Zoladex

Goserelin acetate (equivalent to 3.6 mg goserelin).

ZOLADEX is sterile, white to cream coloured cylindrical depot in which goserelin acetate (equivalent to 3.6 mg of goserelin) is dispersed in a biodegradable matrix of lactide-glycolide copolymer. It is supplied as a single dose SafeSystem syringe applicator with a protective sleeve in a sealed pouch which contains a desiccant.

Pharmacology: Pharmacodynamics: ZOLADEX (D-Ser (Bu^t)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 oestradiol 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 oestradiol concentration in women. During early treatment with ZOLADEX some women may experience vaginal bleeding of variable duration and intensity. Such bleeding probably represents oestrogen withdrawal bleeding and is expected to stop spontaneously.
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 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.
During treatment with LHRH analogues patients may enter the menopause. Rarely, some women do not resume menses on cessation of therapy.
Pharmacokinetics: The bioavailability of ZOLADEX mg is almost complete. Administration of a depot every four weeks ensures that effective concentrations are maintained with no tissue accumulation. 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.
Toxicology: Preclinical safety data: Following long-term repeated dosing with ZOLADEX, 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.

Prostate cancer: ZOLADEX is indicated in the management of prostate cancer suitable for hormonal manipulation.
Breast cancer: ZOLADEX is indicated in the management of breast cancer in premenopausal and perimenopausal women suitable for hormonal manipulation.
Endometriosis: In the management of endometriosis, ZOLADEX alleviates symptoms, including pain, and reduces the size and number of endometrial lesions.
Endometrial thinning: ZOLADEX is indicated for the prethinning of the uterine endometrium prior to endometrial ablation or resection and endometrial biopsy prior to using Zoladex is not showing malignancy or atypical endometrial hyperplasia or pelvic inflammatory disease.
Assisted reproduction: Pituitary downregulation in preparation for superovulation.

Adults: Caution should be taken while inserting ZOLADEX into anterior abdominal wall due to the proximity of underlying inferior epigastric artery and its branches.
Use extra care when administering ZOLADEX to patients with a low body mass index (BMI) and/or who are receiving full anticoagulation medication (see Precautions).
For correct administration of ZOLADEX, see instructions on the instruction card.
One 3.6 mg depot of ZOLADEX injected subcutaneously into the anterior abdominal wall every 28 days.
Assisted reproduction: ZOLADEX is administered to downregulate the pituitary gland, as defined by serum oestradiol levels similar to those observed in the early follicular phase (approximately 150 pmol/l). This will usually take between 7 and 21 days.
When downregulation is achieved, superovulation (controlled ovarian stimulation) with gonadotrophin is commenced. The downregulation achieved with a depot agonist is more consistent suggesting that, in some cases, there may be an increased requirement for gonadotrophin. At the appropriate stage of follicular development, gonadotrophin is stopped and human chorionic gonadotrophin (hCG) is administered to induce ovulation. Treatment monitoring, oocyte retrieval and fertilisation techniques are performed according to the normal practice of the individual clinic.
No dosage adjustment is necessary for patients with renal impairment.
No dosage adjustment is necessary for patients with hepatic impairment.
No dosage adjustment is necessary in the elderly.
Endometriosis should be treated for a period of six months only, since at present there are no clinical data for longer treatment periods. Repeat courses should not be given due to concern about loss of bone mineral density. In patients receiving ZOLADEX for the treatment of endometriosis, the addition of hormone replacement therapy (a daily oestrogenic agent and a progestogenic agent) has been shown to reduce bone mineral density loss and vasomotor symptoms.
For use in endometrial thinning: two depots to be administered 4 weeks apart, with surgery timed for between zero and two weeks after the second depot.
Children: ZOLADEX is not indicated for use in children.

There is limited experience of overdosage in humans. In cases where ZOLADEX has unintentionally been readministered early, or given at a higher dose, no clinically relevant adverse effects have been seen. Animal tests suggest that no effect other than the intended therapeutic effects on sex hormone concentrations and on the reproductive tract will be evident with higher doses of ZOLADEX. If overdosage occurs, this should be managed symptomatically.

ZOLADEX should not be given to patients with a known hypersensitivity to the active substance, to other LHRH analogues, or to any excipients of this product.
ZOLADEX should not be used during pregnancy or lactation.

