Zoladex Information
Zoladex () Indications And Usage
Zoladex () is indicated in the palliative treatment of advanced carcinoma of the prostate
In controlled studies of patients with advanced prostatic cancer comparing Zoladex () 3.6 mg to orchiectomy, the long-term endocrine responses and objective responses were similar between the two treatment arms. Additionally, duration of survival was similar between the two treatment arms in a major comparative trial.
In controlled studies of patients with advanced prostatic cancer, Zoladex () 10.8 mg implant produced pharmacodynamically similar effect in terms of suppression of serum testosterone to that achieved with Zoladex () 3.6 mg implant. Clinical outcome similar to that produced with the use of the Zoladex () 3.6 mg implant administered every 28 days is predicted with the Zoladex () 10.8 mg implant administered every 12 weeks.
The automatic safety feature of the syringe aids in the prevention of needlestick injury.
Zoladex () Dosage And Administration
Zoladex () , at a dose of 10.8 mg, should be administered subcutaneously every 12 weeks 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 12-week schedule.
Zoladex () Dosage Forms And Strengths
Zoladex () 10.8 mg implant is supplied as a sterile and totally biodegradable D,L-lactic and glycolic acids copolymer (12.82-14.76 mg/dose) impregnated with goserelin acetate equivalent to 10.8 mg of goserelin in a disposable syringe device fitted with a 14-gauge x 36 +/- 0.5 mm hypodermic siliconized needle with protective needle sleeve [SafeSystem™ Syringe] (NDC 0310-0951-30).
Zoladex () Warnings And Precautions
Hypersensitivity, antibody formation and acute anaphylactic reactions have been reported with GnRH agonist analogues
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.
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
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 evaluated 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
Zoladex () Adverse Reactions
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.
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%).
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:
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
Plasma Enzymes:
Lipids:
Hypercalcemia:
Changes in Blood Pressure:
Pituitary Apoplexy and Tumors:
Other Adverse Reactions:
Zoladex () Drug Interactions
No formal drug-drug interaction studies have been performed.
No drug interaction studies with other drugs have been conducted with Zoladex () . No confirmed interactions have been reported between Zoladex () and other drugs.
Zoladex () Use In Specific Populations
Pregnancy Category X
Based on mechanism of action in humans and findings of increased pregnancy loss in animal studies, Zoladex () may cause fetal harm when administered to a pregnant woman. Expected hormone changes that occur with Zoladex () treatment increase the risk for pregnancy loss. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus
Zoladex () crosses the placenta in rats and rabbits following subcutaneous administration. Administration of goserelin to pregnant rats and rabbits during organogenesis resulted in increased preimplantation loss and increased resorptions. When pregnant rats received goserelin throughout gestation and lactation, there was a dose-related increase in umbilical hernia in offspring. In additional reproduction studies in rats, goserelin decreased fetus and pup survival. Human dose/exposure multiples could not be calculated from available animal data.
Actual animal doses: rat (≥ 2 mcg/kg/day for pregnancy loss; ≥ 10 mcg/kg/day for umbilical hernia in offspring); rabbits (> 20 mcg/kg/day).
Zoladex () Overdosage
The pharmacologic properties of Zoladex () and its mode of administration make accidental or intentional overdosage unlikely. There is no experience of overdosage from clinical trials. Animal studies indicate that no increased pharmacologic effect occurred at higher doses or more frequent administration. Subcutaneous doses of the drug as high as 1 mg/kg/day in rats and dogs did not produce any nonendocrine related sequelae; this dose is up to 250 times the estimated human daily dose based on the body surface area. If overdosage occurs, it should be managed symptomatically.
Zoladex () Description
Zoladex () ® (goserelin acetate implant) is a GnRH agonist. Goserelin acetate is chemically described as an acetate salt of [D-Ser(Bu)6,Azgly]. Its chemical structure is pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu)-Leu-Arg-Pro-Azgly-NH acetate [CHNO ·(CHO) where x = 1 to 2.4].
Goserelin acetate is an off-white powder with a molecular weight of 1269 Daltons (free base). It is freely soluble in glacial acetic acid. It is soluble in water, 0.1M hydrochloric acid, 0.1M sodium hydroxide, dimethylformamide and dimethyl sulfoxide. Goserelin acetate is practically insoluble in acetone, chloroform and ether.
Zoladex () 10.8 mg implant is supplied as a sterile, biodegradable product containing goserelin acetate equivalent to 10.8 mg of goserelin. Zoladex () is designed for subcutaneous implantation with continuous release over a 12-week period. Goserelin acetate is dispersed in a matrix of D,L-lactic and glycolic acids copolymer (12.82–14.76 mg/dose) containing less than 2% acetic acid and up to 10% goserelin-related substances and presented as a sterile, white to cream colored 1.5 mm diameter cylinder, preloaded in a special single-use syringe with a 14-gauge x 36 +/- 0.5 mm siliconized needle with protective needle sleeve (SafeSystem™ Syringe) in a sealed, light- and moisture-proof, aluminum foil laminate pouch containing a desiccant capsule.
Studies of the D,L-lactic and glycolic acids copolymer have indicated that it is completely biodegradable and has no demonstrable antigenic potential.
Zoladex () is also supplied as a sterile, biodegradable product containing goserelin acetate equivalent to 3.6 mg of goserelin designed for administration every 28 days.
Zoladex () Clinical Pharmacology
Zoladex () is a synthetic decapeptide analogue of GnRH. Zoladex () acts as an inhibitor of pituitary gonadotropin secretion when administered in the biodegradable formulation.
In animal and studies, administration of goserelin resulted in the regression or inhibition of growth of the hormonally sensitive dimethylbenzanthracene (DMBA)-induced rat mammary tumor and Dunning R3327 prostate tumor.
Following initial administration, Zoladex () causes an initial increase in serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels with subsequent increases in serum levels of testosterone. Chronic administration of Zoladex () leads to sustained suppression of pituitary gonadotropins, and serum levels of testosterone consequently fall into the range normally seen in surgically castrated men approximately 21 days after initiation of therapy. This leads to accessory sex organ regression.
In clinical trials using Zoladex () 3.6 mg with follow-up of more than 2 years, suppression of serum testosterone to castrate levels has been maintained for the duration of therapy.
Absorption
The pharmacokinetics of Zoladex () have been determined in healthy male volunteers and patients. In healthy males, radiolabeled goserelin was administered as a single 250 mcg (aqueous solution) dose by the subcutaneous route. The absorption of radiolabeled drug was rapid, and the peak blood radioactivity levels occurred between 0.5 and 1.0 hour after dosing.
The overall pharmacokinetic profile of goserelin following administration of a Zoladex () 10.8 mg depot to patients with prostate cancer was determined. The initial release of goserelin from the depot was relatively rapid resulting in a peak concentration at 2 hours after dosing. From Day 4 until the end of the 12-week dosing interval, the sustained release of goserelin from the depot produced reasonably stable systemic exposure. Mean (Standard Deviation) pharmacokinetic data are presented in Table 4. There is no clinically significant accumulation of goserelin following administration of four depots administered at 12-week intervals.
SD = standard deviation
Serum goserelin concentrations in prostate cancer patients administered three 3.6 mg depots followed by one 10.8 mg depot are displayed in Figure 1. The profiles for both formulations are primarily dependent upon the rate of drug release from the depots. For the 3.6 mg depot, mean concentrations gradually rise to reach a peak of about 3 ng/mL at around 15 days after administration and then decline to approximately 0.5 ng/mL by the end of the treatment period. For the 10.8 mg depot, mean concentrations increase to reach a peak of about 8 ng/mL within the first 24 hours and then decline rapidly up to Day 4. Thereafter, mean concentrations remain relatively stable in the range of about 0.3 to 1 ng/mL up to the end of the treatment period.
Administration of four Zoladex () 10.8 mg depots to patients with prostate cancer resulted in testosterone levels that were suppressed to and maintained within the range normally observed in surgically castrated men (0 – 1.73 nmol/L or 0-50 ng/dL), over the dosing interval in approximately 91% (145/160) of patients studied. In 6 of 15 patients that escaped from castrate range, serum testosterone levels were maintained below 2.0 nmol/L (58 ng/dL) and in only one of the 15 patients did the depot completely fail to maintain serum testosterone levels to within the castrate range over a 336-day period (4 depot injections). In the 8 additional patients, a transient escape was followed 14 days later by a level within the castrate range.
Distribution
The apparent volume of distribution determined after subcutaneous administration of 250 mcg aqueous solution of goserelin was 44.1 ± 13.6 liters for healthy males. The plasma protein binding of goserelin was found to be 27%.
Metabolism
Metabolism of goserelin, by hydrolysis of the C-terminal amino acids, is the major clearance mechanism. The major circulating component in serum appeared to be 1–7 fragment, and the major component present in urine of one healthy male volunteer was 5-10 fragment. The metabolism of goserelin in humans yields a similar but narrow profile of metabolites to that found in other species. All metabolites found in humans have also been found in toxicology species.
Excretion
Clearance of goserelin following subcutaneous administration of a radiolabeled solution of goserelin was very rapid and occurred via a combination of hepatic and urinary excretion. More than 90% of a subcutaneous radiolabeled solution formulation dose of goserelin was excreted in urine. Approximately 20% of the dose recovered in urine was accounted for by unchanged goserelin.
Zoladex () Clinical Studies
The effects of hormonal treatment combined with radiation were studied in 466 patients (231 Zoladex () + flutamide + radiation, 235 radiation alone) with bulky primary tumors confined to the prostate (stage B2) or extending beyond the capsule (stage C), with or without pelvic node involvement.
In this multicentered, controlled trial, administration of Zoladex () (3.6 mg depot) and flutamide capsules (250 mg t.i.d.) prior to and during radiation was associated with a significantly lower rate of local failure compared to radiation alone (16% vs 33% at 4 years, P
In two controlled clinical trials, 160 patients with advanced prostate cancer were randomized to receive either one 3.6 mg Zoladex () implant every four weeks or a single 10.8 mg Zoladex () implant every 12 weeks. Mean serum testosterone suppression was similar between the two arms. PSA falls at three months were 94% in patients who received the 10.8 mg implant and 92.5% in patients that received three 3.6 mg implants.
Periodic monitoring of serum testosterone levels should be considered if the anticipated clinical or biochemical response to treatment has not been achieved. A clinical outcome similar to that produced with the use of the 3.6 mg implant administered every 28 days is predicted with Zoladex () 10.8 mg implant administered every 12 weeks (84 days). Total testosterone was measured by the DPC Coat-A-Count radioimmunoassay method which, as defined by the manufacturers, is highly specific and accurate. Acceptable variability of approximately 20% at low testosterone levels has been demonstrated in the clinical studies performed with the Zoladex () 10.8 mg depot.
Zoladex () How Supplied/storage And Handling
Zoladex () 10.8 mg implant is supplied as a sterile and totally biodegradable D,L-lactic and glycolic acids copolymer (12.82-14.76 mg/dose) impregnated with goserelin acetate equivalent to 10.8 mg of goserelin in a disposable syringe device fitted with a 14-gauge x 36 +/- 0.5 mm siliconized hypodermic needle with protective sleeve [SafeSystem™ Syringe] (NDC 0310-0951-30). The unit is sterile and comes in a sealed, light- and moisture-proof, aluminum foil laminate pouch containing a desiccant capsule. Store at room temperature (do not exceed 25°C [77°F]).
