until the protective sleeve touches the patient's skin. NOTE: The ZOLADEX syringe cannot be used for aspiration. If the hypodermic needle penetrates a large vessel, blood will be seen instantly in the syringe chamber. If a vessel is penetrated, withdraw the needle and inject with a new syringe elsewhere. Monitor patients for signs or symptoms of abdominal hemorrhage. Use extra care when administering ZOLADEX to patients with a low BMI and/or to patients receiving full dose anticoagulation [see Warnings and Precautions ( 5.10 )]. Do not penetrate into muscle or peritoneum. To administer the ZOLADEX implant and to activate the protective sleeve, grasp the barrel at the finger grip and depress the plunger until you cannot depress it any further. If the plunger is not depressed fully , the protective sleeve will NOT activate. When the protective sleeve ‘clicks’, the protective sleeve will automatically begin to slide to cover the needle. NOTE : The needle does not retract. Withdraw the needle and allow protective sleeve to slide and cover needle. Dispose of the syringe in an approved sharps collector. NOTE: In the unlikely event of the need to surgically remove ZOLADEX, it may be localized by ultrasound.

Hypersensitivity ( 4.1 ) Pregnancy unless used for treatment of advanced breast cancer ( 4.2 ) 4.1 Hypersensitivity Anaphylactic reactions to ZOLADEX have been reported in the medical literature. ZOLADEX is contraindicated in those patients who have a known hypersensitivity to GnRH, GnRH agonist analogues or any of the components in ZOLADEX [see Warnings and Precautions ( 5.6 )]. 4.2 Pregnancy ZOLADEX is contraindicated during pregnancy unless ZOLADEX is being used for palliative treatment of advanced breast cancer. ZOLADEX can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus. There is an increased risk for pregnancy loss due to expected hormone changes that occur with ZOLADEX treatment [see Use in Specific Populations ( 8.1 )].

The most common, clinically significant adverse reactions occurring in >10% of men: hot flashes, sexual dysfunction, decreased erections and lower urinary tract symptoms ( 6 ) The adverse event profile was similar for women treated for breast cancer, dysfunctional uterine bleeding or endometriosis and included (>20%): hot flushes, headache, sweating, acne, emotional lability, depression, decreased libido, vaginitis, breast atrophy, seborrhea, and peripheral edema ( 6 ) Tumor flare can occur on the initiation of ZOLADEX for both men and women being treated for cancer ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact TerSera Therapeutics at 1-844-334-4035 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Stage B2-C Prostatic Carcinoma Treatment with ZOLADEX and flutamide did not add substantially to the toxicity of radiation treatment alone. The following adverse experiences were reported during a multicenter clinical trial comparing ZOLADEX + flutamide + radiation versus radiation alone. The most frequently reported (greater than 5%) adverse experiences are listed below: Table 1 ADVERSE EVENTS DURING ACUTE RADIATION THERAPY (within first 90 days of radiation therapy) (n=231) flutamide + ZOLADEX + Radiation % All (n=235) Radiation Only % All Rectum/Large Bowel 80 76 Bladder 58 60 Skin 37 37 Table 2 ADVERSE EVENTS DURING LATE RADIATION PHASE (after 90 days of radiation therapy) (n=231) flutamide + ZOLADEX + Radiation % All (n=235) Radiation Only % All Diarrhea 36 40 Cystitis 16 16 Rectal Bleeding 14 20 Proctitis 8 8 Hematuria 7 12 Additional adverse event data was collected for the combination therapy with radiation group over both the hormonal treatment and hormonal treatment plus radiation phases of the study. Adverse experiences occurring in more than 5% of patients in this group, over both parts of the study, were hot flashes (46%), diarrhea (40%), nausea (9%), and skin rash (8%). 6.2 Prostatic Carcinoma ZOLADEX has been found to be generally well tolerated in clinical trials. Adverse reactions reported in these trials were rarely severe enough to result in the patients’ withdrawal from ZOLADEX treatment. As seen with other hormonal therapies, the most commonly observed adverse events during ZOLADEX therapy were due to the expected physiological effects from decreased testosterone levels. These included hot flashes, sexual dysfunction and decreased erections. Tumor Flare Phenomenon: Initially, ZOLADEX, like other GnRH agonists, causes transient increases in serum levels of testosterone. A small percentage of patients experienced a temporary worsening of signs and symptoms, usually manifested by an increase in cancer-related pain which was managed symptomatically. Isolated cases of exacerbation of disease symptoms, either ureteral obstruction or spinal cord compression, occurred at similar rates in controlled clinical trials with both ZOLADEX and orchiectomy. The relationship of these events to therapy is uncertain [see Warnings and Precautions ( 5.2 )]. In the controlled clinical trials of ZOLADEX versus orchiectomy, the following events were reported as adverse reactions in greater than 5% of the patients. Table 3 TREATMENT RECEIVED 1. Complications related to surgery were reported in 18% of the orchiectomy patients, while only 3% of ZOLADEX patients reported adverse reactions at the injection site. The surgical complications included scrotal infection (5.9%), groin pain (4.7%), wound seepage (3.1%), scrotal hematoma (2.8%), incisional discomfort (1.6%) and skin necrosis (1.2%). ZOLADEX (n=242) ORCHIECTOMY (n=254) ADVERSE EVENT % % Hot Flashes 62 53 Sexual Dysfunction 21 15 Decreased Erections 18 16 Lower Urinary Tract Symptoms 13 8 Lethargy 8 4 Pain (worsened in the first 30 days) 8 3 Edema 7 8 Upper Respiratory Infection 7 2 Rash 6 1 Sweating 6 4 Anorexia 5 2 Chronic Obstructive Pulmonary Disease 5 3 Congestive Heart Failure 5 1 Dizziness 5 4 Insomnia 5 1 Nausea 5 2 Complications of Surgery 0 18 1 The following additional adverse reactions were reported in greater than 1% but less than 5% of the patients treated with ZOLADEX: CARDIOVASCULAR – arrhythmia, cerebrovascular accident, hypertension, myocardial infarction, peripheral vascular disorder, chest pain; CENTRAL NERVOUS SYSTEM – anxiety, depression, headache; GASTROINTESTINAL – constipation, diarrhea, ulcer, vomiting; HEMATOLOGIC – anemia; METABOLIC/NUTRITIONAL – gout, hyperglycemia, weight increase; MISCELLANEOUS – chills, fever; UROGENITAL – renal insufficiency, urinary obstruction, urinary tract infection, breast swelling and tenderness. 6.3 Females As would be expected with a drug that results in hypoestrogenism, the most frequently reported adverse reactions were those related to this effect. 6.4 Endometriosis In controlled clinical trials comparing ZOLADEX every 28 days and danazol daily for the treatment of endometriosis, the following events were reported at a frequency of 5% or greater. Table 4 TREATMENT RECEIVED ZOLADEX (n=411) DANAZOL (n=207) ADVERSE EVENT % % Hot Flushes 96 67 Vaginitis 75 43 Headache 75 63 Emotional Lability 60 56 Libido Decreased 61 44 Sweating 45 30 Depression 54 48 Acne 42 55 Breast Atrophy 33 42 Seborrhea 26 52 Peripheral Edema 21 34 Breast Enlargement 18 15 Pelvic Symptoms 18 23 Pain 17 16 Dyspareunia 14 5 Libido Increased 12 19 Infection 13 11 Asthenia 11 13 Nausea 8 14 Hirsutism 7 15 Insomnia 11 4 Breast Pain 7 4 Abdominal Pain 7 7 Back Pain 7 13 Flu Syndrome 5 5 Dizziness 6 4 Application Site Reaction 6 - Voice Alterations 3 8 Pharyngitis 5 2 Hair Disorders 4 11 Myalgia 3 11 Nervousness 3 5 Weight Gain 3 23 Leg Cramps 2 6 Increased Appetite 2 5 Pruritus 2 6 Hypertonia 1 10 The following adverse events not already listed above were reported at a frequency of 1% or greater, regardless of causality, in ZOLADEX-treated women from all clinical trials: WHOLE BODY – allergic reaction, chest pain, fever, malaise; CARDIOVASCULAR – hemorrhage, hypertension, migraine, palpitations, tachycardia; DIGESTIVE – anorexia, constipation, diarrhea, dry mouth, dyspepsia, flatulence; HEMATOLOGIC – ecchymosis; METABOLIC AND NUTRITIONAL – edema; MUSCULOSKELETAL – arthralgia, joint disorder; CNS – anxiety, paresthesia, somnolence, thinking abnormal; RESPIRATORY – bronchitis, cough increased, epistaxis, rhinitis, sinusitis; SKIN – alopecia, dry skin, rash, skin discoloration; SPECIAL SENSES – amblyopia, dry eyes; UROGENITAL – dysmenorrhea, urinary frequency, urinary tract infection, vaginal hemorrhage. 6.5 Endometrial Thinning The following adverse events were reported at a frequency of 5% or greater in premenopausal women presenting with dysfunctional uterine bleeding in Trial 0022 for endometrial thinning. These results indicate that headache, hot flushes and sweating were more common in the ZOLADEX group than in the placebo group. Table 5 ADVERSE EVENTS REPORTED AT A FREQUENCY OF 5% OR GREATER IN ZOLADEX AND PLACEBO TREATMENT GROUPS OF TRIAL 0022 ZOLADEX 3.6 mg (n=180) Placebo (n=177) ADVERSE EVENT % % Whole Body Headache 32 22 Abdominal Pain 11 10 Pelvic Pain 9 6 Back Pain 4 7 Cardiovascular Vasodilatation 57 18 Migraine 7 4 Hypertension 6 2 Digestive Nausea 5 6 Nervous Nervousness 5 3 Depression 3 7 Respiratory Pharyngitis 6 9 Sinusitis 3 6 Skin and appendages Sweating 16 5 Urogenital Dysmenorrhea 7 9 Uterine Hemorrhage 6 4 Vulvovaginitis 5 1 Menorrhagia 4 5 Vaginitis 1 6 6.6 Breast Cancer The adverse event profile for women with advanced breast cancer treated with ZOLADEX is consistent with the profile described above for women treated with ZOLADEX for endometriosis. In a controlled clinical trial (SWOG–8692) comparing ZOLADEX with oophorectomy in premenopausal and perimenopausal women with advanced breast cancer, the following events were reported at a frequency of 5% or greater in either treatment group regardless of causality. Table 6 TREATMENT RECEIVED ZOLADEX (n=57) OOPHORECTOMY (n=55) ADVERSE EVENT % of Pts. % of Pts. Hot Flashes 70 47 Tumor Flare 23 4 Nausea 11 7 Edema 5 0 Malaise/Fatigue/Lethargy 5 2 Vomiting 4 7 In the Phase II clinical trial program in 333 pre- and perimenopausal women with advanced breast cancer, hot flashes were reported in 75.9% of patients and decreased libido was noted in 47.7% of patients. These two adverse events reflect the pharmacological actions of ZOLADEX. Injection site reactions were reported in less than 1% of patients. 6.7 Hormone Replacement Therapy Clinical studies suggest the addition of Hormone Replacement Therapy (estrogens and/or progestins) to ZOLADEX may decrease the occurrence of vasomotor symptoms and vaginal dryness associated with hypoestrogenism without compromising the efficacy of ZOLADEX in relieving pelvic symptoms. The optimal drugs, dose and duration of treatment has not been established. 6.8 Changes in Bone Mineral Density After 6 months of ZOLADEX treatment, 109 female patients treated with ZOLADEX showed an average 4.3% decrease of vertebral trabecular bone mineral density (BMD) as compared to pretreatment values. BMD was measured by dual-photon absorptiometry or dual energy x-ray absorptiometry. Sixty-six of these patients were assessed for BMD loss 6 months after the completion (posttherapy) of the 6-month therapy period. Data from these patients showed an average 2.4% BMD loss compared to pretreatment values. Twenty-eight of the 109 patients were assessed for BMD at 12 months posttherapy. Data from these patients showed an average decrease of 2.5% in BMD compared to pretreatment values. These data suggest a possibility of partial reversibility. Clinical studies suggest the addition of Hormone Replacement Therapy (estrogens and/or progestins) to ZOLADEX is effective in reducing the bone mineral loss which occurs with ZOLADEX alone without compromising the efficacy of ZOLADEX in relieving the symptoms of endometriosis. The optimal drugs, dose and duration of treatment has not been established [see Patient Counseling Information ( 17.3 )]. 6.9 Changes in Laboratory Values During Treatment Plasma Enzymes: Elevation of liver enzymes (AST, ALT) have been reported in female patients exposed to ZOLADEX (representing less than 1% of all patients). Lipids: In a controlled trial, ZOLADEX therapy resulted in a minor, but statistically significant effect on serum lipids. In patients treated for endometriosis at 6 months following initiation of therapy, danazol treatment resulted in a mean increase in LDL cholesterol of 33.3 mg/dL and a decrease in HDL cholesterol of 21.3 mg/dL compared to increases of 21.3 and 2.7 mg/dL in LDL cholesterol and HDL cholesterol, respectively, for ZOLADEX-treated patients. Triglycerides increased by 8.0 mg/dL in ZOLADEX-treated patients compared to a decrease of 8.9 mg/dL in danazol-treated patients. In patients treated for endometriosis, ZOLADEX increased total cholesterol and LDL cholesterol during 6 months of treatment. However, ZOLADEX therapy resulted in HDL cholesterol levels which were significantly higher relative to danazol therapy. At the end of 6 months of treatment, HDL cholesterol fractions (HDL 2 and HDL 3 ) were decreased by 13.5 and 7.7 mg/dL, respectively, for danazol-treated patients compared to treatment increases of 1.9 and 0.8 mg/dL, respectively, for ZOLADEX-treated patients. 6.10 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ZOLADEX. Because these 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. Bone Mineral Density: Osteoporosis, decreased bone mineral density and bone fracture in men [see Patient Counseling Information ( 17.2 ) and ( 17.3 )]. Cardiovascular: Deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient ischemic attack have been observed in women treated with GnRH agonists. Although a temporal relationship was reported in some cases, most cases were confounded by risk factors or concomitant medication use. It is unknown if there is a causal association between the use of GnRH analogs and these events. Ovarian Cyst: Ovarian cyst formation and, in combination with gonadotropins, ovarian hyperstimulation syndrome (OHSS). Changes in Blood Pressure: Hypotension and hypertension have been reported. These changes are usually transient, resolving either during continued therapy or after cessation of therapy. Pituitary Apoplexy and Tumors: Pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) and pituitary adenoma have been diagnosed. Most of the pituitary apoplexy cases occurred within 2 weeks of the first dose, and some occurred within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. Pituitary tumors have been reported. Acne: Usually within one month of starting treatment. Skin reactions: SJS/TEN, DRESS, AGEP, dermatitis exfoliative, bullous dermatitis, and erythema multiforme. Other Adverse Reactions: Psychotic disorders, convulsions and mood swings, including depression; suicidal ideation and attempt in women.

No formal drug-drug interaction studies have been performed. No confirmed interactions have been reported between ZOLADEX and other drugs. None 7.1 Drug/Laboratory Test Interactions Administration of ZOLADEX in therapeutic doses results in suppression of the pituitary-gonadal system. Because of this suppression, diagnostic tests of pituitary-gonadotropic and gonadal functions conducted during treatment and until the resumption of menses may show results which are misleading. Normal function is usually restored within 12 weeks after treatment is discontinued.