Zoladex (goserelin acetate)

Stage B2-C Prostatic Carcinoma

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)

Table 2 : ADVERSE EVENTS DURING LATE RADIATION PHASE (after 90 days of radiation therapy)

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.

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

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

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

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

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.
• Sixtysix 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.

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 HDL2) 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 bone fracture in men.
• 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.

• 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.
• While a delay of a few days is permissible, every effort should be made to adhere to the 28-day schedule.

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.

Prostatic Carcinoma

• For the management of advanced prostate cancer, Zoladex is intended for long-term administration unless clinically inappropriate.

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.

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.

Breast Cancer

• For the management of advanced breast cancer, Zoladex is intended for long-term administration unless clinically inappropriate.

Renal Or Hepatic Impairment

• No dosage adjustment is necessary for patients with renal or hepatic impairment.

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

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.

• 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.
• It is not known if goserelin is excreted in human milk. 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.