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.

What is in this leaflet

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

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

All medicines have risks and benefits. Your doctor will have weighed the risks of you taking ZOLACOS CP against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine. You may need to read it again.

What ZOLACOS CP is for

ZOLACOS CP combination therapy is the brand name for packs containing ZOLADEX (goserelin) 3.6mg or 10.8mg subcutaneous implant plus COSUDEX (bicalutamide) 50mg tablets.

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 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 should only be taken by men.

Follow all directions given to you by your doctor. They may differ from the information in this leaflet.

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

ZOLACOS CP is not addictive.

Before you use ZOLACOS CP

When you must not use it

Do not use ZOLACOS CP if you are a woman or a child.

Do not use ZOLACOS CP if you are allergic to bicalutamide, goserelin or any of the other ingredients in ZOLACOS CP.

Do not use ZOLACOS CP if you are taking cisapride or the antihistamines, terfenadine and astemizole.

Do not use ZOLACOS CP after the use by (expiry) date printed on the pack. It may have no effect at all or an unexpected effect if you use it after the expiry date.

Do not use ZOLACOS CP if the packaging is torn or shows signs of tampering.

Do not use it to treat any other complaints unless your doctor tells you to.

Do not give this medicine to anyone else.

Before you start to use it

You must tell your doctor if:

  1. you have allergies to:
  • bicalutamide or goserelin, the active ingredients in ZOLACOS CP
  • any of the other ingredients of ZOLACOS CP listed at the end of this leaflet
  • other anti-androgen medicines
  • other LHRH agonistsany other medicines
  • any other substances, such as foods, preservatives or dyes.
    If you have an allergic reaction, you may get a skin rash, hay fever, or have difficulty breathing or feel faint.
  1. you have liver problems
    It may not be safe for you to use ZOLACOS CP if you have problems with your liver.
  2. 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.

Taking other medicines

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

  • cisapride (see When you must not use it)
  • the antihistamines terfenadine and astemizole (see When you must not use it)
  • 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 more monitoring
  • midazolam
  • cyclosporin
  • medicines used to treat high cholesterol
  • calcium channel blockers
  • carbamazepine
  • quinidine
  • antiviral medicines for HIV infection
  • medicines that you buy at the chemist, supermarket or health food shop

These medicines may affect the way ZOLACOS CP works or ZOLACOS CP may affect how these medicines work.

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

If you have not told your doctor about any of these things, tell them before you use any ZOLACOS CP.

Being given ZOLACOS CP

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

How much to take

A ZOLADEX implant will be injected under the skin of your stomach every 28 days for the 3.6mg strength, or once every 3 months for the 10.8mg strength.

One (x1) 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 it

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 it

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

If you forget to take it

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 do not take the dose you have missed.

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

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

Overdose

Immediately telephone your doctor or pharmacist or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too many tablets. Do this even if there are no signs of discomfort or poisoning.

While you are using it

Things you must 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.

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.

Tell any other doctors, dentists and pharmacists who are treating you that you are taking ZOLACOS CP.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking ZOLACOS CP.

ZOLACOS may affect your sperm (semen) while you are taking it and for some time after you stop taking it. As a precaution, you and/or your partner must use adequate contraception while you are taking ZOLACOS and for at least 130 days after you have stopped taking ZOLACOS.

If you go into hospital, please let the medical staff know you are taking ZOLACOS CP.

Things you must 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.

Things to be careful of

Be careful driving or operating machinery until you know how ZOLACOS CP affects you. Some patients may feel dizzy or weak.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ZOLACOS CP.

ZOLACOS CP helps people with advanced prostate cancer, but it may have unwanted side effects in some people.

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

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

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

  • hot flushes or sweating
  • breast tenderness or changes in breast size
  • itching or dry skin, rashes
  • increased hairiness or hair loss
  • stomach pain or indigestion
  • nausea or vomiting
  • diarrhoea or constipation
  • flatulence (wind)
  • dry mouth
  • loss of appetite or weight changes
  • depression
  • unusual tiredness or weakness
  • dizziness or light-headedness
  • changes in blood pressure
  • difficulty sleeping
  • headache
  • pelvic pain
  • painful joints
  • chills
  • tingling in fingers or toes
  • decrease in your sexual drive
  • inability to get or maintain an erection
  • trouble passing urine or experience lower back pain
  • your testicles getting smaller

ZOLACOS CP may also 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.

Tell your doctor immediately if you notice any of the following:

  • frequent urination
  • shortness of breath and dizziness when exercising and looking pale (anaemia)
  • excessive thirst with weight loss, and passing large amounts of urine

These side effects may be serious.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if any of the following happen.

  • 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.

These are all serious side effects. You may need urgent medical attention or hospitalisation.

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

Some people may get other effects while taking ZOLACOS CP.

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

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.

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.

After using ZOLACOS CP

Storage

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 it's 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.

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

Do not leave it on a window sill or in the car on hot days. Heat and dampness can destroy some medicines.

Keep your medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

Ask your pharmacist what to do with any tablets you have left over if your doctor tells you to stop taking them, or you find that the expiry date has passed. Your doctor will dispose of the syringe appropriately.

Product description

What ZOLACOS CP looks like

ZOLACOS CP is available in three different combinations:

1x Zoladex 3.6mg implant syringe + 28 (1 month) tablets Cosudex 50mg

1x Zoladex 10.8mg implant syringe + 28 (1 month) tablets Cosudex 50mg

1x Zoladex 10.8mg implant syringe + 84 (3 month) tablets Cosudex 50mg

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

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.

Ingredients

Each tablet contains 50 mg of bicalutamide as the active ingredient, plus

  • lactose monohydrate
  • sodium starch glycolate
  • povidone
  • magnesium stearate (E572)
  • hypromellose
  • macrogol 300
  • titanium dioxide (E171)

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

Each 10.8mg implant syringe contains the active ingredient goserelin 10.8mg (as the acetate) plus polyglactin.

ZOLACOS CP does not contain added sucrose, gluten, tartrazine or any other azo dyes.

Manufacturer

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

This leaflet was prepared on 18 May 2017.

Australian Registration Numbers

ZOLACOS CP 3.6/50
AUST R 125685

ZOLACOS CP 10.8/50
AUST R 125687

Doc ID-002699670 v6.0

Published by MIMS September 2017

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