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.

SUMMARY CMI

ZOLADEX® 3.6 mg Implant SafeSystem™

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using ZOLADEX 3.6 mg?

ZOLADEX 3.6 mg contains the active ingredient goserelin acetate. ZOLADEX 3.6 mg is used to lower the amount of sex hormones in the body. ZOLADEX 3.6 mg is used to treat breast cancer in some women before menopause, to treat endometriosis and fibroids of the uterus, to thin the lining of the womb before surgery, in combination with other drugs as part of a treatment for infertility and to treat prostate cancer in some men.

For more information, see Section 1. Why am I using ZOLADEX 3.6 mg? in the full CMI.

2. What should I know before I use ZOLADEX 3.6 mg?

Do not use if you have ever had an allergic reaction to goserelin acetate or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use ZOLADEX 3.6 mg? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ZOLADEX 3.6 mg and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How is ZOLADEX 3.6 mg given?

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

More instructions can be found in Section 4. How is ZOLADEX 3.6 mg given? in the full CMI.

5. What should I know while using ZOLADEX 3.6 mg?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using ZOLADEX 3.6 mg.
  • Make sure to keep your appointment for being given ZOLADEX 3.6 mg every four weeks.
  • Use barrier contraceptive methods (condom or diaphragm) while having ZOLADEX 3.6 mg treatment unless it is being used for infertility.
Things you should not do
  • Do not stop being given ZOLADEX 3.6 mg unless you have discussed it with your doctor first.
  • Do not take oral contraceptives while being treated with ZOLADEX 3.6 mg.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how ZOLADEX 3.6 mg affects you.
Looking after your medicine
  • Keep your ZOLADEX 3.6 mg in the package until you take it to the doctor or nurse to give it to you.
  • Keep in a cool, dry place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while using ZOLADEX 3.6 mg? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. Sometimes they are serious, most of the time they are not. Tell your doctor immediately if you have a tumour in your pituitary gland which causes severe headaches, sickness, loss of eyesight and unconsciousness. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

ZOLADEX® 3.6 mg Implant SafeSystem™

Active ingredient: goserelin acetate

Consumer Medicine Information (CMI)

This leaflet provides important information about using ZOLADEX 3.6 mg. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ZOLADEX 3.6 mg.

Where to find information in this leaflet:

1. Why am I using ZOLADEX 3.6 mg?
2. What should I know before I use ZOLADEX 3.6 mg?
3. What if I am taking other medicines?
4. How is ZOLADEX 3.6 mg given?
5. What should I know while using ZOLADEX 3.6 mg?
6. Are there any side effects?
7. Product details

1. Why am I using ZOLADEX 3.6 mg?

ZOLADEX 3.6 mg contains the active ingredient goserelin acetate. ZOLADEX 3.6 mg is a member of the anti-hormonal group of medicines. This means that it affects the levels of various hormones (natural chemicals produced by the body).

ZOLADEX 3.6 mg is used to lower 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.

2. What should I know before I use ZOLADEX 3.6 mg?

Warnings

Do not use ZOLADEX 3.6 mg if:

  • you are allergic to goserelin acetate, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
    Symptoms of an allergic reaction may include:
    - rash
    - hay fever
    - difficulty breathing
    - feeling faint

Check with your doctor if you:

  • have any other medical conditions (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.
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

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.

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.

Children

Do not give ZOLADEX 3.6 mg to children.

There is no information on its use in children.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ZOLADEX 3.6 mg.

4. How is ZOLADEX 3.6 mg given?

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 ZOLADEX 3.6 mg

  • 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 ZOLADEX 3.6 mg

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

If you use too much ZOLADEX 3.6 mg

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.

5. What should I know while using ZOLADEX 3.6 mg?

Things you should 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.

Remind any doctor, dentist or pharmacist you visit that you are using ZOLADEX 3.6 mg.

Things you should not do

  • 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.
  • Do not take oral contraceptives while being treated with ZOLADEX 3.6 mg.
    They interfere with the way it works.
  • Do not use if the packaging is torn or shows signs of tampering.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ZOLADEX 3.6 mg affects you.

Looking after your medicine

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.

Keep in a cool, dry place where the temperature stays below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Serious side effects

Serious side effectsWhat to do
  • 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.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

You may experience the following side effects:

Very common (may affect more than 1 in 10 people)What to do
  • changes in blood pressure
  • hot flushes, sweating or feeling faint
  • chills
  • tingling in fingers or toes
  • swelling, soreness or itchiness of the breasts
  • your testicles getting smaller
  • vaginal dryness
  • mood changes
  • headache
Speak to your doctor if you have any of these very common side effects and they worry you.
Common (may affect up to 1 in 10 people)What to do
  • skin rashes
  • painful joints
  • trouble passing urine or experience lower back pain
Speak to your doctor if you have any of these common side effects and they worry you.

