Consumer medicine information

APO-Bicalutamide Tablets

Bicalutamide

BRAND INFORMATION

Brand name

APO-Bicalutamide

Active ingredient

Bicalutamide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Bicalutamide Tablets.

SUMMARY CMI

APO-BICALUTAMIDE

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 APO-BICALUTAMIDE?

APO-BICALUTAMIDE contains the active ingredient bicalutamide. Bicalutamide is used in combination with other medicines called LHRH agonists to treat advanced prostate cancer and to prevent a side effect of LHRH agonists.

For more information, see Section 1. Why am I using APO-BICALUTAMIDE? in the full CMI.

2. What should I know before I use APO-BICALUTAMIDE?

Do not use if you have ever had an allergic reaction to Bicalutamide 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 APO-BICALUTAMIDE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with APO-BICALUTAMIDE 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 take APO-BICALUTAMIDE?

  • The usual adult dose is one 50 mg tablet taken each day.
  • Swallow your APO-BICALUTAMIDE whole with a full glass of water.

More instructions can be found in Section 4. How do I take APO-BICALUTAMIDE? in the full CMI.

5. What should I know while using APO-BICALUTAMIDE?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using APO-BICALUTAMIDE.
  • Be sure to keep all your appointments with your doctor so your progress can be checked.
  • Use adequate contraception while you are taking APO-BICALUTAMIDE and for at least 130 days after you have stopped taking APO-BICALUTAMIDE.
Things you should not do
  • Do not give APO-BICALUTAMIDE to anyone else, even if they have the same condition as you.
  • Do not take APO-BICALUTAMIDE to treat any other complaints unless your doctor tells you to.
  • Do not stop taking APO-BICALUTAMIDE, or lower the dosage, without checking with your doctor
Driving or using machines
  • Be careful driving or operating machinery until you know how APO-BICALUTAMIDE affects you.
Looking after your medicine
  • Keep your APO-BICALUTAMIDE in the blister foil until it is time to take them.
  • Keep it in a cool, dry place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while using APO-BICALUTAMIDE? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, some can be minor and temporary. However, some side effects may be serious. 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, 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.

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

APO-BICALUTAMIDE

Active ingredient: bicalutamide

Consumer Medicine Information (CMI)

This leaflet provides important information about using APO-BICALUTAMIDE. 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 APO-BICALUTAMIDE.

Where to find information in this leaflet:

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

1. Why am I using APO-BICALUTAMIDE?

APO-BICALUTAMIDE contains the active ingredient bicalutamide. APO-BICALUTAMIDE is an anti-androgen medicine. Androgens such as testosterone are natural male sex hormones. In some types of prostate cancer, androgens may help the cancer cells grow.

APO-BICALUTAMIDE interferes with some of the actions of these hormones. APO-BICALUTAMIDE is used in combination with other medicines called LHRH agonists to treat advanced prostate cancer and to prevent a side effect of LHRH agonists.

APO-BICALUTAMIDE should only be taken by men.

2. What should I know before I use APO-BICALUTAMIDE?

Warnings

Do not use APO-BICALUTAMIDE if:

  • you are allergic to bicalutamide,
  • any of the ingredients listed at the end of this leaflet.
  • you are allergic to lactose

Some of the symptoms of an allergic reaction may include:

  • cough, shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting or hayfever-like symptoms
  • you are allergic to other anti-androgen medicines.

Do not take this medicine if you are taking cisapride, terfenadine or astemizole.

Do not take this medicine if you are female.

Women are not treated with this medicine, as it could cause major defects in unborn children if taken by pregnant women, or harm to infants if taken when breastfeeding

  • Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.
  • If it has expired or is damaged, return it to your pharmacist for disposal.

Check with your doctor if you:

  • have any other medical conditions
  • have liver problems
  • have diabetes
  • have heart conditions, including heart rhythm problems (arrhythmia)
  • take any medicines for any other condition
  • If you have allergies to medicines or substances such as foods, preservatives or dyes.

Tell your doctor if you are planning to start a family, as this medicine may affect your fertility.

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

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

Do not take APO-BICALUTAMIDE if you are a woman.

APO-BICALUTAMIDE 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 APO-BICALUTAMIDE may affect your sperm, effective contraception must be used by you and/or your partner while you are taking APO-BICALUTAMIDE and for at least 130 days after you have stopped taking APO-BICALUTAMIDE.

Children

  • Do not give APO-BICALUTAMIDE to children.
  • There is no experience of its use in children.

