Consumer medicine information

Bicalox

Bicalutamide

BRAND INFORMATION

Brand name

Bicalox

Active ingredient

Bicalutamide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Bicalox.

What is in this leaflet

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

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 BICALOX 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 BICALOX is used for

BICALOX is used in combination with other medicines to treat locally advanced prostate cancer.

BICALOX is an anti-androgen medicine. Androgens such as testosterone are natural male sex hormones. In some types of prostate cancer, androgens can help the cancer cells to grow. Bicalutamide interferes with some of the actions of these hormones.

BICALOX should only be taken by men.

You must follow all the 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.

Always ask your doctor if you need more information.

BICALOX is not addictive.

BICALOX is only available with a doctor’s prescription.

Before you take it

When you must not take it

Do not take BICALOX if you are a woman. Women are not normally treated with BICALOX.

Do not give BICALOX to children. There is no experience of its use in children.

Do not take BICALOX if you are allergic to bicalutamide or any of the other ingredients in BICALOX.

Do not take BICALOX if you are taking cisapride or the antihistamines, terfenadine and astemizole.

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

Do not take BICALOX 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 take it

You must tell your doctor if:

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

Taking other medicines

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

  • cisapride (see When you must not take it);
  • the antihistamines terfenadine and astemizole (see When you must not take it);
  • medicines used to prevent blood clots, especially warfarin;
  • midazolam;
  • cyclosporin;
  • medicines used to treat high cholesterol;
  • calcium channel blockers;
  • carbamazepine;
  • quinidine;
  • antiviral medicines for HIV infection; or
  • medicines that you buy at the chemist, supermarket or health food shop.

These medicines may affect the way BICALOX works.

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 take any BICALOX.

How to take it

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

If you do not understand the instructions on the box, you must ask your doctor or pharmacist for help.

How much to take

The usual adult dose is one 50 mg tablet taken each day.

How and when to take it

Swallow your BICALOX tablet whole with a full glass of water.

Take BICALOX about the same time each day.

BICALOX should be started at the same time as the other medicines you have been given for the treatment of prostate cancer.

It does not matter if you take BICALOX before, with or after food.

How long to take it

Continue taking BICALOX for as long as your doctor or pharmacist tells you.

If you forget to take it

If you miss a dose 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.

If you take too much (overdose)

Immediately telephone your doctor or pharmacist or the Poisons Information Centre (telephone Australia 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 much BICALOX. Do this even if there are no signs of discomfort or poisoning.

While you are taking it

Things you must do

Be sure to keep all your appointments with your doctor so your progress can be checked.

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

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

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

Things you must not do

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

Do not take BICALOX to treat any other complaints unless your doctor tells you to.

Do not stop taking BICALOX, or lower the dosage, without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how BICALOX 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 BICALOX.

BICALOX helps people with advanced prostate cancer, but it may have unwanted side effects in a few 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;
  • diarrhea or constipation;
  • flatulence (wind);
  • dry mouth;
  • loss of appetite or weight changes;
  • depression;
  • unusual tiredness or weakness;
  • dizziness or light-headedness;
  • difficulty sleeping;
  • headache;
  • chills;
  • pelvic pain;
  • decrease in your sexual drive;
  • inability to get or maintain an erection; or
  • photosensitivity reaction of skin.

These are possible side effects of BICALOX.

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

  • frequent urination;
  • shortness of breath and dizziness when exercising and looking pale (anaemia); or
  • 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; or
  • serious breathlessness, or sudden worsening of breathlessness, possibly with a cough or fever; or
  • 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 BICALOX.

After taking it

Storage

Keep your BICALOX tablets in the blister foil until it is time to take them. If you take BICALOX out of the blister foil, it will not keep well.

Keep it in a cool dry place where the temperature stays below 30ºC. Protect from light and moisture.

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.

Product description

What BICALOX looks like

BICALOX™ 50 mg tablets are white to off-white, round film-coated, biconvex tablets, engraved with ‘BC 50’ on one face and plain on other.

BICALOX™ tablets are available in:

Blister packs of 28, 56* or 98* tablets (AUST R: 129117); and

Bottles containing 28*, 100* or 500* tablets (AUST R: 129119).

*Some of these presentations and pack sizes are not marketed.

Ingredients

Active ingredient: bicalutamide.

Inactive ingredients:

  • lactose monohydrate;
  • sodium starch glycollate;
  • povidone;
  • magnesium stearate;
  • hypromellose;
  • titanium dioxide; and
  • macrogol 400.

BICALOX does not contain:

  • added sucrose;
  • gluten;
  • tartrazine or any other azo dyes.

Sponsor/ Marketing Authorisation Holder

Strides Pharma Science Pty Ltd
Sydney, Australia

www.stridespharma.com.au

This leaflet was prepared in December 2020.

Bicalox™ 50 mg blister pack AUST R 129117

Bicalox™ 50 mg bottle AUST R 129119

Version 7

Published by MIMS July 2021

BRAND INFORMATION

Brand name

Bicalox

Active ingredient

Bicalutamide

Schedule

S4

 

1 Name of Medicine

Bicalutamide.

2 Qualitative and Quantitative Composition

Each Bicalox tablet contains 50 mg bicalutamide.
Bicalutamide is a white to almost white powder. Practically insoluble in water, freely soluble in acetone, slightly soluble in anhydrous ethanol and in methylene chloride.

Excipients with known effect.

Lactose monohydrate. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

A white to off white, round, film coated, biconvex tablet, engraved with 'BC 50' on one face and plain on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of advanced prostate cancer in combination with LHRH agonist therapy.

4.2 Dose and Method of Administration

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

Bicalox is contraindicated in females and children; also, in case of 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.

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 six months of bicalutamide therapy.
Rare cases of death or hospitalisation due to severe liver injury have been observed with (see Section 4.8 Adverse Effects (Undesirable Effects)) bicalutamide. 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.

Use in the elderly.

Please see Section 4.2 Dose and Method of Administration.

Paediatric use.

Please see Section 4.3 Contraindications.

Effects on laboratory tests.

No data available.

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.

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 humans. 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.

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 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. It is therefore recommended that if bicalutamide is started in patients who are already receiving coumarin anticoagulants, prothrombin time should be closely monitored.

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.

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 seven weeks after the end of an eleven week period of dosing.
(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)

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.
Bicalutamide 50 mg in general 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 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.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
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.

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 '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 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 randomised to receive bicalutamide 50 mg once daily (404 patients) or flutamide 250 mg three times a day (409 patients), 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 Cooperative Oncology 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. (Lancet 1995; 346: 265-269) 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/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.

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 one week. On daily administration of bicalutamide, the (R)-enantiomer accumulates about tenfold 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.

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 bicalutamide 5, 15 or 75 mg/kg/day. 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 two 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 humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Bicalox tablet contains following excipients: lactose monohydrate, sodium starch glycollate, povidone, magnesium stearate, hypromellose, macrogol 400 and 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 30°C. Protect from light and moisture.

6.5 Nature and Contents of Container

Bicalox 50 mg tablets are available in PVC/PVDC/Al blister packs of 28, 56* and 98* tablets (AUST R: 129117); and HDPE bottles containing 28*, 100* and 500* tablets (AUST R: 129119).
*Some of these presentations and pack sizes are not marketed.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical name: (2RS)-N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]- 2-hydroxy-2-methylpropanamide.
Molecular formula: C18H14F4N2O4S.
Molecular weight: 430.4.

Chemical structure.


CAS number.

90357-06-5.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes