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.

What is in this leaflet

This leaflet answers some common questions about bicalutamide. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine 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 want to read it again.

What this medicine is used for

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.

How it works

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 to grow.

Bicalutamide interferes with some of the actions of these hormones.

Bicalutamide should only be taken by men.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

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

This medicine is not addictive.

This medicine must not be used in children.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

  • bicalutamide
  • any of the ingredients listed at the end of this leaflet
  • 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.

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.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • liver problems
  • diabetes
  • heart conditions, including heart rhythm problems (arrhythmia)

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.

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 interact with bicalutamide. 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.

How to take this medicine

Follow carefully all directions given to you by your doctor or pharmacist.

They may differ to the information contained in this leaflet.

How much to take

The usual dose is one tablet taken each day. This dose may be reduced if you have severe liver problems.

How to take it

Swallow your tablet whole with a full glass of water.

When to take it

Take this medicine 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.

How long to take it for

Continue taking your medicine for as long as your doctor tells you. Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is almost time to take your next dose (i.e. less than 12 hours to the next dose), skip the missed dose and take your next dose at the usual time.

Otherwise take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses. 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 take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to the Emergency Department at your nearest hospital if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

If you are about to be started on any new medicine, tell your doctor that you are taking this medicine.

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.

Keep all your doctor’s appointments, as your doctor may do tests to make sure the medicine is working and to prevent side effects.

Things you must not do

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not take your medicine to treat any other complaint unless your doctor or pharmacist tells you to.

Do not stop taking your medicine, or change the dosage, without first checking with your doctor.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you. Some people may feel sleepy, dizzy or weak when taking this medicine.

Side effects

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

All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Tell your doctor or pharmacist if you notice any of the following:

  • hot flushes or sweating
  • breast tenderness or swelling
  • mild rash, itching or dry skin
  • increased hairiness, or loss of hair
  • stomach upsets, such as pain, indigestion, nausea, vomiting, diarrhoea, constipation, wind
  • dry mouth
  • loss of appetite, weight changes
  • depression
  • unusual tiredness, weakness, problems sleeping, feeling sleepy
  • dizziness or light-headedness
  • headache
  • chills
  • pelvic pain
  • decrease in your sexual drive, inability to get or maintain an erection

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

  • 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

The above list includes serious side effects that may need medical attention.

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Emergency department at your nearest hospital:

  • 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

The above list includes very serious side effects and you may need urgent medical attention or hospitalisation.

Other side effects not listed above may occur in some patients.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it. If you take your medicine out of its pack it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this 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

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine left over.

Product description

What it 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

Ingredients

Each tablet contains 50 mg of bicalutamide as the active ingredient.

It also contains the following:

  • lactose
  • sodium starch glycollate
  • povidone
  • magnesium stearate
  • hypromellose
  • macrogol 400
  • titanium dioxide

This medicine does not contain gluten, sucrose, tartrazine or any other azo dyes.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park, NSW 2113
Australia

APO and APOTEX are the registered trademarks of Apotex Inc.

This leaflet was prepared in May 2019.

Published by MIMS July 2019

BRAND INFORMATION

Brand name

APO-Bicalutamide

Active ingredient

Bicalutamide

Schedule

S4

 

1 Name of Medicine

Bicalutamide.

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

Chemical structure.


CAS number.

90357-06-5.

2 Qualitative and Quantitative Composition

Each tablet contains 50 mg bicalutamide as the active ingredient.

Excipients with known effect.

Lactose monohydrate.
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.

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.

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.

4.3 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.

4.8 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 Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

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.

4.7 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.

4.9 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).

7 Medicine Schedule (Poisons Standard)

S4.

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.

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.

Summary Table of Changes