Zoladex 3.6

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%).

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].

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

ADVERSE EVENT	ZOLADEX (n=242) %	ORCHIECTOMY (n=254) %
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	181
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%).

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.

Females

As would be expected with a drug that results in hypoestrogenism, the most frequently reported adverse reactions were those related to this effect.

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

ADVERSE EVENT	ZOLADEX (n=411) %	DANAZOL (n=207) %
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.

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

ADVERSE EVENT	ZOLADEX 3.6 mg (n=180) %	Placebo (n=177) %
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

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

ADVERSE EVENT	ZOLADEX (n=57) % of Pts.	OOPHORECTOMY (n=55) % 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.

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.

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 INFORMATION].

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 (HDL2 and HDL3) 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.

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 bony fracture in men [see PATIENT INFORMATION].

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.

Other Adverse Reactions

Psychotic disorders, convulsions and mood swings.

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