1 INDICATIONS AND USAGE

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)].

1.2Prostatic 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 (2.6), 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.

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.

1.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.

2.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.

3.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.

4.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.

5.Do not penetrate into muscle or peritoneum.

6.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.

7.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.

3 DOSAGE FORMS AND STRENGTHS

ZOLADEX is supplied as a sterile and totally biodegradable D,L-lactic and glycolic acids copolymer (13.3-14.3 mg/dose) impregnated with goserelin acetate equivalent to 3.6 mg of goserelin in a disposable syringe device fitted with a 16-gauge x 36 +/- 0.5 mm siliconized hypodermic needle with protective needle sleeve [SafeSystem™ Syringe] (NDC 0310-0950-36).

4 CONTRAINDICATIONS

4.1Hypersensitivity

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) and Adverse Reactions (6.10)].

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)].

5 WARNINGS AND PRECAUTIONS

5.1Women 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 increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes [see Adverse Reactions (6.10) and Patient Counseling Information (17.1)].

5.4 Cardiovascular Diseases

Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be eva luated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice [see Patient Counseling Information (17.1)].

5.5 Hypercalcemia

As with other GnRH agonists or hormonal therapies (antiestrogens, estrogens, etc.), hypercalcemia has been reported in some prostate and breast cancer patients with bone metastases after starting treatment with ZOLADEX. If hypercalcemia does occur, appropriate treatment measures should be initiated.

5.6 Hypersensitivity

Hypersensitivity, antibody formation and acute anaphylactic reactions have been reported with GnRH agonist analogues [see Contraindications (4.1) and Adverse Reactions (6.10)].

Of 115 women worldwide treated with ZOLADEX and tested for development of binding to goserelin following treatment with ZOLADEX, one patient showed low-titer binding to goserelin. On further testing of this patient's plasma obtained following treatment, her goserelin binding component was found not to be precipitated with rabbit antihuman immunoglobulin polyvalent sera. These findings suggest the possibility of antibody formation.

5.7 Cervical Resistance

The pharmacologic action of ZOLADEX on the uterus and cervix may cause an increase in cervical resistance. Therefore, care should be taken when dilating the cervix for endometrial ablation.

6 ADVERSE REACTIONS

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:

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%).

6.2Prostatic 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.

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: