Consumer medicine information

Zolacos CP

Goserelin; Bicalutamide

BRAND INFORMATION

Brand name

ZolaCos CP

Active ingredient

Goserelin; Bicalutamide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zolacos CP.

SUMMARY CMI

ZOLACOS® CP

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 ZOLACOS CP?

ZOLACOS CP contains the active ingredient goserelin and bicalutamide. ZOLACOS CP is used to treat advanced prostate cancer in men. It is not a cure for prostate cancer. Bicalutamide tablets can also be used to treat disease flare associated with previous goserelin therapy.

For more information, see Section 1. Why am I using ZOLACOS CP? in the full CMI.

2. What should I know before I use ZOLACOS CP?

Do not use if you have ever had an allergic reaction to ZOLACOS CP 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 ZOLACOS CP? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ZOLACOS CP 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 do I use ZOLACOS CP?

  • A ZOLADEX implant will be injected under the skin of your stomach every 28 days for the 3.6 mg strength, or once every 3 months for the 10.8 mg strength.
  • One 50 mg tablet of COSUDEX is then taken each day for one or three months, as considered appropriate by your doctor.

More instructions can be found in Section 4. How do I use ZOLACOS CP? in the full CMI.

5. What should I know while using ZOLACOS CP?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using ZOLACOS CP.
  • Keep all your appointments with your doctor so your progress can be checked.
Things you should not do
  • Do not give ZOLACOS CP to anyone else, even if they have the same condition as you.
  • Do not use ZOLACOS CP to treat any other complaints unless your doctor tells you to.
  • Do not stop taking ZOLACOS CP, or change the dosage, without checking with your doctor.
Driving or using machines
  • Be careful driving or operating machinery until you know how ZOLACOS CP affects you.
Looking after your medicine
  • Keep your tablets in the blister foil until it is time to take them.
  • Keep the implant in its foil packaging until it is time for administration by your doctor.
  • Keep the packaging in a cool dry place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while using ZOLACOS CP? 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 chest pain, yellowing of the skin or eyes and dark coloured urine, rash, hives or severe itching of the skin, swelling of the face, lips, tongue and or/throat which may cause difficulty in swallowing, swelling of other parts of the body including hands, feet or ankles, serious breathlessness, or sudden worsening of breathlessness, possibly with a cough or fever and shortness of breath, wheezing or trouble breathing.

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

ZOLACOS® CP

Active ingredients: bicalutamide and goserelin

Consumer Medicine Information (CMI)

This leaflet provides important information about using ZOLACOS CP. 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 ZOLACOS CP.

Where to find information in this leaflet:

1. Why am I using ZOLACOS CP?
2. What should I know before I use ZOLACOS CP?
3. What if I am taking other medicines?
4. How do I use ZOLACOS CP?
5. What should I know while using ZOLACOS CP?
6. Are there any side effects?
7. Product details

1. Why am I using ZOLACOS CP?

ZOLACOS CP contains the active ingredient goserelin and bicalutamide. ZOLACOS CP is a combination pack consisting of an anti-androgen (COSUDEX) medicine and a Luteinising Hormone Releasing Hormone (LHRH) agonist (ZOLADEX). Androgens such as testosterone are natural male sex hormones. In some types of prostate cancer, androgens may help the cancer cells to grow. LHRH agonists reduce the level of testosterone in men. ZOLACOS CP interferes with some of the actions of these hormones.

ZOLACOS CP is used to treat advanced prostate cancer in men. It is not a cure for prostate cancer. Bicalutamide tablets can also be used to treat disease flare associated with previous goserelin therapy.

ZOLACOS CP should only be taken by men.

2. What should I know before I use ZOLACOS CP?

Warnings

Do not use ZOLACOS CP if:

  • you are a woman or a child.
  • you are allergic to bicalutamide, goserelin or any of the ingredients listed at the end of this leaflet.
  • you are allergic to other anti-androgen medicines or other LHRH agonists.
  • Always check the ingredients to make sure you can use this medicine.
  • you are taking cisapride or the antihistamines, terfenadine and astemizole.

Symptoms of an allergic reaction may include:

  • skin rash
  • hay fever
  • difficulty breathing
  • feeling faint

Check with your doctor if 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 ZOLACOS CP.
  • have liver problems. It may not be safe for you to use ZOLACOS CP if you have problems with your liver.
  • 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

ZOLACOS CP may cause a period of low fertility or infertility whilst you are taking it and for a period afterwards. NOTE however that you may not be infertile. As ZOLACOS CP may affect your sperm, effective contraception must be used by you and/or your partner while you are taking ZOLACOS CP and for at least 130 days after you have stopped taking ZOLACOS CP.

It is also unlikely that you can father a child while using ZOLACOS CP, but you must use your normal contraceptive method to make sure.

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.

Some medicines may interfere with ZOLACOS CP and affect how it works.

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

  • cisapride (see Warnings)
  • the antihistamines terfenadine and astemizole (see Warnings)
  • medicines used to prevent blood clots, especially warfarin as ZOLACOS CP may reduce their effectiveness which may lead to bleeding and you therefore may need monitoring
  • midazolam
  • ciclosporin
  • medicines used to treat high cholesterol
  • calcium channel blockers
  • carbamazepine
  • quinidine
  • antiviral medicines for HIV infection

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

4. How do I use ZOLACOS CP?

How much to take

  • A ZOLADEX implant will be injected under the skin of your stomach every 28 days for the 3.6 mg, or once every 3 months for the 10.8 mg strength.
  • One 50 mg tablet of COSUDEX is then taken each day for one or three months, as considered appropriate by your doctor.
  • Swallow your tablet whole with a full glass of water.

When to take ZOLACOS CP

  • The implant will be administered once a month or once every three months by your doctor.
  • Take the tablets at about the same time each day.
  • It does not matter if you take the tablets before, with or after food.

How long to take ZOLACOS CP

  • Your doctor will tell you how long you will need to be given ZOLACOS CP.

If you forget to use ZOLACOS CP

COSUDEX should be used regularly at the same time each day. If you miss taking a tablet, take it as soon as you remember, as long as it is 12 hours before the next dose is due.

If it is less than 12 hours to the next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you use too much ZOLACOS CP

If you think that you have used too much ZOLACOS CP, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using ZOLACOS CP?

Things you should do

  • Be sure to keep all your appointments with your doctor so your progress can be checked. This is to ensure that your hormone levels will not rise and your illness will not get worse.
  • If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking ZOLACOS CP.
  • If you go into hospital, please let the medical staff know you are taking ZOLACOS CP.

Remind any doctor, dentist or pharmacist you visit that you are using ZOLACOS CP.

Things you should not do

  • Do not give ZOLACOS CP to anyone else, even if they have the same condition as you.
  • Do not use ZOLACOS CP to treat any other complaints unless your doctor tells you to.
  • Do not stop taking ZOLACOS CP, or change the dosage, without checking with your doctor.
  • Do not use ZOLACOS CP 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 ZOLACOS CP affects you.

Some patients may feel dizzy or weak.

Looking after your medicine

  • Keep your tablets in the blister foil until it is time to take them. If you take the tablets out of the blister foil, they will not keep well.
  • Keep the implant in its foil packaging until it is time for administration by your doctor.
  • Keep the packaging 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.

You may experience the following side effects:

Very common (may affect more than 1 in 10 people)What to do
  • hot flushes or sweating
  • breast tenderness or changes in breast size
  • stomach pain or indigestion
  • nausea or vomiting
  • diarrhoea or constipation
  • unusual tiredness or weakness
  • dizziness or light-headedness
  • changes in blood pressure
  • headache
  • chills
  • tingling in fingers or toes
  • decrease in your sexual drive
  • inability to get or maintain an erection
  • your testicles getting smaller
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
  • itching or dry skin, rashes
  • increased hairiness or hair loss
  • flatulence (wind)
  • dry mouth
  • loss of appetite or weight changes
  • depression
  • difficulty sleeping
  • pelvic pain
  • 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.

Serious side effects

Serious side effectsWhat to do
  • chest pain
  • yellowing of the skin or eyes and dark coloured urine
  • rash, hives or severe itching of the skin
  • swelling of the face, lips, tongue and/or throat, which may cause difficulty in swallowing
  • swelling of other parts of the body including hands, feet or ankles
  • serious breathlessness, or sudden worsening of breathlessness, possibly with a cough or fever
  • shortness of breath, wheezing or trouble breathing
  • dizziness when exercising and looking pale (anaemia)
  • frequent urination
  • excessive thirst with weight loss, and passing large amounts of urine

Tell your doctor immediately if any of these things happen while you are using ZOLACOS CP:

  • have trouble passing urine
  • feel weak in the arms or legs
  • feel numb in the arms or legs
  • have pain in the kidneys
  • have pain in the bones or backbone

These may mean that the cancer is growing.

If you have a tumour in your pituitary gland, ZOLACOS CP 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.

ZOLACOS CP lowers the amount of sex hormones in your body so your sex drive will probably be reduced.

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 ZOLACOS CP contains

Active ingredient
(main ingredient)		bicalutamide and goserelin (as the acetate)
Other ingredients
(inactive ingredients)		COSUDEX contains:
  • lactose monohydrate
  • sodium starch glycolate
  • povidone
  • magnesium stearate (E572)
  • hypromellose
  • macrogol 300
  • titanium dioxide (E171)
ZOLADEX contains:
  • polyglactin
Potential allergenslactose

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

What ZOLACOS CP looks like

ZOLACOS CP contains a syringe with a small pellet containing goserelin and 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.

The tablets are packaged in a blister strip and are white, round film-coated tablets. One side of the tablet is marked CDX 50 and the other side has an arrow shape.

The tablets are packed in blister foils of 28 tablets.

ZOLACOS CP is available in three different combinations:

  • 1 x Zoladex 3.6 mg implant syringe + 28 (1 month) tablets Cosudex 50 mg (Aust R 125685).
  • 1 x Zoladex 10.8 mg implant syringe + 28 (1 month) tablets Cosudex 50 mg (Aust R 125687).
  • 1 x Zoladex 10.8 mg implant syringe + 84 (3 month) tablets Cosudex 50 mg (Aust R 125687).

Who distributes ZOLACOS CP

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

This leaflet was prepared in July 2024.

ZolaCos, Cosudex, Zoladex and Zoladex SafeSystem are registered trademarks of the AstraZeneca group of companies.

© AstraZeneca 2024

[VV-RIM-06620900 v1]

Published by MIMS September 2024

BRAND INFORMATION

Brand name

ZolaCos CP

Active ingredient

Goserelin; Bicalutamide

Schedule

S4

 

1 Name of Medicine

Bicalutamide and goserelin acetate.

2 Qualitative and Quantitative Composition

Zolacos is a combination pack containing Cosudex and Zoladex.
Each Cosudex (bicalutamide) tablet contains 50 mg bicalutamide. Each Zoladex implant contains goserelin 3.6 mg or 10.8 mg (as goserelin acetate).

Excipients with known effect.

Each Cosudex tablet contains lactose monohydrate.
For the full list of excipients for Cosudex and Zolacos, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Cosudex are white, round, biconvex film-coated tablets, impressed with CDX50 on one side and an arrow shaped logo on the other side.
Zoladex is a sterile white to cream coloured cylindrical implant.

4 Clinical Particulars

4.1 Therapeutic Indications

For the treatment of advanced prostate cancer.
Bicalutamide is also indicated for the prevention of disease flare associated with initial goserelin treatment.

4.2 Dose and Method of Administration

Adult males including the elderly.

Bicalutamide.

One tablet (50 mg) once a day.
Treatment with Cosudex 50 mg should be started at the same time as treatment with a gonadotrophin releasing hormone agonist (GnRH agonist).

Goserelin.

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).
One 3.6 mg implant of goserelin every 28 days or one 10.8 mg implant of goserelin every 3 months, injected subcutaneously into the anterior abdominal wall.
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 goserelin, see instructions on the administration card.
Do not omit or delay injections as serum testosterone levels may rise.

Elderly.

No dosage adjustment is necessary in the elderly.

Use in patients with renal impairment.

No dosage adjustment is necessary for patients with renal impairment.

Use in patients with hepatic impairment.

No dosage adjustment is necessary for patients with mild hepatic impairment. Increased accumulation of bicalutamide may occur in patients with moderate to severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use). In such cases, a lower or less frequent dose may be considered.

4.3 Contraindications

Bicalutamide.

