General: Rarely, hypersensitivity reactions (including urticaria and anaphylaxis) have been reported in patients receiving ZOLADEX.

Males: 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.

Initially, ZOLADEX, like other LHRH agonists, causes transient increases in serum levels of testosterone. A small percentage of patients experienced a temporary worsening of signs and symptoms (see WARNINGS section), 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.

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.

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.

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:

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.

Hormone Replacement Therapy: Clinical studies suggest the addition of Hormone Replacement Therapy (estrogens and/pr 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 occrrs 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.

Changes in Laboratory Values During Treatment

Plasma Enzymes: Elevations 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.

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.

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.

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.

POSTMARKETING ADVERSE EVENTS

Pituitary Apoplexy

During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was 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.

No formal drug-drug interaction studies have been performed. No confirmed interactions have been reported between ZOLADEX and other drugs.

Bookmark this page: