Zoladex contains goserelin acetate (equivalent to 3.6 mg goserelin).
Zoladex LA contains goserelin acetate (equivalent to 10.8 mg goserelin).
Excipients/Inactive Ingredients: Zoladex LA: A blend of high and low molecular weight lactide/glycolide copolymers.
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.
Zoladex: Prostate cancer: ZOLADEX 3.6 mg is indicated in the management of prostate cancer suitable for hormonal manipulation.
Breast cancer: ZOLADEX 3.6 mg is indicated in the management of breast cancer in premenopausal and perimenopausal women suitable for hormonal manipulation.
Endometriosis: In the management of endometriosis, ZOLADEX 3.6 mg alleviates symptoms, including pain, and reduces the size and number of endometrial lesions.
Endometrial thinning: ZOLADEX 3.6 mg is indicated for the prethinning of the uterine endometrium prior to endometrial ablation or resection.
Uterine fibroids: In conjunction with iron therapy in the haematological improvement of anaemic patients with fibroids, prior to surgery.
Assisted reproduction: Pituitary downregulation in preparation for superovulation.
Zoladex LA: Prostate cancer: ZOLADEX LA 10.8 mg is indicated in the management of prostate cancer suitable for hormonal manipulation.
Endometriosis: ZOLADEX LA 10.8 mg is indicated in the management of endometriosis including alleviation of symptoms, such as pain, and reduction in the size and number of endometrial lesions.
Uterine fibroids: ZOLADEX LA 10.8 mg is indicated in the management of fibroids including shrinkage of lesions, improvement in the patient's haematological status and reduction of symptoms, such as pain. It can be used as an adjunct to surgery to facilitate the operative technique and reduce operative blood loss.
Breast cancer: ZOLADEX LA 10.8 mg is indicated in the management of estrogen-receptor-positive breast cancer in premenopausal women.
Caution should be taken while inserting ZOLADEX 3.6 mg/ZOLADEX LA 10.8 mg into the anterior abdominal wall due to the proximity of underlying inferior epigastric artery and its branches.
Use extra care when administering ZOLADEX 3.6 mg/ZOLADEX LA 10.8 mg to patients with a low body mass index and/or who are receiving full anticoagulation medication (see Precautions).
For correct administration of ZOLADEX 3.6 mg/ZOLADEX LA 10.8 mg, see instructions on instruction card (see Instructions for use, handling and disposal under Cautions for Usage).
Zoladex: Adults: One 3.6 mg depot of ZOLADEX injected subcutaneously into the anterior abdominal wall, every 28 days.
Assisted reproduction: ZOLADEX 3.6 mg 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 3.6 mg 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.
For women who are anaemic as a result of uterine fibroids, ZOLADEX 3.6 mg depot with supplementary iron may be given for up to three months before surgery.
Children: ZOLADEX 3.6 mg is not indicated for use in children.
Zoladex LA: Adult Men: One 10.8 mg depot of ZOLADEX LA 10.8 mg injected subcutaneously into the anterior abdominal wall, every 3 months (see Pharmacology: Pharmacodynamics under Actions).
Adult Women: One depot of ZOLADEX LA 10.8 mg injected subcutaneously into the anterior abdominal wall, every 12 weeks.
Elderly: No dosage adjustment is necessary in the elderly.
Renal Impairment: No dosage adjustment is necessary for patients with renal impairment.
Hepatic Impairment: No dosage adjustment is necessary for patients with hepatic impairment.
Children: Not indicated for use in children.
There is limited experience of overdosage in humans. In cases where ZOLADEX 3.6 mg/ZOLADEX LA 10.8 mg has unintentionally been re-administered 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 3.6 mg/ZOLADEX LA 10.8 mg. If overdosage occurs, this should be managed symptomatically.
Zoladex: ZOLADEX 3.6 mg 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 3.6 mg should not be used during pregnancy or lactation.
Zoladex LA: Known hypersensitivity to the active substance, to other LHRH analogues, or to any excipients of this product.
Pregnancy and lactation (see Use in Pregnancy & Lactation).
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 results in vascular injury and haemorrhagic shock requiring blood transfusions and surgical intervention. Extra care should be taken when administering ZOLADEX 3.6 mg/ZOLADEX LA 10.8 mg to patients with a low body mass index and/or receiving full anticoagulation medications.
The use of ZOLADEX 3.6 mg/ZOLADEX LA 10.8 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.
The use of LHRH agonists may cause a reduction in bone mineral density. Currently available ZOLADEX 3.6 mg data indicate a mean loss of 4.6% in vertebral bone mineral density following a six month 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 3.6 mg 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. In men, preliminary data suggest the use of a bisphosphonate in combination with a LHRH agonist may reduce mineral loss.
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.
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 Torsade de Pointes prior to initiating ZOLADEX.
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.
Zoladex: ZOLADEX 3.6 mg should be used with caution in women with known metabolic bone disease.
ZOLADEX 3.6 mg may cause an increase in uterine cervical resistance, which may result in difficulty in dilating the cervix.
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. 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, physicians should assess the benefit risk ration including the potential for Torsade de Pointes prior to initiating ZOLADEX.
Assisted Reproduction: ZOLADEX 3.6 mg 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 3.6 mg, 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 3.6 mg be used with caution in assisted reproduction regimens in patients with polycystic ovarian syndrome as follicle recruitment may be increased.
Zoladex LA: In women, ZOLADEX LA 10.8 mg is only indicated for use in endometriosis, fibroids and breast cancer in premenopausal women. For female patients requiring treatment with goserelin for other conditions, refer to the prescribing information for ZOLADEX 3.6 mg. There is no experience of the use of hormone replacement therapy in women receiving ZOLADEX LA 10.8 mg.
Time to return of menses after cessation of therapy with ZOLADEX LA 10.8mg may be prolonged in some patients.
The use of ZOLADEX may cause an increase in cervical resistance and care should be taken when dilating the cervix.
There are no clinical data on the effects of treating benign gynaecological conditions with ZOLADEX for periods in excess of six months.
In the case of disease progression without anti-tumour effect of ZOLADEX, multiple treatments may be considered.
Effects on ability to drive and use machines: There is no evidence that ZOLADEX 3.6 mg/ZOLADEX LA 10.8 mg results in impairment of ability to drive or operate machinery.
Use in children: ZOLADEX 3.6 mg/ZOLADEX LA 10.8 mg is not indicated for use in children as safety and efficacy have not been established in this group of patients.
Pregnancy: Zoladex: Although reproductive toxicology in animals gave no evidence of teratogenic potential, ZOLADEX 3.6 mg 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 3.6 mg 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 3.6 mg and any subsequent abnormalities of oocyte development or pregnancy and outcome.
Zoladex LA: ZOLADEX LA 10.8 mg 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 until menses resume (also see the warning relating to time to return of menses in Precautions).
Lactation: The use of ZOLADEX 3.6 mg/ZOLADEX LA 10.8 mg during breast feeding is not recommended.
The following frequency categories for adverse drug reactions (ADRs) were calculated based on reports from ZOLADEX 3.6 mg/ZOLADEX LA 10.8 mg clinical trials and post-marketing sources.
Zoladex: (See Table 1.)
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Zoladex LA: The most commonly observed adverse reactions include hot flushes, hyperhidrosis and injection site reactions. The following convention has been used for classification of frequency: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000) and Unknown (cannot be estimated from the available data). (See Table 2.)
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Post-marketing experience: A small number of cases of changes in blood count, hepatic dysfunction, pulmonary embolism and interstitial pneumonia have been reported in connection with this medicine.
Rarely, breast cancer patients with metastases have developed hypercalcaemia on initiation of therapy. In the presence of symptoms indicative of hypercalcaemia (e.g. thirst), hypercalcaemia should be excluded.
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 Torsade de Pointes should be carefully evaluated. (See Precautions.)
Zoladex LA: None known.
Instructions for use, handling and disposal: For correct administration of ZOLADEX 3.6 mg/ZOLADEX LA 10.8 mg, see instructions on instruction card.
Use as directed by the prescriber. Use extra care when administering ZOLADEX 3.6 mg/ZOLADEX LA 10.8 mg to patients with a low body mass index 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.
Zoladex LA: Incompatibilities: None known.
L02AE03 - goserelin ; Belongs to the class of gonadotropin releasing hormone analogues. Used in endocrine therapy.
Zoladex depot inj 3.6 mg
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Zoladex LA depot inj 10.8 mg
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