ZOLADEX^® (goserelin acetate implant)

Indications

ZOLADEX 3.6 mg 1-month Depot is indicated for the following:

• Prostatic Carcinoma: ZOLADEX is indicated in the palliative treatment of advanced carcinoma of the prostate.
• Stage B2-C Prostatic Carcinoma: ZOLADEX is indicated for use in combination with flutamide for the management of locally confined Stage T2b-T4 (Stage B2-C) carcinoma of the prostate. Treatment with ZOLADEX and flutamide should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy.

ZOLADEX 10.8 mg 3-month Depot is indicated for the following:

• Prostatic Carcinoma: 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.
• Stage B2-C Prostatic Carcinoma: ZOLADEX is indicated for use in combination with flutamide for the management of locally confined Stage T2b-T4 (Stage B2-C) carcinoma of the prostate. Treatment with ZOLADEX and flutamide should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy.

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.

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.

Safety

ZOLADEX, like other luteinizing hormone-releasing hormone analogs (LHRH-As), may cause a transient rise in testosterone. When used alone, there may be a temporary worsening of prostate cancer symptoms at the start of therapy.

Development of diabetes has been reported in men receiving LHRH-As like ZOLADEX. Consider monitoring blood glucose in patients receiving ZOLADEX.

The most common adverse events (incidence > 5%) in advanced carcinoma of the prostate clinical trials were: for ZOLADEX 3.6 mg depot—hot flashes (62%), sexual dysfunction (21%), decreased erections (18%), lower urinary tract symptoms (13%), lethargy (8%), pain (worsened in the first 30 days) (8%), edema (7%), upper respiratory infection (7%), rash (6%), and sweating (6%); for ZOLADEX 10.8 mg depot—hot flashes (64%), pain (general) (14%), gynecomastia (8%), pelvic pain (6%), and bone pain (6%).

In the locally advanced carcinoma of the prostate clinical trial, additional adverse event data were collected for the combination therapy with radiation group during both the hormonal treatment and hormonal treatment plus radiation phases of this study. Adverse experiences (incidence > 5%) in both phases of this study were hot flashes (46%), diarrhea (40%), nausea (9%), and skin rash (8%).

Dosing

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

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 of a few days is permissible, every effort should be made to adhere to the 12-week schedule.

Efficacy

Clinical Studies - Prostatic Carcinoma: In controlled studies of patients with advanced prostatic cancer comparing ZOLADEX 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 comparative trial.

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-ACount radioimmunoassay method which, as defined by the manufacturers, is highly specific and accurate. Acceptable variability of approximately 20% at low testosterone.

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, P0.001). 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, P0.001). 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, P0.001).