Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Gonadotropin releasing hormone analogues, 
ATC code: L02AE03.

ZOLADEX (D-Ser(But)6 Azgly10 LHRH) is a synthetic analogue of naturally occurring LHRH.
On chronic administration ZOLADEX results in inhibition of pituitary LH secretion leading to a fall in serum testosterone concentrations in males and serum estradiol concentrations in females. This effect is reversible on discontinuation of therapy. Initially, ZOLADEX, like other LHRH agonists, may transiently increase serum testosterone concentration in men and serum estradiol concentration in women.

Prostate cancer:

In men, by around 21 days after the first depot injection, testosterone concentrations have fallen to within the castrate range and remain suppressed with continuous treatment every 28 days. This inhibition leads to prostate tumour regression and symptomatic improvement in the majority of patients.

Page 11 of 15
In the management of patients with metastatic prostate cancer, ZOLADEX has been shown in comparative clinical trials to give similar survival outcomes to those obtained with surgical castrations.

In a combined analysis of 2 randomised controlled trials comparing bicalutamide 150 mg monotherapy versus castration (predominantly in the form of ZOLADEX), there was no significant difference in overall survival between bicalutamide-treated patients and castration- treated patients (hazard ratio = 1.05 [CI 0.81 to 1.36]) with locally advanced prostate cancer.
However, equivalence of the two treatments could not be concluded statistically.

In comparative trials, ZOLADEX has been shown to improve disease-free survival and overall survival when used as an adjuvant therapy to radiotherapy in patients with high-risk localised (T1-T2 and PSA of at least 10 ng/mL or a Gleason score of at least 7), or locally advanced (T3- T4) prostate cancer. The optimum duration of adjuvant therapy has not been established; a comparative trial has shown that 3 years of adjuvant ZOLADEX gives significant survival improvement compared with radiotherapy alone. Neo-adjuvant ZOLADEX prior to radiotherapy has been shown to improve disease-free survival in patients with high risk localised or locally advanced prostate cancer.

After prostatectomy, in patients found to have extra-prostatic tumour spread, adjuvant ZOLADEX may improve disease free survival periods, but there is no significant survival improvement unless patients have evidence of nodal involvement at time of surgery. Patients with pathologically staged locally advanced disease should have additional risk factors such as PSA of at least 10 ng/mL or a Gleason score of at least 7 before adjuvant ZOLADEX should be considered. There is no evidence of improved clinical outcomes with use of neo- adjuvant ZOLADEX before radical prostatectomy.


Breast Cancer:

In women serum estradiol concentrations are suppressed by around 21 days after the first depot injection and, with continuous treatment every 28 days, remain suppressed at levels comparable with those observed in postmenopausal women. This suppression is associated with a response in hormone-dependent breast cancer, uterine fibroids, endometriosis and suppression of follicular development within the ovary. It will produce endometrial thinning and will result in amenorrhoea in the majority of patients.

Page 12 of 15
During treatment with LHRH analogues patients may enter the menopause. Rarely, some women do not resume menses on cessation of therapy.

ZOLADEX in combination with iron has been shown to induce amenorrhoea and improve haemoglobin concentrations and related haematological parameters in women with fibroids who are anaemic. The combination produced a mean haemoglobin concentration 1 g/dl above that achieved by iron therapy alone.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
The bioavailability of ZOLADEX is almost complete. Administration of a depot every four weeks ensures that effective concentrations are maintained with no tissue accumulations. ZOLADEX is poorly protein bound and has a serum elimination half-life of two to four hours in subjects with normal renal function. The half-life is increased in patients with impaired renal function.
For the compound given monthly in a depot formulation, this change will have minimal effect.
Hence, no change in dosing is necessary in these patients. There is no significant change in pharmacokinetics in patients with hepatic failure.