ZOLADEX 3.6 mg is not indicated for use in children as safety and efficacy have not been established in this group of patients.
Injection site injury has been reported with ZOLADEX, including events of pain, haematoma, haemorrhage and vascular injury. Monitor affected patients for signs or symptoms of abdominal haemorrhage. In very rare cases, administration error resulted in vascular injury and haemorrhagic shock requiring blood transfusions and surgical intervention. Extra care should be taken when administering ZOLADEX to patients with a low BMI and/or receiving full anticoagulation medications (see Dosage & Administration).
Males: The use of ZOLADEX 3.6 mg in men at particular risk of developing ureteric obstruction or spinal cord compression should be considered carefully and the patients monitored closely during the first month of therapy. If spinal cord compression or renal impairment due to ureteric obstruction are present or develop, specific standard treatment of these complications should be instituted.
Cardiovascular Diseases: Increased risk of myocardial infarction and sudden cardiac death has been reported in association with use of GnRH analogs in men. Monitor for cardiovascular disease and manage according to current clinical practice.
Females: The use of LHRH agonists may cause a reduction in bone mineral density. Currently available ZOLADEX data indicate a mean loss of 4.6% in vertebral bone mineral density following a six-months course of treatment with progressive recovery to a mean loss compared to baseline of 2.6% six months after cessation of treatment. In patients receiving ZOLADEX for the treatment of endometriosis, the addition of hormone replacement therapy (a daily oestrogenic agent and a progestogenic agent) has been shown to reduce bone mineral density loss and vasomotor symptoms.
A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycaemic control in those with pre-existing diabetes mellitus. Consideration should therefore be given to monitoring blood glucose.
ZOLADEX should be used with caution in women with known metabolic bone disease.
Currently, there are no clinical data on the effects of treating benign gynaecological conditions with ZOLADEX 3.6 mg for periods in excess of six months.
Androgen deprivation therapy may prolong the QT interval, although a causal association has not been established with ZOLADEX. In patients with a history of or who have risk factors for QT prolongation and in patients receiving concomitant medicinal products that may prolong the QT interval (see Interactions) physicians should assess the benefit risk ratio including the potential for Torsades de Pointes prior to initiating ZOLADEX.
Assisted Reproduction: ZOLADEX should only be administered as part of a regimen for assisted reproduction under the supervision of a specialist experienced in the area.
As with other LHRH agonists, there have been reports of ovarian hyperstimulation syndrome (OHSS) associated with the use of ZOLADEX, in combination with gonadotrophin. It has been suggested that the downregulation achieved with a depot agonist may lead, in some cases, to an increased requirement for gonadotrophin. The stimulation cycle should be monitored carefully to identify patients at risk of developing OHSS because its severity and incidence may be dependent on the dose regimen of gonadotrophin. Human chorionic gonadotrophin (hCG) should be withheld, if appropriate.
It is recommended that ZOLADEX be used with caution in assisted reproduction regimens in patients with polycystic ovarian syndrome as follicle recruitment may be increased.
Effect on ability to drive or operate machinery: There is no evidence that ZOLADEX 3.6 mg results in impairment of ability to drive or operate machinery.

Although reproductive toxicology in animals gave no evidence of teratogenic potential, ZOLADEX should not be used in pregnancy as there is a theoretical risk of abortion or foetal abnormality if LHRH agonists are used during pregnancy. Potentially fertile women should be examined carefully before treatment to exclude pregnancy. Non-hormonal methods of contraception should be employed during therapy and in the case of endometriosis until menses are resumed.
Pregnancy should be excluded before ZOLADEX is used for assisted reproduction. The clinical data from use in this setting are limited but the available evidence suggests there is no causal association between ZOLADEX and any subsequent abnormalities of oocyte development or pregnancy and outcome.
The use of ZOLADEX during breast feeding is not recommended.

The following frequency categories for adverse drug reactions (ADRs) were calculated based on reports from ZOLADEX clinical trials and post-marketing sources. (See table.)


Click on icon to see table/diagram/image

None known.
Since androgen deprivation treatment may prolong the QT interval, the concomitant use of ZOLADEX with medicinal products known to prolong the QT interval or medicinal products able to induce Torsades de Pointes should be carefully evaluated (see Precautions).

Instructions for use, handling and disposal: For correct administration of ZOLADEX, see instructions on the instruction card. Use as directed by the prescriber. Use extra care when administering ZOLADEX to patients with low BMI and/or who are receiving full anticoagulation medication (see Precautions).
Use only if pouch is undamaged. Use immediately after opening pouch. Dispose of the syringe in an approved sharps collector.

Do not store above 25°C.

Cancer Hormone Therapy / Trophic Hormones & Related Synthetic Drugs

L02AE03 - goserelin ; Belongs to the class of gonadotropin releasing hormone analogues. Used in endocrine therapy.

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