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Pharmacology: Pharmacodynamics: Mode of action: ZOLADEX 3.6 mg/ZOLADEX LA 10.8 mg (D-Ser(But)6 Azgly10 LHRH) is a synthetic analogue of naturally occurring LHRH. On chronic administration ZOLADEX 3.6 mg/ZOLADEX LA 10.8 mg results in inhibition of pituitary LH secretion leading to a fall in serum testosterone concentrations in males and serum oestradiol concentrations in females. This effect is reversible on discontinuation of therapy. Initially, ZOLADEX 3.6 mg/ZOLADEX LA 10.8 mg, like other LHRH agonists, may transiently increase serum testosterone concentrations in men and serum oestradiol concentrations in women.
During early treatment with ZOLADEX 3.6 mg, some women may experience vaginal bleeding of variable duration and intensity. Such bleeding probably represents oestrogen withdrawal bleeding and is expected to stop spontaneously.
During treatment with LHRH analogues patients may enter the menopause. Rarely, some women do not resume menses on cessation of therapy.
Zoladex: 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.
In women serum oestradiol 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, endometriosis, uterine fibroids and suppression of follicular development within the ovary. It will produce endometrial thinning and will result in amenorrhoea in the majority of patients.
ZOLADEX 3.6 mg 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 1g/dl above that achieved by iron therapy alone.
Zoladex LA: In men by around 21 days after the first depot injection, testosterone concentrations have decreased to within the castrate range and remain suppressed with treatment every 3 months. If in exceptional circumstances repeat dosing does not occur at 3 months, data indicate that castrate levels of testosterone are maintained for up to 16 weeks in the majority of patients.
In women, serum oestradiol concentrations are suppressed by around 4 weeks after the first depot injection and remain suppressed until the end of the treatment period at levels comparable with those observed in postmenopausal women. Suppression of oestradiol is associated with a response in endometriosis, uterine fibroids and breast cancer in premenopausal women and will result in amenorrhoea in the majority of patients.
Clinical Data: Breast cancer: Japanese Phase II study: Disease free survival following subcutaneous administration of ZOLADEX LA 10.8mg once every 12 weeks as adjuvant therapy to premenopausal women with estrogen-receptor-positive breast cancer who underwent radical surgery was assessed in comparison with ZOLADEX 3.6 mg once every 4 weeks, both in combination with tamoxifen citrate (the duration of treatment was 96 weeks). Four (4.7%) and 1 (1.2%) events were observed in the ZOLADEX LA 10.8mg group and ZOLADEX 3.6 mg group, respectively, with median (min, max) disease-free survival of 675.0 days (142 days, 687 days) and 675.5 days (160 days, 685 days) in the ZOLADEX LA 10.8mg group and ZOLADEX 3.6 mg group, respectively.
Asian multinational Phase III study: The efficacy and safety of subcutaneous administration of ZOLADEX LA 10.8mg once every 12 weeks to premenopausal women with estrogen-receptor-positive advanced/recurrent breast cancer were assessed in comparison with ZOLADEX 3.6 mg once every 4 weeks, both in combination with tamoxifen citrate (the duration of treatment was 24 weeks). The proportion of patients who were progression free (%PFS) at Week 24, the primary endpoint, were 67/109 (61.5%) in the ZOLADEX LA 10.8mg and 68/113 (60.2%) in the Zoladex 3.6 mg with the difference [95% CI] of 1.29% [-11.40 - 13.90], which met the pre-specified non-inferiority criterion.
Pharmacokinetics: ZOLADEX 3.6 mg/ZOLADEX LA 10.8 mg 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 (Zoladex); for the compound given, as recommended, in a 10.8mg depot formulation this change will not lead to any accumulation (Zoladex LA). Hence, no change in dosing is necessary in these patients. There is no significant change in pharmacokinetics in patients with hepatic failure.
Zoladex: The bioavailability of ZOLADEX 3.6 mg is almost complete. Administration of a depot every four weeks ensures that effective concentrations are maintained with no tissue accumulation.
Zoladex LA: Administration of ZOLADEX LA 10.8 mg in accordance with the dosage recommendations ensures that exposure to goserelin is maintained with no clinically significant accumulation.
Toxicology: Preclinical safety data: Following long-term repeated dosing with ZOLADEX 3.6 mg/ZOLADEX LA 10.8 mg, an increased incidence of benign pituitary tumours has been observed in male rats. Whilst this finding is similar to that previously noted in this species following surgical castration, any relevance to humans has not been established.
In mice, long-term repeated dosing with multiples of the human dose produced histological changes in some regions of the digestive system manifested by pancreatic islet cell hyperplasia and a benign proliferative condition in the pyloric region of the stomach, also reported as a spontaneous lesion in this species. The clinical relevance of these findings is unknown.