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

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.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What ZOLADEX 3.6 mg contains

Active ingredient
(main ingredient)		goserelin (as the acetate)
Other ingredients
(inactive ingredients)		polyglactin

Do not take this medicine if you are allergic to any of these ingredients.

What ZOLADEX 3.6 mg looks like

ZOLADEX 3.6 mg (Aust R 24368) 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" halfway up the syringe and is white or cream coloured.

Who distributes ZOLADEX 3.6 mg

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
MACQUARIE PARK NSW 2113
Telephone: 1800 805 342

This leaflet was prepared in May 2024.

Zoladex, Zoladex SafeSystem and SafeSystem are trade marks of the AstraZeneca group of companies.

© AstraZeneca 2024

[VV-RIM-06055532 v1]

Published by MIMS July 2024

BRAND INFORMATION

Brand name

Zoladex 3.6 mg Implant

Active ingredient

Goserelin

Schedule

S4

 

1 Name of Medicine

Goserelin acetate.

2 Qualitative and Quantitative Composition

Each Zoladex SafeSystem implant contains goserelin 3.6 mg (as goserelin acetate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

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 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.

4 Clinical Particulars

4.1 Therapeutic 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 pre- 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.

4.2 Dose and Method of Administration

Caution should be taken while inserting Zoladex into the 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 BMI and/or who are receiving full anticoagulation medication (see Section 4.4 Special Warnings and Precautions for Use).
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 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.
The implant is released continuously over at least 28 days when injected subcutaneously.

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 Section 5.1 Pharmacodynamic Properties, Clinical trials, Prostate cancer - 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 Section 4.4 Special Warnings and Precautions for Use). 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.

Special patient populations.

Renal impairment.

No dosage adjustment is necessary for patients with renal impairment.

Hepatic impairment.

No dosage adjustment is necessary for patients with hepatic impairment.

Use in the elderly.

No dosage adjustment is necessary in the elderly.

Paediatric use.

Not indicated for use in children.

4.3 Contraindications

Zoladex is contraindicated in patients with known hypersensitivity to luteinising hormone releasing hormone (LHRH), LHRH agonist analogues or any of the components of Zoladex.
Pregnancy and lactation (see Section 4.6 Fertility, Pregnancy and Lactation).

4.4 Special Warnings and Precautions for Use

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 Section 4.2 Dose and Method of 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 gonadotrophin releasing hormone (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 pre-thinning 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 (HRT; 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 bone mineral density (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.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

Zoladex is not indicated for use in children as safety and efficacy have not been established in this group of patients.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No data available.

4.6 Fertility, Pregnancy and Lactation

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).
(Category D)
(See Section 4.3 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. Non-hormonal 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.
 (See Section 4.3 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.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

The following frequency categories for adverse drug reactions (ADRs) were calculated based on reports from Zoladex clinical trials and postmarketing sources. See Table 1.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

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.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Goserelin acetate is a GnRH agonist (also known as LHRH agonist).
Goserelin acetate is a potent synthetic decapeptide analogue of 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.

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 2 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 3 and 4). Neoadjuvant Zoladex therapy for two months prior and during radiotherapy significantly improved disease free survival but not overall survival compared to radiotherapy alone (Table 5). 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 6) and radiotherapy alone (Table 7). There was no significant difference in disease free survival between 3 months and 6 months neoadjuvant plus adjuvant Zoladex (Table 7).
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 pre-/perimenopausal women in early breast cancer (see Table 8). 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 9).
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 10.
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 physiologic 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.

5.2 Pharmacokinetic Properties

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. Goserelin 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 non-renal, 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 inter-individual 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.

5.3 Preclinical Safety Data

Genotoxicity.

Mutagenicity tests for gene mutations and chromosomal damage have provided no evidence for mutagenic effects.

Carcinogenicity.

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Zoladex 3.6 mg SafeSystem implant contains the excipient polyglactin.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Zoladex 3.6 mg SafeSystem implant is supplied as a sterile, biodegradable cylindrical implant containing the equivalent of 3.6 mg of goserelin base together with the inactive ingredient polyglactin and is presented as 1x (one) pre-filled syringe applicator for subcutaneous injection per carton.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


Molecular formula: C59H84N18O14 (base).
Molecular weight: 1269 (base).

CAS number.

65807-02-5 (goserelin base).

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

Summary Table of Changes