Consumer medicine information

Zoladex 3.6 mg implant SafeSystem

Goserelin

BRAND INFORMATION

Brand name

Zoladex 3.6 mg Implant

Active ingredient

Goserelin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zoladex 3.6 mg implant SafeSystem.

What is in this leaflet

This leaflet answers some of the common questions people ask about ZOLADEX 3.6 mg. It does not contain all the information that is known about ZOLADEX 3.6 mg.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor will have weighed the risks of you being administered ZOLADEX 3.6 mg against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What ZOLADEX is for

ZOLADEX 3.6 mg lowers the amount of sex hormones in the body. In women it reduces the level of oestrogen. In men it reduces the level of testosterone.

ZOLADEX 3.6 mg can treat breast cancer in some women before menopause or the 'change of life'. It is not a cure for breast cancer.

ZOLADEX 3.6 mg is also used to treat endometriosis and fibroids of the uterus. These are not cancer.

ZOLADEX 3.6 mg is used to thin the lining of the womb before surgery.

ZOLADEX 3.6 mg is also used in combination with other drugs as part of a treatment for infertility.

ZOLADEX 3.6 mg can treat prostate cancer in some men. It is not a cure for prostate cancer.

Your doctor will have explained why you are being treated with ZOLADEX 3.6 mg and told you what dose you will be given.

Follow all directions given to you by your doctor carefully.

They may differ from the information contained in this leaflet.

Your doctor may prescribe this medicine for another use. Ask your doctor if you want more information.

ZOLADEX 3.6 mg is not addictive.

Before you are given ZOLADEX 3.6 mg

When you must not be given it

ZOLADEX 3.6 mg will not be given to children.

There is no information on its use in children.

It will not be used after the use by (expiry) date printed on the pack.

It may have no effect at all, or worse, an entirely unexpected effect if it is used after the expiry date.

ZOLADEX 3.6 mg will not be used if the packaging is torn or shows signs of tampering.

Before you start to use it

You must tell your doctor if:

  • you have any allergies to any ingredients listed at the end of this leaflet or any other substances
    If you have an allergic reaction, you may get a rash, hay fever, difficulty breathing or feel faint.
  • you are pregnant, intend to become pregnant or are breastfeeding.
    Unless you are using ZOLADEX 3.6 mg as part of a fertility treatment do not use it while you are pregnant. It may affect the baby. We do not know if ZOLADEX 3.6 mg passes into breast milk.
  • you have heart or blood vessel conditions, including heart rhythm problems (arrhythmia), or are being treated with medicines for these conditions.
    The risk of you having further heart rhythm problems may increase if you are taking ZOLADEX 3.6 mg.

Taking other medicines

Tell your doctor if you are taking any other medicines, including

  • medicines that you buy at the chemist, supermarket or health food shop.

Your doctor or pharmacist can tell you what to do if you are taking any other medicines.

If you have not told your doctor about any of these things, tell them before you are administered ZOLADEX 3.6 mg.

Being given ZOLADEX 3.6 mg

How much you will be given

A ZOLADEX 3.6 mg implant will be injected under the skin of your stomach every 28 days.

The implant is a very small pellet that is given by a special needle and syringe known as SafeSystem. The injection will not hurt very much.

The pellet is designed to slowly release the medicine into your body over four weeks.

The ZOLADEX 3.6 mg SafeSystem incorporates a protective needle sleeve that automatically locks in place following administration of the implant to aid in the prevention of needle stick injury.

How long to use it

The length of time you will use ZOLADEX 3.6 mg for depends on what illness is being treated.

Your doctor will tell you how long you will need to be given ZOLADEX 3.6 mg.

If you forget to be given it

Your doctor will make an appointment for your next dose if you need it, so you will not forget your next dose.

Overdose

The doctor or nurse giving you ZOLADEX 3.6 mg will be experienced in the use of it, so it is unlikely that you will be given an overdose.

While you are using it

Things you must do

Make sure to keep your appointment for being given ZOLADEX 3.6 mg every four weeks.

If you do not, your hormone level will rise and your illness may get worse.

Use barrier contraceptive methods (condom or diaphragm) while having ZOLADEX 3.6 mg treatment, unless it is being used for infertility.

Tell your doctor immediately if you become pregnant.

Things you must not do

Do not take oral contraceptives while being treated with ZOLADEX 3.6 mg.

They interfere with the way it works.

Do not stop being given ZOLADEX 3.6 mg unless you have discussed it with your doctor first.

Your doctor will have explained why you need to be given ZOLADEX and for how long.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using ZOLADEX 3.6 mg.

ZOLADEX 3.6 mg helps most people with the illnesses it treats, but it may have unwanted side effects in a few people.

It can be hard to work out whether side effects are caused by ZOLADEX 3.6 mg or the disease that is being treated.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • skin rashes
  • painful joints
  • hot flushes, sweating or feeling faint
  • chills
  • tingling in fingers or toes
  • swelling, soreness or itchiness of the breasts
  • vaginal dryness
  • headache
  • mood changes
  • trouble passing urine or experience lower back pain
  • your testicles getting smaller

These are all mild side effects of ZOLADEX 3.6 mg.

ZOLADEX 3.6 mg lowers the amount of sex hormones in your body so your sex drive will probably be reduced.

It is unlikely that you can father a child or fall pregnant while using ZOLADEX 3.6 mg, unless it is for infertility treatment.

Use a barrier contraceptive method to make sure.

Most women stop having periods while being treated with ZOLADEX 3.6 mg. Some may go through menopause while being given ZOLADEX 3.6 mg and not have periods again when the treatment is finished.

In men and in women who have not gone through the 'change of life', ZOLADEX 3.6 mg is likely to reduce the amount of calcium in their bones leading to a loss in bone mineral density. It is known that bone mineral density loss partially recovers in the next several months following cessation of therapy. However, doctors do not know if bone mineral density loss will recover completely in every person. Discuss this with your doctor or pharmacist if you are concerned.

If you have a tumour in your pituitary gland, ZOLADEX 3.6 mg may make the tumour bleed or collapse. This is very rare but causes severe headaches, sickness, loss of eyesight and unconsciousness.

Your doctor will be happy to discuss these things with you if you want more information.

Tell your doctor if you notice anything else that is making you feel unwell.

Some people may get other side effects while being treated with ZOLADEX 3.6 mg.

After using it

Storage

Keep your ZOLADEX 3.6 mg in the package until you take it to the doctor or nurse to give it to you.

If you take ZOLADEX 3.6 mg out of the pack you may dislodge the pellet in the syringe.

It should be kept in a cool, dry place where the temperature stays below 25°C.

Do not store it or any other medicine in the bathroom or near a sink.

Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Do not leave it in the car on hot days.

Disposal

Any ZOLADEX 3.6 mg, which is not used, will be disposed of in a safe manner by your doctor or pharmacist.

Product description

What ZOLADEX 3.6 mg looks like

ZOLADEX 3.6 mg comes in a special syringe, called the SAFESYSTEM and a siliconised needle.

The small pellet containing ZOLADEX 3.6 mg is about the size of a grain of rice. It can be seen in the "window" half way up the syringe and is white or cream coloured

Ingredients

ZOLADEX 3.6 mg implant contains the active ingredient goserelin 3.6 mg (as the acetate) plus polyglactin.

Distributor

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
MACQUARIE PARK NSW 2113

Telephone: 1800 805342

This leaflet was prepared on 16th May 2017.

Australian Registration Number AUST R 24368

Doc ID-002754320 v4.0

BRAND INFORMATION

Brand name

Zoladex 3.6 mg Implant

Active ingredient

Goserelin

Schedule

S4

 

Name of the medicine

Goserelin acetate.

Excipients.

Polyglactin.

Description

Molecular formula: C59H84N18O14 (base). Molecular weight: 1269 (base). CAS: 65807-02-5 (goserelin base).
It is a Gonadotrophin Releasing Hormone agonist (GnRH agonist). Also known as Luteinising Hormone Releasing Hormone agonist (LHRH agonist).
Zoladex SafeSystem implant contains goserelin acetate in an amount equivalent to 3.6 mg of goserelin base.
A sterile white to cream coloured cylindrical implant in which goserelin acetate is dispersed in a cylindrical polyglactin co-polymer rod of a biodegradable and biocompatible matrix.
The implant is released continuously over at least 28 days when injected subcutaneously.
The implant is supplied in a purpose designed single dose syringe applicator with 16 gauge needle. The SafeSystem incorporates a protective needle sleeve that automatically locks in place following administration of the implant to aid in the prevention of needle stick injury.

Pharmacology

Goserelin acetate is a potent synthetic decapeptide analogue of luteinising hormone releasing hormone (LHRH). When given acutely, goserelin acetate will release luteinising hormone (LH) from the pituitary gland. However, following chronic administration, goserelin acetate is a potent inhibitor of gonadotrophin production resulting in gonadal suppression and consequently sex organ regression.
In animals and humans, following an initial stimulation of pituitary LH secretion and a transient elevation in serum testosterone in males, or serum oestradiol in females, chronic administration results in inhibition of gonadotrophin secretion. The result is a sustained suppression of pituitary LH occurring within 3 weeks after initiation of therapy. This suppression of hormones in both men and women is then maintained as long as treatment is continued. During early treatment with goserelin acetate 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 implant injection, testosterone concentrations have decreased 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 implant injection and, with continuous treatment every 28 days, remain suppressed at levels comparable with those observed in postmenopausal women. This suppression is associated with endometrial thinning, suppression of follicular development within the ovary and a response in hormone dependent breast cancer (tumours that are ER positive and/or PgR positive), endometriosis and uterine fibroids and will result in amenorrhoea in the majority of patients.
During treatment with a LHRH agonist patients may enter the natural menopause. Rarely, some women do not resume menses on cessation of therapy.

Pharmacokinetics.

Although bioavailability from the implant may be variable, the formulation releases the drug at effective concentrations to sustain a biological response for at least 28 days.
Goserelin acetate has a serum elimination half-life of approximately 4.2 hours in male subjects with normal renal function compared to 13 minutes for natural LHRH. Zoladex is poorly protein bound (20-28%).
Although the half-life is increased in patients with impaired renal function, absolute clearance is still relatively rapid. The existence of a nonrenal, presumably hepatic clearance and the absence of an increased incidence of possible adverse reactions in such patients imply that no adjustment in the proposed dosage regimen is necessary in patients with renal impairment. There is no significant change in pharmacokinetics in patients with hepatic impairment.
Zoladex implant releases goserelin acetate continuously with peak serum concentrations occurring approximately 2 weeks after administration with interindividual differences in these peak concentrations (1.76 ± 0.52 nanogram per mL to 5.04 ± 0.71 nanogram per mL).
Serum goserelin concentrations become low by day 28; delaying or omitting scheduled doses should be avoided.
There is no evidence of drug accumulation when Zoladex implant is administered at 4 weekly intervals.

Clinical Trials

Prostate cancer. Adjuvant and neoadjuvant Zoladex therapy in combination with radiotherapy.

Five phase III, open labelled, randomised, controlled, multicentred clinical trials have been conducted to evaluate the added value of adjuvant and/or neoadjuvant Zoladex therapy in combination with radiotherapy in patients with histologically proven prostate cancer. The majority of patients had locally advanced disease (T2 N+, T3 or T4, N0/Nx, M0). All studies have been performed by three independent collaborative oncology groups (European Organisation for Research and Treatment of Cancer (EORTC), the Radiation Therapy Oncology Group (RTOG)) and the Trans-Tasman Radiation Oncology Group (TROG), and have reported results from median follow-up of more than 5 years. Table 1 summarises the study design, patient populations and median follow-up periods for these studies.
Adjuvant Zoladex therapy long-term (≥ 3 years) significantly improved disease free survival and overall survival compared to radiotherapy alone (Tables 2 and 3). Neoadjuvant Zoladex therapy for two months prior and during radiotherapy significantly improved disease free survival but not overall survival compared to radiotherapy alone (Table 4). A combination of neoadjuvant and adjuvant Zoladex therapy with radiotherapy also significantly improved disease free survival but not overall survival compared to neoadjuvant Zoladex with radiotherapy (Table 5) and radiotherapy alone (Table 6). There was no significant difference in disease free survival between 3 months and 6 months neoadjuvant plus adjuvant Zoladex (Table 6).

Adjuvant therapy in early breast cancer.

Several clinical trials, each open and randomised, were evaluated to assess the efficacy and safety of long-term adjuvant Zoladex therapy in the standard of care for premenopausal/ perimenopausal women in early breast cancer (see Table 7). All trials were conducted by independent collaborative oncology groups, and the protocolled duration of Zoladex treatment, administered at four weekly intervals, varied from 2 years to 5 years. The key efficacy endpoints in both the pivotal and supportive trials were disease free survival and overall survival. The ZIPP trials were designed to allow data to be pooled.

Results from the ZEBRA trial.

There was a statistically significant interaction between trial treatment and ER status (hazard ratio = 0.54; 95% CI = 0.37, 0.78; p = 0.001). In a prospective, protocolled subgroup analysis by oestrogen receptor (ER) status, Zoladex 3.6 mg was equivalent to CMF in terms of disease free survival in patients with ER positive tumours. Analyses of overall survival were comparable, although the confidence intervals were wider. In patients with ER negative tumours, disease free survival and overall survival were significantly greater in the CMF group. These results are tabulated below (see Table 8).
The Kaplan-Meier disease free survival curve for ER positive patients does not indicate any loss of efficacy 6 years after starting Zoladex 3.6 mg therapy (i.e. 4 years after cessation of therapy).

Bone mineral density (BMD).

Following two years of Zoladex 3.6 mg treatment in early breast cancer, the average loss of BMD was 6.2% and 11.5% at the femoral neck and lumbar spine, respectively. This loss has been shown to be partially reversible at the one year off treatment follow-up with recovery to 3.4% and 6.4% below baseline at the femoral neck and lumbar spine, respectively.

Amenorrhoea.

Six months after completing the 2 year course of Zoladex 3.6 mg therapy, < 40% of patients were amenorrhoeic. If patients who were not menstruating normally at trial entry, or had a hysterectomy or had recurrence during the trial (and therefore may have received another amenorrhoea inducing treatment) are excluded, the number of amenorrhoeic patients 6 months post treatment was < 24%. Most of these patients were aged > 40 years of age at trial entry.

Safety.

Patients receiving Zoladex 3.6 mg experienced higher incidences of effects caused by oestrogen suppression (e.g. hot flushes, vaginal dryness/ soreness etc.), than patients receiving combination chemotherapy (CMF), but within 6 months of completing therapy, these incidences had decreased to below those seen in CMF patients. Patients who received CMF experienced a higher incidence of the expected side effects of chemotherapy (e.g. cytopenia, nausea, vomiting and alopecia), than patients who received Zoladex 3.6 mg.

Results from the supportive trials.

The main disease free survival and overall survival analyses are tabulated in Table 9.
Overall the efficacy data demonstrates that Zoladex 3.6 mg is effective as an alternative to combination chemotherapy, in patients with hormone receptor-positive early breast cancer (as demonstrated by the ZEBRA trial). Zoladex may also provide additional therapeutic benefit when used after combination chemotherapy (as demonstrated by study INT0101). The clinical evaluation of Zoladex is mainly in studies of two years duration when it has been shown to be equivalent to chemotherapy. Studies up to five years have shown the efficacy and safety of Zoladex. Treatment for greater than five years has not been studied. Both efficacy and tolerability should be considered when deciding on the treatment duration for an individual patient.

Endometrial thinning.

Two pivotal trials were conducted with Zoladex when used as an endometrial thinning agent prior to endometrial ablation.
In a randomised multicentre trial in 358 women with dysfunctional uterine bleeding, patients were administered either Zoladex 3.6 mg implant or sham injection on two occasions. All patients underwent endometrial ablation using loop diathermy alone or in combination with rollerball approximately six weeks after the first injection. The median endometrial thickness prior to surgery was significantly less in the Zoladex treated group (1.50 mm) compared to the placebo group (3.55 mm). Six months after surgery, the amenorrhoea rate was statistically significantly higher in the Zoladex treated group than the sham group (40% versus 26%). At twelve months follow-up, the proportion of patients who remained amenorrhoeic was higher in the Zoladex treated group than in the sham group (46% versus 29%) and few gynaecological interventions were required in either group. Although there was no statistically significant difference in improvement in overall menorrhagia (amenorrhoea plus severe hypomenorrhoea) between the Zoladex and sham groups, there was a trend in favour of Zoladex.
In a randomised trial conducted in 160 women with dysfunctional uterine bleeding, a comparison of one or two implants of Zoladex 3.6 mg administered at an interval of four weeks with laser ablation occurring four weeks after Zoladex administration was made. The median endometrial thickness prior to surgery was significantly less in the group treated with two implants (0.5 mm) compared to the group treated with one implant (1 mm). There was no difference in amenorrhoea rates at 24 weeks between groups. Of the patients that completed the trial, 53% and 20% reported hypomenorrhoea and normal menses respectively six months after surgery.

Endometriosis.

In a double blind, multicentre study 345 patients with endometriosis were randomised to one of three treatment groups for a 24 week treatment and 48 week follow-up period. Patients were randomised to receive Zoladex alone (HRT0) or with once daily doses of either 0.3 mg oestrogen/5 mg medroxyprogesterone acetate (MPA) (HRT1) or 0.625 mg oestrogen/5 mg MPA (HRT2). Bone mineral density was measured at the lumbar spine (L2-4) using DEXA in most cases, at pretreatment and at weeks 12, 24, 48 and 72 of the study respectively. The mean percentage losses in bone mineral density at the lumbar spine in the HRT0, HRT1 and HRT2 groups at 12 weeks were 2.1%, 1.1% and 0.8%, at 24 weeks 4.1%, 1.9% and 1.6%, at 48 weeks (e.g. 24 weeks post-treatment follow-up) 2.8%, 1.7% and 1.2% and at 72 weeks (e.g. 48 weeks post-treatment follow-up) 1.7%, 1.2% and 0.5% respectively.
The mean percentage loss in BMD at the lumbar spine was statistically significantly lower in the two HRT treatment groups than in the Zoladex alone group (p < 0.001 at 12 and 24 weeks and p = 0.03 at week 48 respectively). Decreases in the mean values from baseline occurred in all three treatment groups with no statistically significant differences between the groups during the 24 week treatment period for both the total pelvic symptom scores and the total subjective symptom scores.
At week 12 there was a higher percentage of patients in the Zoladex alone group than in either of the HRT groups with hot flushes (94.8%, 56.2% and 45.2% respectively). At week 24 there was a higher percentage of patients with vaginal dryness in the Zoladex alone group (51.4%) than in the lower dose HRT group (39.4%) and the higher dose HRT group (25.55%) respectively. The study showed that Zoladex plus HRT was as effective as Zoladex alone in relieving pelvic symptoms of endometriosis and reduced both the loss of BMD and the physiological side effects of hot flushes and vaginal dryness.

Assisted reproduction.

When Zoladex 3.6 mg is used for assisted reproduction, the trials and literature reports consistently show higher success rates than human menopausal gonadotrophin (hMG) alone, or hMG in combination with clomiphene citrate. In this setting, Zoladex 3.6 mg is effective in suppression of ovarian activity with pregnancy and live birth rates comparable with other gonadotrophin releasing hormone agonists.

Indications

Prostate cancer.

Palliative treatment of metastatic (M+) or locally advanced prostate cancer, where suitable for hormonal manipulation.
Adjuvant and neoadjuvant therapy in combination with radiotherapy for the management of locally advanced prostate cancer in men suitable for hormonal manipulation.

Breast cancer.

Treatment of advanced breast cancer (T3b, T4 or any T with N2, 3 or M+) in premenopausal women suitable for hormonal manipulation.
Adjuvant therapy in early breast cancer, in premenopausal and perimenopausal women suitable for hormonal manipulation.

Endometriosis.

In the management of visually proven endometriosis to reduce symptoms including pain and the size and number of endometrial lesions.

Uterine fibroids.

In the management of fibroids, Zoladex shrinks the lesions and reduces the symptoms, including pain. Zoladex also increases the haemoglobin concentration and haematocrit in women with anaemia attributable to menorrhagia. It is used as an adjunct to surgery to facilitate the operative technique and reduce operative blood loss.

Endometrial thinning.

Use as an endometrial thinning agent prior to endometrial ablation.

Assisted reproduction.

Pituitary down regulation in preparation for controlled ovarian superstimulation.

Contraindications

Zoladex is contraindicated in patients with known hypersensitivity to LHRH, LHRH agonist analogues or any of the components of Zoladex.
Pregnancy and lactation (see Precautions, Use in pregnancy, Use in lactation).

Precautions

Zoladex 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 and Administration).
Serum testosterone concentrations in males or serum oestradiol concentrations in females may rise if an implant is omitted or delayed.
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.

Advanced or metastatic breast or prostate cancer.

Initially, Zoladex, like other LHRH agonists, transiently increases serum testosterone in males and serum oestradiol in females. Although not necessarily associated, there have been reports of temporary increase in bone pain in patients with advanced cancer and bony metastases. These events may last up to two weeks and may need to be managed symptomatically. Some patients may experience a temporary increase in signs and symptoms, which can be managed symptomatically. Rarely, patients with bony metastases have developed hypercalcaemia on initiation of therapy.
The use of Zoladex in patients with metastatic cancer who are 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. Isolated cases of short-term worsening of these signs and symptoms have been reported during the initial four weeks of Zoladex therapy.

Hyperglycaemia and diabetes.

Hyperglycaemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycaemia may represent development of diabetes mellitus or worsening of glycaemic control in patients with diabetes. Monitor blood glucose and/or glycosylated haemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for the treatment of hyperglycaemia or diabetes.

Cardiovascular disease.

An increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and managed according to current clinical practice.

Endometrial thinning.

The use of Zoladex may cause an increase in cervical resistance and care should be taken when dilating the cervix. When Zoladex is used as a prethinning agent prior to endometrial ablation, clinical trials demonstrate an increased incidence of operative complications (such as cervical tears) related to cervical resistance.

Bone mineral density.

The use of Zoladex causes a loss of bone mineral density. Currently available data suggest that partial recovery of bone loss occurs on cessation of therapy. The following comments are available for:

Endometriosis.

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 loss in the lumbar spine but not in the femoral neck. Furthermore, hormone replacement therapy has been demonstrated to reduce the vasomotor symptoms in patients receiving Zoladex. If HRT is to be used, the product information for the particular HRT to be used should be reviewed before starting treatment. Despite the addition of hormone replacement therapy, there are no clinical data on the effects on bone of treating benign gynaecological conditions with Zoladex for a continuous period in excess of six months or with repeat courses. Therefore no repeat courses of Zoladex (or any other LHRH agonist) should be administered following the initial 6 months course of Zoladex therapy without assessment of the risk of developing osteoporosis. Current data suggest that at least 2 years are required between courses of treatment.

Early breast cancer.

Following two years treatment for early breast cancer, the average loss of BMD was 6.2% and 11.5% at the femoral neck and lumbar spine respectively. This loss has been shown to be partially reversible at the one year off treatment follow-up with recovery to 3.4% and 6.4% below baseline at the femoral neck and lumbar spine respectively.
Particular care should be taken in assessing women for treatment if they exhibit risk factors for osteoporosis such as family history, slight build, heavy smoking and low dietary calcium intake or in women with chronic anovulatory menstrual disturbances, women treated with glucocorticoids, or chronically immobilised. Patients with significant risk factors should have bone density measured before commencing treatment. The clinician should discuss relevant risk factors with patients on an individual basis.

Ovarian hyperstimulation.

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 gonadotrophins. The stimulation cycle should be monitored carefully to identify patients at risk of developing OHSS. Human chorionic gonadotrophin (hCG) should be withheld, if appropriate.
As there are relatively few data in patients with polycystic ovarian syndrome, caution in using Zoladex is recommended as these patients are at a greater risk of developing OHSS.
Pregnancy should be excluded before Zoladex is used for assisted reproduction. When Zoladex is used in this setting (i.e. for assisted reproduction), there is no clinical evidence to suggest a causal association between Zoladex and any subsequent abnormalities of oocyte development or pregnancy and outcome.

QT/QTc interval prolongation.

Androgen deprivation therapy may prolong QT/QTc interval. Prescribers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities and in patients taking drugs known to prolong the QT interval. Electrolyte imbalances should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes.

Carcinogenicity/ mutagenicity.

After subcutaneous implant injections once every 4 weeks for 1 year to male and female rats at doses equivalent to 4 times the recommended monthly dose for a human (based on AUC), an increased incidence of benign pituitary microadenomas was found.
This finding is similar to that previously noted in this species following surgical castration and appears to be a species specific response to castration. Any relevance to humans has not been established. No increase in pituitary adenomas was seen in mice receiving injections of goserelin every 3 weeks for 2 years at doses up to 2400 microgram/kg/day (approximately 18 to 37 times the recommended monthly dose for a human (based on Cmax)). An increased incidence of histiocytic sarcomas of the bone marrow of the vertebral column and femur were observed in male mice given 2400 microgram/kg/day but not in female mice, or rats of either sex. The relevance of these tumours 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 proliferation 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.
Mutagenicity tests for gene mutations and chromosomal damage have provided no evidence for mutagenic effects.

Effects on fertility.

The expected pharmacology of Zoladex is the suppression of gonad function to castrate levels. As a result there is profound impairment of fertility. In rats this is expressed as:
Male: decrease in weight and atrophic histological changes in the testes, epididymis, seminal vesicle and prostate gland with complete suppression of spermatogenesis.
Female: suppression of ovarian function with decreased size and weight of the ovaries and secondary sex organs; arrest of follicular development at the antral stage and reduction in size and number of the corpora lutea.
Except for the testes, almost complete reversal of these effects in male and female rats was observed several weeks after dosing was stopped, however, fertility and general reproductive performance were reduced in those that became pregnant after goserelin was discontinued.
Based on histological examination, drug effects on reproductive organs seem to be completely reversible in male and female dogs when drug treatment was stopped after continuous administration for 1 year at doses equivalent to 214 microgram/kg/day (approximately 57 times the recommended monthly dose for a human based on AUC).

Use in pregnancy.

(Category D)
(See Contraindications). Zoladex should not be used in pregnancy as there is a theoretical risk of abortion or fetal abnormality if LHRH agonists are used during pregnancy. Potentially fertile women should be examined carefully before treatment to exclude pregnancy. A pregnancy test should be performed prior to administering the Zoladex implant. Nonhormonal methods of contraception should be employed during therapy and it is generally recommended that the initial injection should be given early in the follicular phase of the menstrual cycle except in the case of assisted reproduction when the initial injection may be given in the luteal or follicular phase of the menstrual cycle, in accordance with the specialist's normal practice.
Subcutaneous injection of goserelin into pregnant rats or rabbits at doses greater than 10 to 20 microgram/kg/day has been shown to cause foetal deaths and termination of pregnancy. Parturition in rats is inhibited at doses greater than 0.01 microgram/kg/day. There was no conclusive evidence of any teratogenic effects in animals, although a low incidence of head malformations in rabbits may have been secondary to the endocrine effects of the drug.

Use in lactation.

(See Contraindications). The use of goserelin during breastfeeding is not recommended.
A study in lactating rats showed that drug related material is excreted in milk after subcutaneous administration of radiolabelled goserelin acetate; most of the excreted radioactivity was associated with inactive metabolites, although small amounts of parent drug were detectable. There are no adequate studies on the effects of goserelin administered to lactating women.

Effect on ability to drive and use machinery.

There is no evidence that Zoladex 3.6 mg results in impairment of ability to drive or operate machinery.

Interactions

None known.

Effect on laboratory tests.

None known.

Adverse Effects

The following frequency categories for adverse drug reactions (ADRs) were calculated based on reports from Zoladex clinical trials and postmarketing sources. See Table 10.

Dosage and Administration

Caution should be taken while inserting Zoladex into the interior 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 BMI and/or who are receiving full anticoagulation medication (see Precautions).
Before injection, it should be ensured that the implant is visible in the window of the applicator. The plunger should not be withdrawn once the needle is in position. The plunger should be fully depressed to expel the implant into subcutaneous tissue well away from the point of entry and to activate the protective needle sleeve.
For correct administration of Zoladex, see instructions on the administration card.
Do not omit or delay injections, as serum testosterone or serum oestradiol levels may rise in males and females respectively.

Prostate cancer.

One 3.6 mg implant of Zoladex injected subcutaneously into the anterior abdominal wall, every 28 days.
Adjuvant and/or neoadjuvant Zoladex therapy in combination with radiotherapy may include short-term use of an antiandrogen to prevent flare (see Clinical Trials, Adjuvant and neoadjuvant Zoladex therapy in combination with radiotherapy).

Breast cancer.

Early breast cancer.

Zoladex 3.6 mg therapy as an alternative to combination chemotherapy: one 3.6 mg implant of Zoladex injected subcutaneously into the anterior abdominal wall, every 28 days, for 2 years.
Adjuvant Zoladex 3.6 mg therapy post combination chemotherapy: one 3.6 mg implant of Zoladex injected subcutaneously into the anterior abdominal wall, every 28 days, for 5 years.

Advanced breast cancer.

One 3.6 mg implant of Zoladex injected subcutaneously into the anterior abdominal wall, every 28 days.

Endometrial thinning.

When used as an endometrial thinning agent prior to endometrial ablation, Zoladex 3.6 mg should be administered as one implant followed by surgery at four weeks or a course of two implants inserted four weeks apart followed by surgery within two to four weeks of the insertion of the second implant. A second implant may be required to allow flexible surgical timing.

Benign gynaecological disorders.

The recommended duration of therapy is six months. As safety data are not available for subsequent courses or courses longer than six months, retreatment cannot be recommended at this point in time. If longer duration of treatment is contemplated, an assessment of the risk of significant changes in bone mass should be made for each patient and the measurement of bone density considered (see Precautions). The risks and benefits of treatment with Zoladex should be considered for each patient and discussed between patient and prescriber.
In the treatment of uterine fibroids, Zoladex may be used for a period of 3 to 6 months. Because it is used as an adjunct to surgery, no data are available on the safety or efficacy of subsequent courses of treatment.

Assisted reproduction.

Once pituitary down regulation has been achieved with Zoladex (long protocol) controlled ovarian superstimulation and oocyte retrieval should be carried out. The protocol employed throughout should follow normal practice.

Elderly.

No dosage adjustment is necessary in the elderly.

Children.

Not indicated for use in children.

Renal impairment.

No dosage adjustment is necessary for patients with renal impairment.

Hepatic impairment.

No dosage adjustment is necessary for patients with hepatic impairment.

Overdosage

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.

Presentation

Implant for subcutaneous injection, 3.6 mg (sterile, biodegradable, cylindrical): 1's (prefilled, single dose syringe applicator (SafeSystem with protective needle sleeve) in a carton).

Storage

Store below 25°C.

Poison Schedule

S4.