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Zoladex 10.8 mg


Mechanism of Action

ZOLADEX is a synthetic decapeptide analogue of LHRH. ZOLADEX acts as a potent inhibitor of pituitary gonadotropin secretion when administered in the biodegradable formulation.

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 animal and in in vitro 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.

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.



The pharmacokinetics of goserelin have been determined in healthy male volunteers and patients. In healthy males, radiolabeled goserelin was administered as a single 250 μg (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 (goserelin acetate implant) 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 1. There is no clinically significant accumulation of goserelin following administration of four depots administered at 12-week intervals. Pharmacokinetic data were obtained using an RIA method, which has been shown to be specific for goserelin in the presence of its metabolites.

Table 1 — Goserelin pharmacokinetic parameters for the 10.8 mg depot

Parameter n Mean (SD) 95% CI
Lower Upper
Systemic clearance (mL/min) 41 121 (42.4) 108 134
Cmax (ng/mL) 41 8.85 (2.83) 7.96 9.74
Tmax (h) 41 1.80 (0.34) 1.70 1.92
Cmin (ng/mL) 44 0.37 (0.21) 0.30 0.43
Elimination Half-life (h) ¶ 7 4.16 (1.12) 3.12 5.20
¶ = determined after subcutaneous administration of 250 μg aqueous solution of goserelin.
SD = standard deviation 95%
CI = 95% confidence interval

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.

Figure 1: Goserelin serum concentrations during dosing three ZOLADEX 3.6 mg depots (0, 28, 56 days) then one ZOLADEX 10.8 mg (goserelin acetate implant) depot (84 days) to prostate cancer patients.

 Goserelin serum concentrations during dosing - Illustration

Administration of four ZOLADEX 10.8 mg (goserelin acetate implant) 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.


The apparent volume of distribution determined after subcutaneous administration of 250 μg 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 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.


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.

Special Populations

Renal Insufficiency

In clinical trials with the solution formulation of goserelin, subjects with impaired renal function (creatinine clearance less than 20 mL/min) had a serum elimination half-life of 12.1 hours compared to 4.2 hours for subjects with normal renal function (creatinine clearance greater than 70 mL/min). However, there was no evidence for any accumulation of goserelin on multiple dosing of the ZOLADEX 10.8 mg (goserelin acetate implant) depot to subjects with impaired renal function. There was no evidence for any increase in incidence of adverse events in renally impaired patients administered the 10.8 mg depot. These data indicate that there is no need for any dosage adjustment when administering ZOLADEX 10.8 mg (goserelin acetate implant) to subjects with impaired renal function.

Hepatic Insufficiency

The clearance and half-life of goserelin administered as an aqueous solution are not affected by hepatic impairment. These data indicate that there is no need for any dosage adjustment when administering ZOLADEX 10.8 mg (goserelin acetate implant) to subjects with impaired hepatic function.


There is no need for any dosage adjustment when administering ZOLADEX 10.8 mg to geriatric patients.

Body Weight

A decline of approximately 1 to 2.5% in the AUC after administration of a 10.8 mg depot was observed with a kilogram increase in body weight. In obese patients who have not responded clinically, testosterone levels should be monitored closely.

Drug-Drug Interactions

No formal drug-drug interaction studies have been performed.

Clinical Studies - Prostatic Carcinoma

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 (goserelin acetate implant) 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.

Clinical Studies - Stage B2-C Prostatic Carcinoma

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 < 0.001). The combination therapy also resulted in a trend toward reduction in the incidence of distant metastases (27% vs 36% at 4 years, P=0.058). Median disease-free survival was significantly increased in patients who received complete hormonal therapy combined with radiation as compared to those patients who received radiation alone (4.4 vs 2.6 years, P < 0.001). Inclusion of normal PSA level as a criterion for disease-free survival also resulted in significantly increased median disease-free survival in patients receiving the combination therapy (2.7 vs 1.5 years, P < 0.001).

Last reviewed on RxList: 3/5/2009
This monograph has been modified to include the generic and brand name in many instances.

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