6.1Clinical Trials
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 ( 5.1 ) and Patient Counseling Information ( 17.2 )].
6.3Prostatic Carcinoma
Two controlled clinical trials using ZOLADEX 10.8 mg versus ZOLADEX 3.6 mg were conducted. During a comparative phase, patients were randomized to receive either a single 10.8 mg implant or three consecutive 3.6 mg implants every 4 weeks over weeks 0-12. During this phase, the only adverse event reported in greater than 5% of patients was hot flashes, with an incidence of 47% in the ZOLADEX 10.8 mg group and 48% in the ZOLADEX 3.6 mg group.
From weeks 12-48 all patients were treated with a 10.8 mg implant every 12 weeks. During this noncomparative phase, the following adverse events were reported in greater than 5% of patients: Table 3 ADVERSE EVENTS WERE REPORTED IN GREATER THAN 5% OF PATIENTS ADVERSE EVENTS ZOLADEX 10.8 mg (n=157) % Hot Flashes 64 Pain (general) 14 Gynecomastia 8 Pelvic Pain 6 Bone Pain 6 Asthenia 5 The following adverse events were reported in greater than 1%, but less than 5% of patients treated with ZOLADEX 10.8 mg implant every 12 weeks.
Some of these are commonly reported in elderly patients. WHOLE BODY – Abdominal pain, Back pain, Flu syndrome, Headache, Sepsis, Aggravation reaction CARDIOVASCULAR – Angina pectoris, Cerebral ischemia, Cerebrovascular accident, Heart failure, Pulmonary embolus, Varicose veins DIGESTIVE – Diarrhea, Hematemesis ENDOCRINE – Diabetes mellitus HEMATOLOGIC – Anemia METABOLIC – Peripheral edema NERVOUS SYSTEM – Dizziness, Paresthesia, Urinary retention RESPIRATORY – Cough increased, Dyspnea, Pneumonia SKIN – Herpes simplex, Pruritus UROGENITAL – Bladder neoplasm, Breast pain, Hematuria, Impotence, Urinary frequency, Urinary incontinence, Urinary tract disorder, Urinary tract infection, Urination impaired The following adverse events not already listed above were reported in patients receiving ZOLADEX 3.6 mg in other clinical trials.
Inclusion does not necessarily represent a causal relationship to ZOLADEX 10.8 mg. WHOLE BODY: Allergic reaction, Chills, Fever, Infection, Injection site reaction, Lethargy, Malaise CARDIOVASCULAR: Arrhythmia, Chest pain, Hemorrhage, Hypertension, Migraine, Myocardial infarction, Palpitations, Peripheral vascular disorder, Tachycardia DIGESTIVE: Anorexia, Constipation, Dry mouth, Dyspepsia, Flatulence, Increased appetite, Nausea, Ulcer, Vomiting HEMATOLOGIC: Ecchymosis METABOLIC: Edema, Gout, Hyperglycemia, Weight increase MUSCULOSKELETAL: Arthralgia, Hypertonia, Joint disorder, Leg cramps, Myalgia, Osteoporosis NERVOUS SYSTEM: Anxiety, Depression, Emotional lability, Headache, Insomnia, Nervousness, Somnolence, Thinking abnormal RESPIRATORY: Bronchitis, Chronic obstructive pulmonary disease, Epistaxis, Rhinitis, Sinusitis, Upper respiratory infection, Voice alterations SKIN: Acne, Alopecia, Dry skin, Hair disorders, Rash, Seborrhea, Skin discoloration, Sweating SPECIAL SENSES: Amblyopia, Dry eyes UROGENITAL: Breast tenderness, Decreased erections, Renal insufficiency, Sexual dysfunction, Urinary obstruction
6.5Postmarketing 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. Hypercalcemia : In patients with bone metastases. Bone Mineral Density: Osteoporosis, decreased bone mineral density and bone fracture in men [see Patient Counseling Information ( 17.2 )].
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. Skin reactions: SJS/TEN, DRESS, AGEP, dermatitis exfoliative, bullous dermatitis, and erythema multiforme. Psychiatric Disorders: Psychotic disorders, mood swings; suicidal ideation and attempt.
Other Adverse Reactions: Convulsions.
