ZOLADEX

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION 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 syrin…

5 WARNINGS AND PRECAUTIONS Women of Childbearing Potential and Pregnancy: Pregnancy must be excluded for use in benign gynecological conditions. Women should avoid pregnancy ( 5.1 ) Tumor Flare Phenomenon: Transient worsening of tumor symptoms may occur during the first few weeks of treatment with ZOLADEX, which may include ureteral obstruction and spinal cord compression. Monitor patients at risk for complications of tumor flare ( 5.2 , 6.2 ) Hyperglycemia and Diabetes: Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH analogs. Monitor blood glucose level and manage according to current clinical practice ( 5.3 ) Cardiovascular Diseases: Increased risk of myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH analogs in men. Monitor for cardiovascular disease and manage according to current clinical practice ( 5.4 ) Hypercalcemia: Hypercalcemia has been reported in patients with bone metastases treated with ZOLADEX. Monitor and manage appropriately ( 5.5 ) Hypersensitivity: Systemic hypersensitivity has been reported in patients receiving goserelin/ZOLADEX implants ( 4.1 , 5.6 ) Severe Cutaneous Adverse Reactions: ZOLADEX can cause severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis. Interrupt ZOLADEX if signs or symptoms of SCARs develop. Permanently discontinue ZOLADEX if SCARs are confirmed. ( 5.7 ) Cervical Resistance: Increase in cervical resistance may occur. Caution is recommended when dilating the cervix for endometrial ablation ( 5.8 ) Effect on QT/QTc Interval: Androgen deprivation therapy may prolong the QT interval. Consider risks and benefits ( 5.9 ) Injection Site Injury: Injection site injury and vascular injury have been reported during administration of ZOLADEX ( 5.10 ) Depression: Depression may occur or worsen in women receiving GnRH agonists. Monitor and manage appropriately ( 5.11 ) 5.1 Women of Childbearing Potential and Pregnancy Before starting treatment with ZOLADEX, pregnancy must be excluded for women using ZOLADEX for benign gynecological conditions. Women of childbearing potential should be advised to avoid becoming pregnant. Effective nonhormonal contraception must be used by all premenopausal women during ZOLADEX therapy and for 12 weeks following discontinuation of therapy. When used every 28 days, ZOLADEX usually inhibits ovulation and stops menstruation; however, pregnancy prevention is not ensured. Effects on reproductive function are expected to occur with chronic administration as a result of the anti-gonadotrophic properties of the drug. Based on mechanism of action in humans and findings of increased pregnancy loss in animal studies, ZOLADEX can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy for the palliative treatment of breast cancer, then the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations ( 8.1 )]. 5.2 Tumor Flare Phenomenon Initially, ZOLADEX, like other GnRH agonists, causes transient increases in serum levels of testosterone in men with prostate cancer, and estrogen in women with breast cancer. Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostate or breast cancer, may occasionally develop during the first few weeks of ZOLADEX treatment. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically. As with other GnRH agonists, isolated cases of ureteral obstruction and spinal cord compression have been observed in patients with prostate cancer. If spinal cord compression or renal impairment secondary to ureteral obstruction develops, standard treatment of these complications should be instituted. For extreme cases in prostate cancer patients, an immediate orchiectomy should be considered. 5.3 Hyperglycemia and Diabetes Hyperglycemia and an in…

4 CONTRAINDICATIONS 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 )].

7 DRUG INTERACTIONS 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.

8.1 Pregnancy ZOLADEX is contraindicated during pregnancy unless ZOLADEX is being used for palliative treatment of advanced breast cancer. There are no adequate and well-controlled studies in pregnant women using ZOLADEX. Based on mechanism of action in humans and findings of increased pregnancy loss in animal studies, 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. ZOLADEX crosses the placenta in rats and rabbits following subcutaneous administration. Administration of goserelin to pregnant rats and rabbits during organogenesis resulted in increased preimplantation loss and increased resorptions. When pregnant rats received goserelin throughout gestation and lactation, there was a dose-related increase in umbilical hernia in offspring. In additional reproduction studies in rats, goserelin decreased fetus and pup survival. Human dose/exposure multiples could not be calculated from available animal data. Actual animal doses: rat (≥ 2 mcg/kg/day for pregnancy loss; > 10 mcg/kg/day for umbilical hernia in offspring); rabbits (> 20 mcg/kg/day).

8.3 Nursing Mothers It is not known if goserelin is excreted in human milk. Goserelin is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ZOLADEX, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

6 ADVERSE REACTIONS 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 …