3. What if I am taking other medicines?

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

Some medicines may interfere with APO-BICALUTAMIDE and affect how it works. These include:

  • cisapride
  • terfenadine, astemizole
  • medicines used to prevent blood clots, especially warfarin
  • cimetidine, used for stomach problems
  • ketoconazole, used to treat fungal infections
  • midazolam or carbamazepine, used for treating seizures
  • cyclosporin, used after organ transplants
  • statins used to treat high cholesterol (e.g. simvastatin, atorvastatin, pravastatin, rosuvastatin, simvastatin)
  • calcium channel blockers used to treat high blood pressure (e.g. felodipine, nifedipine, amlodipine)
  • quinidine, used to treat certain heart problems
  • some medicines used to treat viral infections (e.g. ritonavir, saquinavir)
  • other medicines which interfere with the liver's CYP450 enzyme system

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with bicalutamide.

4. How do I take APO-BICALUTAMIDE?

How much to take

  • The usual adult dose is one 50 mg tablet taken each day. This dose may be reduced if you have severe liver problems
  • Swallow your APO-BICALUTAMIDE tablet whole with a full glass of water.
  • Follow the directions given to you by your doctor or pharmacist carefully, they may differ from the information contained in the leaflet.

How to take APO-BICALUTAMIDE

  • Take APO-BICALUTAMIDE at about the same time each day.
  • Taking it at the same time each day will have the best effect and will also help you remember when to take it. It does not matter if you take it with or without food.
  • APO-BICALUTAMIDE 50 mg should be started at the same time as the other medicines you have been given for the treatment of prostate cancer.

How long to take APO-BICALUTAMIDE

  • Continue taking APO-BICALUTAMIDE for as long as your doctor or pharmacist tells you.
  • Make sure you have enough to last over weekends and holidays.

If you forget to use APO-BICALUTAMIDE

APO-BICALUTAMIDE should be used regularly at the same time each day. If you miss your dose at the usual time, 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 for your 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.

This may increase the chance of unwanted side effects.

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

If you use too much APO-BICALUTAMIDE

If you think that you have used too much APO-BICALUTAMIDE, 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 APO-BICALUTAMIDE?

Things you should do

  • Keep all your doctor's appointments, as your doctor may do tests to make sure the medicine is working and to prevent side effects.
  • Tell any other doctors, dentists and pharmacists who are treating you that you are taking APO-BICALUTAMIDE.
  • If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking APO-BICALUTAMIDE.
  • You will need to take another prostate cancer medicine (an LHRH agonist) whilst you are taking bicalutamide. The two medicines need to work together to have an effect.
  • APO-BICALUTAMIDE 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 APO-BICALUTAMIDE and for at least 130 days after you have stopped taking APO-BICALUTAMIDE.

Remind any doctor, dentist or pharmacist you visit that you are using APO-BICALUTAMIDE.

Things you should not do

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

Some patients may feel sleepy, dizzy or weak when taking this medicine.

Looking after your medicine

  • Keep your APO-BICALUTAMIDE tablets in the blister foil until it is time to take it.

If you take APO-BICALUTAMIDE out of the blister foil, it may not keep well.

  • Keep your medicine in a cool dry place where the temperature will stay 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.

Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

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

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.

Less serious side effects:

Less serious side effectsWhat to do
  • Hot flushes or sweating
  • breast tenderness, changes in breast size or swelling
  • stomach pain or indigestion,
  • nausea or vomiting
  • diarrhoea or constipation,
  • unusual tiredness or weakness
  • dizziness or light-headedness
  • headache
  • chill
  • itching or dry skin, rashes
  • increased hairiness or hair loss
  • flatulence (wind)
  • dry mouth
  • loss of appetite or weight changes
  • depression
  • difficulty sleeping, feeling sleepy
  • pelvic pain
  • decrease in your sexual drive
  • inability to get or maintain an erection
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • chest pain, with or without a feeling of tightness radiating to the shoulders back, neck jaw or arms, with sweating, chills, nausea, vomiting and paleness
  • Yellowing of the skin or eyes and dark coloured urine (jaundice)
  • cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, or other parts of the body; rash, itching or hives on the skin; fainting; hayfever-like symptoms (signs of an allergic reaction)
  • serious breathlessness or sudden worsening of breathlessness, possibly with a cough or fever
  • frequent urination (including at night) blood in the urine
  • becoming out of breath and dizzy when exercising, looking pale (anaemia)
  • excessive thirst with weight loss, passing large amounts of urine, sweet smelling breath
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.

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 APO-BICALUTAMIDE contains

Active ingredient
(main ingredient)		bicalutamide
Other ingredients
(inactive ingredients)
  • lactose monohydrate
  • sodium starch glycollate type A
  • povidone
  • magnesium stearate
  • hypromellose
  • macrogol 400
  • titanium dioxide
Potential allergensLactose

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

What APO-BICALUTAMIDE looks like

White to off white, round, biconvex, film coated tablets debossed "B50" on one side and plain on other side. Available in blister packs of 28 tablets.

AUST R 194683

Who distributes APO-BICALUTAMIDE

Arrotex Pharmaceuticals Pty Ltd
15 – 17 Chapel Street
Cremorne VIC 3121
www.arrotex.com.au

This leaflet was prepared in February 2025.

