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 10.8 mg implant is supplied as a sterile, biodegradable product containing 11.3 mg goserelin acetate equivalent to 10.8 mg of goserelin. ZOLADEX is designed for subcutaneous implantation with continuous release over a 12-week period. Goserelin acetate, containing up to 10% goserelin-related substances, is dispersed in a matrix of D,L-lactic and glycolic acids copolymer (to a total implant weight of 36.0 mg, containing less than 2% total acetic acid) and presented as a sterile, white to cream colored 1.5 mm diameter cylinder, preloaded in a special single-use syringe with a 14-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 also supplied as a sterile, biodegradable product containing goserelin acetate equivalent to 3.6 mg of goserelin designed for administration every 28 days.

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 ) Use as palliative treatment of advanced carcinoma of the prostate ( 1.2 ) 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 )]. In controlled studies of patients with advanced prostatic cancer comparing ZOLADEX 3.6 mg to orchiectomy, the long-term endocrine responses and objective responses were similar between the two treatment arms. Additionally, duration of survival was similar between the two treatment arms in a major comparative trial. In controlled studies of patients with advanced prostatic cancer, ZOLADEX 10.8 mg implant produced pharmacodynamically similar effect in terms of suppression of serum testosterone to that achieved with ZOLADEX 3.6 mg implant. Clinical outcome similar to that produced with the use of the ZOLADEX 3.6 mg implant administered every 28 days is predicted with the ZOLADEX 10.8 mg implant administered every 12 weeks. The automatic safety feature of the syringe aids in the prevention of needlestick injury.

ZOLADEX, at a dose of 10.8 mg, should be administered subcutaneously every 12 weeks into the anterior abdominal wall below the navel line using an aseptic technique under the supervision of a physician [see Dosage and Administration ( 2.5 )]. While a delay of a few days is permissible, every effort should be made to adhere to the 12-week schedule. ZOLADEX, at a dose of 10.8 mg, should be administered subcutaneously every 12 weeks into the anterior abdominal wall below the navel line ( 2.1 , 2.5 ) 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 one ZOLADEX 3.6 mg depot, followed in 28 days by one ZOLADEX 10.8 mg depot, should be administered. 2.2 Prostatic Carcinoma For the management of advanced prostate cancer, ZOLADEX is intended for long-term administration unless clinically inappropriate. 2.3 Renal or Hepatic Impairment No dosage adjustment is necessary for patients with renal or hepatic impairment. 2.4 Women ZOLADEX 10.8 mg implant is not indicated in women as the data are insufficient to support reliable suppression of serum estradiol. For female patients requiring treatment with goserelin, refer to prescribing information for ZOLADEX 3.6 mg implant. 2.5 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 blue 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 ( 5.7 )]. 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 ( 4.2 , 8.1 ) 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 ( 5.2 )]. 4.2 Pregnancy Expected hormonal changes that occur with ZOLADEX treatment increase the risk for pregnancy loss. ZOLADEX may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [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 ) Tumor flare can occur on the initiation of ZOLADEX therapy ( 5.1 , 6.1 ) 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 Clinical Trials 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 ( 5.1 ) and Patient Counseling Information ( 17.2 )]. 6.2 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%). 6.3 Prostatic Carcinoma Two controlled clinical trials using ZOLADEX 10.8 mg versus ZOLADEX 3.6 mg were conducted. During a comparative phase, patients were randomized to receive either a single 10.8 mg implant or three consecutive 3.6 mg implants every 4 weeks over weeks 0-12. During this phase, the only adverse event reported in greater than 5% of patients was hot flashes, with an incidence of 47% in the ZOLADEX 10.8 mg group and 48% in the ZOLADEX 3.6 mg group. From weeks 12-48 all patients were treated with a 10.8 mg implant every 12 weeks. During this noncomparative phase, the following adverse events were reported in greater than 5% of patients: Table 3 ADVERSE EVENTS WERE REPORTED IN GREATER THAN 5% OF PATIENTS ADVERSE EVENTS ZOLADEX 10.8 mg (n=157) % Hot Flashes 64 Pain (general) 14 Gynecomastia 8 Pelvic Pain 6 Bone Pain 6 Asthenia 5 The following adverse events were reported in greater than 1%, but less than 5% of patients treated with ZOLADEX 10.8 mg implant every 12 weeks. Some of these are commonly reported in elderly patients. WHOLE BODY – Abdominal pain, Back pain, Flu syndrome, Headache, Sepsis, Aggravation reaction CARDIOVASCULAR – Angina pectoris, Cerebral ischemia, Cerebrovascular accident, Heart failure, Pulmonary embolus, Varicose veins DIGESTIVE – Diarrhea, Hematemesis ENDOCRINE – Diabetes mellitus HEMATOLOGIC – Anemia METABOLIC – Peripheral edema NERVOUS SYSTEM – Dizziness, Paresthesia, Urinary retention RESPIRATORY – Cough increased, Dyspnea, Pneumonia SKIN – Herpes simplex, Pruritus UROGENITAL – Bladder neoplasm, Breast pain, Hematuria, Impotence, Urinary frequency, Urinary incontinence, Urinary tract disorder, Urinary tract infection, Urination impaired The following adverse events not already listed above were reported in patients receiving ZOLADEX 3.6 mg in other clinical trials. Inclusion does not necessarily represent a causal relationship to ZOLADEX 10.8 mg. WHOLE BODY: Allergic reaction, Chills, Fever, Infection, Injection site reaction, Lethargy, Malaise CARDIOVASCULAR: Arrhythmia, Chest pain, Hemorrhage, Hypertension, Migraine, Myocardial infarction, Palpitations, Peripheral vascular disorder, Tachycardia DIGESTIVE: Anorexia, Constipation, Dry mouth, Dyspepsia, Flatulence, Increased appetite, Nausea, Ulcer, Vomiting HEMATOLOGIC: Ecchymosis METABOLIC: Edema, Gout, Hyperglycemia, Weight increase MUSCULOSKELETAL: Arthralgia, Hypertonia, Joint disorder, Leg cramps, Myalgia, Osteoporosis NERVOUS SYSTEM: Anxiety, Depression, Emotional lability, Headache, Insomnia, Nervousness, Somnolence, Thinking abnormal RESPIRATORY: Bronchitis, Chronic obstructive pulmonary disease, Epistaxis, Rhinitis, Sinusitis, Upper respiratory infection, Voice alterations SKIN: Acne, Alopecia, Dry skin, Hair disorders, Rash, Seborrhea, Skin discoloration, Sweating SPECIAL SENSES: Amblyopia, Dry eyes UROGENITAL: Breast tenderness, Decreased erections, Renal insufficiency, Sexual dysfunction, Urinary obstruction 6.4 Changes in Laboratory Values During Treatment Plasma Enzymes: Elevation of liver enzymes (AST, ALT) have been reported in female patients exposed to ZOLADEX 3.6 mg (representing less than 1% of all patients). There was no other evidence of abnormal liver function. Causality between these changes and ZOLADEX have not been established. Lipids : In a controlled trial in females, ZOLADEX 3.6 mg implant therapy resulted in a minor, but statistically significant effect on serum lipids (i.e., increases in LDL cholesterol of 21.3 mg/dL; increases in HDL cholesterol of 2.7 mg/dL; and triglycerides increased by 8.0 mg/dL). 6.5 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. Hypercalcemia : In patients with bone metastases. Bone Mineral Density: Osteoporosis, decreased bone mineral density and bone fracture in men [see Patient Counseling Information ( 17.2 )]. 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.

No formal drug-drug interaction studies have been performed. No drug interaction studies with other drugs have been conducted with ZOLADEX. 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 may show results which are misleading.