Bicalutamide is contraindicated in females and children.
Known hypersensitivity to bicalutamide or any other constituents of the formulation.
Co-administration of terfenadine, astemizole or cisapride with bicalutamide is contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Goserelin.

Goserelin is contraindicated in patients with known hypersensitivity to GnRH or GnRH agonist analogues or any of the components of Zoladex.

4.4 Special Warnings and Precautions for Use

Bicalutamide.

Hyperglycaemia.

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 Cosudex in combination with a GnRH agonist and manage with current practice for the treatment of hyperglycaemia or diabetes.

Potentiation of coumarin anticoagulant effects.

Potentiation of coumarin anticoagulant effects have been reported in patients receiving concomitant Cosudex therapy, which may result in increased Prothrombin Time (PT) and International Normalised Ratio (INR). Some cases have been associated with risk of bleeding. Close monitoring of PT/INR is advised and anticoagulant dose adjustment should be considered (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in patients with metastatic prostate cancer.

In patients with metastatic prostate cancer, treatment with bicalutamide monotherapy has been associated with reduced survival compared to castration. Bicalutamide should therefore not be used without concomitant GnRH agonist therapy in these patients.

Use in hepatic impairment.

Bicalutamide is extensively metabolised in the liver. Data suggests that its elimination may be slower in subjects with severe hepatic impairment and this could lead to increased accumulation of bicalutamide. Therefore, bicalutamide should be used with caution in patients with moderate to severe hepatic impairment.
Periodic liver function testing should be considered due to the possibility of hepatic changes. The majority of these changes occur within the first 6 months of bicalutamide therapy.
Rare cases of death or hospitalisation due to severe liver injury have been observed with bicalutamide (see Section 4.8 Adverse Effects (Undesirable Effects)). Bicalutamide therapy should be discontinued if at any time a patient develops jaundice or if serum ALT rises above two times the upper limit of normal.

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.

Goserelin.

Injection site injury.

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.

Patients with low BMI and/or receiving full anticoagulation medications.

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).

Effects on bone.

Goserelin may cause a temporary increase in bone pain in patients with advanced cancer and bone metastases which may last for up to two weeks.
Goserelin causes loss of bone mineral density.

Ureteric obstruction or spinal cord compression.

Goserelin may also increase the risk of developing ureteric obstruction or spinal cord compression in patients with metastatic cancer during the initial month of therapy. The use of goserelin in patients at risk should be considered carefully and patients monitored closely during the first month of therapy.
The above events may be related to the transient increase in serum testosterone concentration with goserelin. The use of antiandrogen therapy at the start of goserelin therapy has been reported to prevent the possible sequelae of the initial rise in serum testosterone.

Injection omission or delay.

Serum testosterone concentrations in males may rise if an implant is omitted or delayed.

Hyperglycaemia.

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.

QT/QTc interval prolongation.

See Bicalutamide above.

Use in the elderly.

No dosage adjustment is necessary in the elderly.

Paediatric use.

Cosudex is contraindicated in children.
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

Bicalutamide.

Bicalutamide is extensively metabolised (via oxidation and glucuronidation) in the liver. Bicalutamide has shown no evidence of causing enzyme induction in humans during dosing at 50 mg daily in man. In vitro studies have shown that (R)-bicalutamide is an inhibitor of CYP3A4, with lesser inhibitory effects on CYP2C9, 2C19 and 2D6 activity.
The clinically or potentially significant drug interactions between bicalutamide and the following agents/ drug classes, which are theoretical or have been observed, are described below. The drug-drug interactions described include both interactions mediated through effects on P450 metabolism and interactions mediated through other mechanisms.
Effects of bicalutamide on other medicines.

GnRH agonists.

Although there is no evidence of any pharmacodynamic or pharmacokinetic interactions between bicalutamide and GnRH agonists at steady state, bicalutamide may prevent the harmful clinical consequences of flare associated with the start of GnRH agonist therapy.

Cytochrome P450.

Bicalutamide is an inhibitor of CYP3A4 and has been shown to increase plasma levels of midazolam by up to 80%. Therefore, concomitant use of terfenadine, astemizole and cisapride is contraindicated. Caution should be exercised with other drugs metabolised by CYP3A4, such as cyclosporin, calcium channel blockers, HIV antivirals, HMG-CoA reductase inhibitors, carbamazepine, quinidine etc.
Demonstrated interactions.

Warfarin.

In vitro studies have shown that bicalutamide can displace the coumarin anticoagulant, warfarin, from its protein binding sites. There have been reports of increased effect of warfarin and other coumarin anticoagulants when co-administered with Cosudex. It is therefore recommended that if bicalutamide is administered in patients who are already receiving coumarin anticoagulants, PT/INR should be closely monitored and adjustments of anticoagulant dose considered (see Section 4.4 Special Warnings and Precautions for Use).
Theoretical interactions. Caution should be exercised when prescribing bicalutamide with other drugs which may inhibit drug oxidation, e.g. cimetidine and ketoconazole. In theory, this could result in increased plasma concentrations of bicalutamide and an increase in adverse reactions.

Goserelin.

No data available.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Bicalutamide.

Administration of bicalutamide may lead to inhibition of spermatogenesis. The long-term effects of bicalutamide on male fertility have not been studied. Atrophy of seminiferous tubules of the testes, atrophy of the epididymis, and atrophy of the male reproductive glands are predicted class effects of antiandrogens and have been observed in rats at exposures less than the therapeutic concentrations at the recommended clinical dose of 50 or 150 mg. Reversal of seminiferous tubule and seminal vesicle atrophy occurred in most animals by 4 months after the completion of dosing in a 6-month rat study. In this study, prostate atrophy was not fully reversible by 4 months after the completion of dosing. No recovery of seminiferous tubule atrophy was observed at 24 weeks after the completion of dosing in a 12-month rat study. Following 12 months of repeated dosing in dogs, the incidence of testicular atrophy was the same in dosed and control dogs after a 6 month recovery period. In male rats dosed at 250 mg/kg/day (less than human therapeutic concentrations after the recommended clinical dose of 50 mg or 150 mg), the precoital interval and time to successful mating were increased in the first pairing but no effects on fertility following successful mating were seen. These effects were reversed by 7 weeks after the end of an 11 week period of dosing. A period of subfertility or infertility should be assumed in man.
Antiandrogen therapy may cause morphological changes in spermatozoa. Although the effect of bicalutamide on sperm morphology has not been evaluated and no such changes have been reported for patients who received Cosudex, patients and/or their partners should follow adequate contraception during Cosudex therapy and for 130 days after Cosudex therapy.

Goserelin.

The expected pharmacology of goserelin 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)
ZolaCos CP 3.6/50 and 10.8/50 are not indicated in females.
(

Note.

Bicalutamide is contraindicated in females. See Section 4.3 Contraindications).
 ZolaCos CP 3.6/50 and 10.8/50 are not indicated in females.
(

Note.

Bicalutamide is contraindicated in females. See Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

During treatment with Cosudex, somnolence has been reported. Those patients who experience this symptom should observe caution when driving or using machines.
There is no evidence that goserelin results in impairment of ability to drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

In general, combination treatment has been well tolerated with few withdrawals due to adverse events.

Clinical trial data - combination therapy (with medical castration) in advanced prostate cancer.

The following adverse experiences were reported in clinical trials (as possible adverse drug reactions in the opinion of investigating clinicians, with a frequency of ≥ 1%) during treatment with Cosudex 50 mg plus a luteinising hormone releasing hormone agonist (LHRH agonist). No causal relationship of these experiences to drug treatment has been made and some of the experiences reported are those that commonly occur in elderly patients. See Table 1.

Increased PT/INR.

Accounts of coumarin anticoagulants interacting with Cosudex have been reported in post marketing surveillance (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.4 Special Warnings and Precautions for Use).

Goserelin.

The following frequency categories for adverse drug reactions (ADRs) were calculated based on reports from Zoladex clinical trials and post-marketing sources. See Table 2.

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

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

Bicalutamide.

There is no human experience of overdosage. There is no specific antidote; treatment should be symptomatic. Dialysis may not be helpful, since bicalutamide is highly protein bound and is not recovered unchanged in the urine. General supportive care, including frequent monitoring of vital signs, is indicated.

Goserelin.

There is limited experience of overdosage in humans. In cases where goserelin 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 goserelin. If overdosage occurs, this should be managed symptomatically.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Bicalutamide.

Bicalutamide is a non-steroidal anti-androgen, devoid of other endocrine activity. It binds to androgen receptors without activating gene expression, and thus inhibits the androgen stimulus. This inhibition impairs the growth and encourages apoptosis in androgen-dependent tumour cells and regression of prostatic tumours. In a subset of patients who experience disease progression while receiving bicalutamide, discontinuation of the drug may result in an 'anti-androgen withdrawal syndrome', which manifests as a fall in prostate specific antigen (PSA) level. It is unknown whether this phenomenon translates to a prolongation of tumour response or survival.
Bicalutamide is a racemate with its anti-androgenic activity being almost exclusively in the (R)-enantiomer.

Goserelin.

Goserelin acetate is a synthetic analogue of GnRH. When administered to males, it initially stimulates secretion of luteinising hormone (LH) and follicle stimulating hormone (FSH) from the pituitary gland with subsequent increase in serum testosterone concentration. Chronic administration leads to sustained suppression of pituitary gonadotrophins and consequent reduction in serum testosterone concentration to the level normally seen in surgically castrated men within three weeks. This suppression is maintained as long as therapy is continued and can lead to accessory sex organ regression.

Clinical trials.

Combination therapy (with medical castration) in advanced prostate cancer.

In a large multicentre, controlled clinical trial, 813 patients with previously untreated advanced prostate cancer were randomised to receive bicalutamide 50 mg once daily (404 patients) or flutamide 250 mg (409 patients) three times a day, each in combination with a GnRH agonist (either goserelin acetate implant or leuprorelin acetate depot). At the time of analysis, the median time of follow-up was 49 weeks. Bicalutamide/GnRH agonist therapy was associated with a statistically significant (p = 0.005) improvement in time to treatment failure.
Subjective responses (including scores for pain, analgesic use and Eastern Oncology Cooperative Group (ECOG) performance status) assessed in patients with symptoms at entry were seen in 95 (52%) patients treated with bicalutamide and in 88 (54%) patients treated with flutamide, each in combination therapy with GnRH agonists. This small difference was not statistically significant between bicalutamide combination therapy and flutamide combination therapy. In an analysis conducted after a median follow-up of 160 weeks was reached, 213 (52.7%) patients treated with bicalutamide-GnRH agonist therapy and 235 (57.5%) patients treated with flutamide-GnRH agonist therapy had died. There was no significant difference in survival between treatment groups. The hazard ratio for time to death (survival) was 0.87 (95% CI 0.72 to 1.05).

Meta-analysis.

There is considerable debate regarding the relative merits of combination versus monotherapy in advanced prostate cancer, summarised by Dalesio et al 19951 in their meta-analysis of trials of maximal androgen blockade (MAB). This analysis showed no statistically significant reduction in the annual odds of death in favour of MAB. The meta-analysis included the effect of MAB only on mortality, and did not measure other end-points such as time to disease progression.
1Prostate Cancer Trialists' Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Lancet 1995; 346: 265-269.

5.2 Pharmacokinetic Properties

Bicalutamide.

Absorption.

Bicalutamide is well absorbed following oral administration. There is no evidence of any clinically relevant effect of food on bioavailability.

Distribution.

Bicalutamide is highly protein bound (racemate 96%, (R)-enantiomer 99.6%).
Steady-state plasma concentrations of the (R)-enantiomer of approximately 9 microgram per mL are observed during daily administration of bicalutamide (50 mg). At steady state the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers.

Metabolism.

Bicalutamide undergoes stereospecific metabolism. Bicalutamide is extensively metabolised (via oxidation and glucuronidation).

Excretion.

Metabolites are eliminated via the kidneys and bile in approximately equal proportions.
The (S)-enantiomer is rapidly cleared relative to the (R)-enantiomer, the latter having a plasma elimination half-life of about 1 week. On daily administration of bicalutamide, the (R)-enantiomer accumulates about 10-fold in plasma as a consequence of its long half-life.

Special populations.

The pharmacokinetics of the (R)-enantiomer are unaffected by age, renal impairment or mild to moderate hepatic impairment. There is evidence that for subjects with severe hepatic impairment, the (R)-enantiomer is more slowly eliminated from plasma.

Goserelin.

Zoladex implants release goserelin acetate continuously. After administration of the 3.6 mg implant, the peak serum concentration is not reached until about 2 weeks later whereas after the 10.8 mg implant, the peak serum concentration occurs within 24 hours. There is considerable variability in serum goserelin concentration, the peak concentration varying up to 5-fold after the 3.6 mg and 10-fold after the 10.8 mg implant.
Although bioavailability from the implants is variable, drug is released at effective concentrations to sustain suppression of serum testosterone concentration for at least 28 days with goserelin 3.6 mg and 3 months with goserelin 10.8 mg. Goserelin is poorly protein bound (20-28%).
Serum goserelin concentration becomes low by day 28 in the case of the 3.6 mg implant and 3 months in the case of the 10.8 mg implant. Delaying or omitting scheduled doses should be avoided since it may lead to increased serum testosterone levels and loss of efficacy.
There is no evidence of significant drug accumulation when Zoladex 3.6 mg is administered at 4 weeks intervals and Zoladex 10.8 mg at 3 month intervals.
Goserelin is cleared mainly by metabolism. The serum elimination half-life is approximately 4 hours. Dosage adjustment is not required in renal or hepatic impairment.

5.3 Preclinical Safety Data

Bicalutamide.

Genotoxicity.

Bicalutamide was inactive in in vitro tests for gene mutation and in in vitro and in vivo tests for clastogenicity.

Carcinogenicity.

Two year oral carcinogenicity studies were conducted in male and female rats and mice at doses of 5, 15 or 75 mg/kg/day of bicalutamide. A variety of tumour target organ effects were identified and were attributed to the antiandrogenicity of bicalutamide, namely, testicular benign interstitial (Leydig) cell tumours in male rats at all dose levels and uterine adenocarcinoma in female rats at 75 mg/kg/day (at these dose levels plasma (R)-bicalutamide concentrations were less than human therapeutic concentrations after the maximum recommended clinical dose of 150 mg). There is no evidence of Leydig cell hyperplasia in patients; uterine tumours are not relevant to the indicated patient population.
A small increase in the incidence of hepatocellular carcinoma in male mice given 75 mg/kg/day of bicalutamide (approximately 2 times human therapeutic concentrations after the maximum recommended clinical dose of 150 mg) and an increased incidence of benign thyroid follicular cell adenomas in rats given 5 mg/kg/day (less than the human therapeutic concentrations after the maximum recommended clinical dose of 150 mg) and above were recorded. These neoplastic changes were progressions of non-neoplastic changes related to hepatic enzyme induction observed in animal toxicity studies. Enzyme induction has not been observed following bicalutamide administration in man.

Goserelin.

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 2,400 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 2,400 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

Each Cosudex tablet contains the following excipients: lactose monohydrate, sodium starch glycollate, povidone, magnesium stearate, hypromellose, macrogol 300 and titanium dioxide.
Each Zoladex 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

ZolaCos CP is available in three different packs:
1x Zoladex 3.6 mg implant syringe + 28 (1 month) tablets Cosudex 50 mg.
1x Zoladex 10.8 mg implant syringe + 28 (1 month) tablets Cosudex 50 mg.
1x Zoladex 10.8 mg implant syringe + 84 (3 month) tablets Cosudex 50 mg (3 x 28 tablet packs).
Cosudex 50 mg tablets are packed in PVC/aluminium blisters in packs of 28 tablets.
Zoladex SafeSystem implant is supplied in a pre-filled syringe applicator for subcutaneous injection with a styrene-butadiene plastic copolymer implant chamber in packs of 1 implant.

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

Bicalutamide is a fine white to off-white powder. At 37°C it is practically insoluble in water (4.6 mg/litre), acid (4.6 mg/litre at pH 1) and alkali (3.7 mg/litre at pH 8). In organic solvents it is slightly soluble in ethanol, sparingly soluble in methanol and freely soluble in acetone and tetrahydrofuran.

Chemical structure.

Bicalutamide.


(RS)-4'-cyano-α', α', α',-trifluoro-3- (4-fluorophenylsulphonyl)- 2-hydroxy-2- methylpropiono- m-toluidide.
Molecular formula: C18H14F4N2O4S.
Molecular weight: 430.38.

Goserelin (as acetate).


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

CAS number.

Bicalutamide.

90357-06-5.

Goserelin.

65807-02-5 (goserelin base).

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

Summary Table of Changes