Published by MIMS April 2025

BRAND INFORMATION

Brand name

APO-Bicalutamide

Active ingredient

Bicalutamide

Schedule

S4

 

1 Name of Medicine

Bicalutamide.

2 Qualitative and Quantitative Composition

Each tablet contains 50 mg bicalutamide as the active ingredient.

Excipients with known effect.

Contains lactose.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White to off white, round, biconvex, film coated tablets debossed "B50" on one side and plain on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of advanced prostate cancer in combination with LHRH agonist therapy.
Prevention of disease flare associated with the use of LHRH agonists.

4.2 Dose and Method of Administration

APO-Bicalutamide tablets 50 mg are intended for oral administration.

Dosage.

Adult males including the elderly.

One tablet (50 mg) once a day.
Treatment with bicalutamide 50 mg should be started at the same time as treatment with a LHRH agonist.

Renal impairment.

No dosage adjustment is necessary for patients with renal impairment.

Hepatic impairment.

No dosage adjustment is necessary for patients with mild hepatic impairment.
Increased accumulation 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 is contraindicated in females and children.
Known hypersensitivity to bicalutamide or any other constituents of the formulation.
Coadministration of terfenadine, astemizole or cisapride with bicalutamide is contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Hyperglycaemia.

A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycaemic control in those with pre-existing diabetes. Consideration should therefore be given to monitoring blood glucose in patients receiving bicalutamide in combination with LHRH agonists.

Potentiation of coumarin anticoagulant effects.

Potentiation of coumarin anticoagulant effects have been reported in patients receiving concomitant bicalutamide 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; Section 4.8 Adverse Effects (Undesirable Effects)).

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 LHRH 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.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 CYP 3A4, with lesser inhibitory effects on CYP 2C9, 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.

LHRH agonists.

Although there is no evidence of any pharmacodynamic or pharmacokinetic interactions between bicalutamide 50 mg and LHRH agonists at steady state, bicalutamide 50 mg may prevent the harmful clinical consequences of flare associated with the start of LHRH agonist therapy.

Cytochrome P450.

Bicalutamide is an inhibitor of CYP 3A4 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 CYP 3A4, 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 bicalutamide. It is therefore recommended that if bicalutamide is started in patients who are already receiving coumarin anticoagulants, prothrombin time (PT)/INR should be closely monitored and adjustments of anticoagulant dose considered (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

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 effects.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Administration of bicalutamide may lead to inhibition of spermatogenesis. The long-term effects of bicalutamide on male fertility have not been studied. In male rats dosed at 250 mg/kg/day (less than human therapeutic concentrations after the maximum recommended clinical dose of 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 should be assumed in man.
Anti-androgen 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 bicalutamide, patients should follow adequate contraception during bicalutamide therapy and for 130 days after bicalutamide therapy.
(Category D)
Bicalutamide is contraindicated in females and must not be given to pregnant women.
 Bicalutamide is contraindicated in females and must not be given to breastfeeding mothers.

4.7 Effects on Ability to Drive and Use Machines

During treatment with bicalutamide, somnolence has been reported. Those patients who experience this symptom should observe caution when driving or using machines.

4.8 Adverse Effects (Undesirable Effects)

Bicalutamide 50 mg in general, has been well tolerated with few withdrawals due to adverse events.
Bicalutamide 50 mg may be associated with the occurrence of diarrhoea and vomiting.

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 bicalutamide 50 mg plus an 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 anticoagulants interacting with bicalutamide have been reports in post marketing surveillance (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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 http://www.tga.gov.au/reporting-problems and contact Arrotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Symptoms.

There is no human experience of overdosage.

Treatment.

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

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Bicalutamide is a nonsteroidal antiandrogen, 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 antiandrogen 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 antiandrogenic activity being almost exclusively in the (R)-enantiomer.

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 randomized to receive bicalutamide 50 mg once daily (404 patients) or flutamide 250 mg (409 patients) three times a day, each in combination with a luteinising hormone releasing hormone agonist (LHRH agonist) (either goserelin acetate implant or leuprorelin acetate depot). At the time of analysis, the median time of follow-up was 49 weeks. Bicalutamide/ LHRH 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 LHRH agonists. This small difference was not statistically significant between bicalutamide 50 mg combination therapy and flutamide combination therapy.

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 endpoints such as time to disease progression.

5.2 Pharmacokinetic Properties

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 50 mg of bicalutamide. At steady state the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers.

Metabolism and excretion.

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

5.3 Preclinical Safety Data

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, sodium starch glycollate type A, povidone, magnesium stearate, hypromellose, macrogol 400, titanium dioxide

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. Protect from moisture.

6.5 Nature and Contents of Container

Blister pack of 28 tablets (AUST R 194683).
APO and APOTEX are registered trademarks of Apotex Inc.

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/L), acid (4.6 mg/L at pH 1) and alkali (3.7 mg/L 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.


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

CAS number.

90357-06-5.

References

1. Prostate 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.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes