Consumer medicine information

Calutex

Bicalutamide

BRAND INFORMATION

Brand name

Calutex

Active ingredient

Bicalutamide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Calutex.

What is in this leaflet

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

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

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

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

What Calutex is used for

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

Calutex contains bicalutamide as the active ingredient. Bicalutamide belongs to a group of medicines called anti-androgens.

Androgens such as testosterone are natural male sex hormones. In some types of prostate cancer, androgens may help the cancer cells to grow. Calutex interferes with some of the actions of these hormones.

Calutex should only be taken by men.

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

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

Calutex is only available with a doctor’s prescription.

It is not addictive.

Before you take it

When you must not take it

Do not take Calutex if you are a woman.

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

Do not take Calutex if you are allergic to bicalutamide or any of the other tablet ingredients listed at the end of the leaflet.

Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty in breathing; swelling of the face, lips, tongue or any other part of the body; rash, itching or hives on the skin.

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

Do not take Calutex 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 Calutex 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 you have had any allergies to any other anti-androgen medicines, any other medicines or substances such as foods, preservatives or dyes.

Tell your doctor if you have or have had any liver problems. It may not be safe for you to take Calutex if you have problems with your liver.

Tell your doctor if you are diabetic. Your doctor may need to monitor your blood glucose levels whilst taking this medicine.

Tell your doctor if you have heart or blood vessel conditions, including heart rhythm problems (arrhythmia), or are being treated with medicines for these conditions. The risk of you having further heart rhythm problems may increase if you are taking Calutex.

Tell your doctor or pharmacist if you are taking coumarin anticoagulants. Taking Calutex with these medicines may increase the risk of bleeding.

Taking other medicines

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

Some medicines may be affected by Calutex or may affect how well it works. These include:

  • cisapride
  • the antihistamines terfenadine and astemizole
  • medicines used to prevent blood clots, especially warfarin
  • ketoconazole
  • cimetidine
  • midazolam
  • cyclosporin
  • medicines used to treat high cholesterol
  • calcium channel blockers
  • carbamazepine
  • quinidine
  • antiviral medicines for HIV infection.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking this medicine.

How to take it

How much to take

Take your medicine as directed by your doctor.

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

How to take it

Swallow the tablet whole with a glass of water.

When to take it

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

This medicine can be taken before, with or after food.

How long to take it

Continue taking Calutex for as long as your doctor 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.

However, 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.

Ask your doctor or pharmacist if you are not sure what to do.

If you take too much (overdose)

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

While you are taking it

Things you must do

Be sure to keep all your doctor’s appointments so your condition can be monitored.

Tell any other doctors, dentists and pharmacists who are treating you that you are taking Calutex, especially if you are about to be started on any new medicine.

Calutex 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 Calutex and for at least 130 days after you have stopped taking this medicine.

Things you must not do

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

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

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

Things to be careful of

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

Calutex helps most 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
  • diarrhoea or constipation
  • flatulence (wind)
  • dry mouth
  • depression
  • loss of appetite or weight changes
  • unusual tiredness or weakness
  • dizziness or light-headedness
  • headache
  • swelling of hands, ankles or feet
  • difficulty sleeping
  • chills
  • pelvic pain
  • depression
  • decrease in your sexual drive
  • inability to get or maintain an erection.

These are common side effects of Calutex.

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

  • chest pain
  • 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:

  • severe 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
  • serious breathlessness, or sudden worsening of breathlessness, possibly with a cough or fever
  • shortness of breath, wheezing or trouble breathing.

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

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may occur in some patients.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After taking it

Storage

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

Keep it 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

If your doctor tells you to stop taking Calutex or you find that the expiry date has passed, ask your pharmacist what to do with any tablets that are left over.

Product Description

What it looks like

Calutex 50 mg are white, biconvex film-coated tablets.

Available in blister packs of 28 tablets.

Ingredients

Active ingredient:

Each tablet contains 50 mg of bicalutamide.

Inactive ingredients:

  • lactose monohydrate
  • sodium starch glycollate
  • povidone
  • magnesium stearate
  • Opadry complete film coating system white Y-1-1700.

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

Sponsor

Aspen Pharma Pty Ltd
34-36 Chandos Street
St Leonards NSW 2065
Australia

Australia Registration Number:
AUST R 135858

This leaflet was revised in May 2019.

Published by MIMS July 2019

BRAND INFORMATION

Brand name

Calutex

Active ingredient

Bicalutamide

Schedule

S4

 

1 Name of Medicine

Bicalutamide.

2 Qualitative and Quantitative Composition

Calutex tablets contain bicalutamide 50 mg as the active ingredient.
Excipients with known effect include lactose monohydrate. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Calutex is a white, film coated biconvex tablet containing bicalutamide 50 mg as the active ingredient.

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

Adult males, including the elderly.

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

Use in adult males with renal impairment.

No dosage adjustment is necessary for patients with renal impairment.

Use in adult males with 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

Females; children; known hypersensitivity to bicalutamide or any other constituents of the formulation.
Coadministration of terfenadine, astemizole or cisapride with Calutex 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 (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. Calutex 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 suggest that its elimination may be slower in subjects with severe hepatic impairment and this could lead to increased accumulation of bicalutamide. Therefore, Calutex 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 bicalutamide (see Section 4.8 Adverse Effects (Undesirable Effects)). Calutex 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.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

See Section 4.3 Contraindications.

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 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 and LHRH agonists at steady state, bicalutamide 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, e.g. cyclosporin, calcium channel blockers, HIV antivirals, HMG-CoA reductase inhibitors, carbamazepine, quinidine.

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 Calutex is started in patients who are already receiving coumarin anticoagulants, prothrombin time 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 Calutex 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. 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 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 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.
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 bicalutamide, patients and/or their partners should follow adequate contraception during bicalutamide therapy and for 130 days after bicalutamide therapy.
(Category D)
Calutex is contraindicated in females and must not be given to pregnant women.
 Calutex 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 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.
Bicalutamide in general has been well tolerated, with few withdrawals due to adverse events. The pharmacological action of bicalutamide may give rise to certain expected effects. These include hot flushes, pruritus, breast tenderness and gynaecomastia which may be reduced by concomitant castration. Bicalutamide may also be associated with the occurrence of diarrhoea, nausea, vomiting, asthenia and dry skin.
Hepatic changes (elevated levels of transaminases, jaundice), rarely severe, have been observed in clinical trials with bicalutamide. The changes were frequently transient, resolving or improving with continued therapy or following cessation of therapy (see Section 4.4 Special Warnings and Precautions for Use). Hepatic failure has been rarely observed.
Hypersensitivity reactions, including angioneurotic oedema and urticaria, and interstitial lung disease have been reported uncommonly.

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 greater than or equal to 1% during treatment with bicalutamide 50 mg plus an LHRH agonist. No causal relationship of these experiences to drug treatment has been demonstrated and some of the experiences reported are those that commonly occur in elderly patients. See Table 1.

4.9 Overdose

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 13 11 26 (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 randomised to receive bicalutamide 50 mg once daily (404 patients) or flutamide 250 mg three times a day (409 patients), each in combination with luteinising hormone releasing hormone (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 (EOCG) 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 risk of death in favour of MAB. The meta-analysis only included the effect of MAB 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 tablets. 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). Its metabolites are eliminated via the kidneys and bile in approximately equal proportions.

Excretion.

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

Lactose monohydrate, sodium starch glycollate, povidone, magnesium stearate and Opadry Complete film coating system White Y-1-1700.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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

PVC/Aluminium blister packs of 28 tablets.

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

The active ingredient, 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-alpha',alpha',alpha',-trifluoro-3-(4-fluorophenylsulfonyl)-2- hydroxy-2-methylpropiono-m-toluidide. Molecular formula: C18H14F4N2O4S; molecular weight: 430.38.

CAS number.

90357-06-5.

Chemical structure.


7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes