Bicalutamide Tablets USP 150mg Taj Pharma

1. Name of the medicinal product

Bicalutamide 50mg Film-coated Tablets Taj Pharma
Bicalutamide 150mg Film-coated Tablets Taj Pharma

2. Qualitative and quantitative composition

a) Each film-coated tablet contains:
Bicalutamide USP                              50mg
Excipients                                             q.s.
Colour: Titanium Dioxide USP

b) Each film-coated tablet contains:
Bicalutamide USP                              150mg
Excipients                                             q.s.
Colour: Titanium Dioxide USP

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

4. Clinical particulars

4.1 Therapeutic indications

Treatment of advanced prostate cancer in combination with luteinizing-hormone releasing hormone (LHRH) analogue therapy or surgical castration.

4.2 Posology and method of administration

Posology

Adult males including the elderly: one tablet (50 mg) once a day.

Treatment with Bicalutamide should be started at least 3 days before commencing treatment with an LHRH analogue, or at the same time as surgical castration.

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).

Paediatric population: Bicalutamide is contraindicated for use in children (see section 4.3).

4.3 Contraindications

Bicalutamide is contraindicated in females and children (see section 4.6).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration of terfenadine, astemizole or cisapride with Bicalutamide is contraindicated (see section 4.5).

4.4 Special warnings and precautions for use

Initiation of treatment should be under the direct supervision of a specialist.

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 changes are expected to occur within the first 6 months of Bicalutamide therapy.

Severe hepatic changes and hepatic failure have been observed rarely with Bicalutamide, and fatal outcomes have been reported (see section 4.8). Bicalutamide therapy should be discontinued if changes are severe.

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.

Bicalutamide has been shown to inhibit cytochrome P450 (CYP3A4), as such caution should be exercised when co-administered with drugs metabolised predominantly by CYP3A4 (see sections 4.3 and 4.5).

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Androgen deprivation therapy may prolong the QT interval.

In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Bicalutamide.

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 and for 130 days after Bicalutamide therapy.

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 sections 4.5 and 4.8).

4.5 Interaction with other medicinal products and other forms of interaction

There is no evidence of any pharmacodynamic or pharmacokinetic interactions between Bicalutamide and LHRH analogues.

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.

Although clinical studies using antipyrine as a marker of cytochrome P450 (CYP) activity showed no evidence of a drug interaction potential with Bicalutamide, mean midazolam exposure (AUC) was increased by up to 80%, after co-administration of Bicalutamide for 28 days. For drugs with a narrow therapeutic index such an increase could be of relevance. As such, concomitant use of terfenadine, astemizole and cisapride is contraindicated (see section 4.3) and caution should be exercised with the co-administration of Bicalutamide with compounds such as ciclosporin and calcium channel blockers. Dosage reduction may be required for these drugs particularly if there is evidence of enhanced or adverse drug effect. For ciclosporin, it is recommended that plasma concentrations and clinical condition are closely monitored following initiation or cessation of Bicalutamide therapy.

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 which theoretically could lead to an increase in side effects.

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 administered in patients who are concomitantly receiving coumarin anticoagulants, PT/INR should be closely monitored and adjustments of anticoagulant dose considered (see sections 4.4 and 4.8).

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Bicalutamide with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

Bicalutamide is contraindicated in females and must not be given to pregnant women.

Breast-feeding

Bicalutamide is contraindicated during breast-feeding.

Fertility

Reversible impairment of male fertility has been observed in animal studies (see section 5.3). A period of subfertility or infertility should be assumed in man.

4.7 Effects on ability to drive and use machines

Bicalutamide is unlikely to impair the ability of patients to drive or operate machinery. However, it should be noted that occasionally somnolence may occur. Any affected patients should exercise caution.

4.8 Undesirable effects

In this section, undesirable effects are defined as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to ≤1/100); rare (≥1/10,000 to ≤1/1,000); very rare (≤1/10,000); not known (cannot be estimated from the available data).

Table 1 Frequency of Adverse Reactions

1. Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy.
2. Listed as an adverse drug reaction following review of post-marketed data. Frequency has been determined from the incidence of reported adverse events of hepatic failure in patients receiving treatment in the open-label Bicalutamide arm of the 150 mg EPC studies.
3. May be reduced by concomitant castration.
4. Observed in a pharmaco-epidemiology study of LHRH agonists and anti-androgens used in the treatment of prostate cancer. The risk appeared to be increased when Bicalutamide 50 mg was used in combination with LHRH agonists, but no increase in risk was evident when Bicalutamide 150 mg was used as a monotherapy to treat prostate cancer.
5. Listed as an adverse drug reaction following review of post-marketed data. Frequency has been determined from the incidence of reported adverse events of interstitial pneumonia in the randomised treatment period of the 150 mg EPC studies.

Increased PT/INR: Accounts of coumarin anticoagulants interacting with Bicalutamide have been reported in post marketing surveillance (see sections 4.4. and 4.5).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose

There is no human experience of overdosage. There is no specific antidote; treatment should be symptomatic. Dialysis may not be helpful, since Bicalutamide is highly protein bound and is not recovered unchanged in the urine. General supportive care, including frequent monitoring of vital signs, is indicated.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-androgens.

Mechanism of action

Bicalutamide is a non-steroidal antiandrogen, devoid of other endocrine activity. It binds to androgen receptors without activating gene expression, and thus inhibits the androgen stimulus. Regression of prostatic tumours results from this inhibition. Clinically, discontinuation of Bicalutamide can result in antiandrogen withdrawal syndrome in a subset of patients.

Bicalutamide is a racemate with its antiandrogenic activity being almost exclusively in the (R)-enantiomer.

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%) and extensively metabolised (via oxidation and glucuronidation): Its metabolites are eliminated via the kidneys and bile in approximately equal proportions.

Biotranformation

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.

Steady state plasma concentrations of the (R)-enantiomer of approximately 9 microgram/ml are observed during daily administration of 50 mg doses of Bicalutamide. At steady state the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers.

Elimination

In a clinical study the mean concentration of R-bicalutamide in semen of men receiving Bicalutamide 150 mg was 4.9 microgram/ml. The amount of bicalutamide potentially delivered to a female partner during intercourse is low and by extrapolation possibly equates to approximately 0.3 microgram/kg. This is below that required to induce changes in offspring of laboratory animals.

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

Bicalutamide is a potent antiandrogen and a mixed function oxidase enzyme inducer in animals. Target organ changes, including tumour induction, in animals, are related to these activities. Atrophy of seminiferous tubules of the testes is a predicted class effect with antiandrogens and has been observed for all species examined. Reversal of testicular atrophy occurred 4 months after the completion of dosing in a 6-month rat study (at doses of approximately 1.5 times human therapeutic concentrations at the recommended dose of 50 mg). No recovery was observed at 24 weeks after the completion of dosing in a 12-month rat study (at doses of approximately 2 times human concentrations at the recommended human dose of 50 mg). Following 12-months of repeated dosing in dogs (at doses of approximately 7 times human therapeutic concentrations at the recommended human dose of 50 mg), the incidence of testicular atrophy was the same in dosed and control dogs after a 6 month recovery period. In a fertility study (at doses of approximately 1.5 times human therapeutic concentrations at the recommended human dose of 50 mg), male rats had an increased time to successful mating immediately after 11 weeks of dosing; reversal was observed after 7 weeks off-dose.

6. Pharmaceutical particulars

6.1 List of excipients

Bicalutamide includes the following excipients: Lactose Monohydrate, Magnesium Stearate, Hypromellose, Macrogol, Povidone, Sodium Starch Glycolate, Titanium Dioxide.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

Packed in Plastic Box.

30 Film-Coated Tablets per pack.

6.6 Special precautions for disposal and other handling

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7.Manufactured in India by:
Taj Pharmaceuticals Ltd.
at:Survey No.188/1 to, 190/1 to 4,
Athiyawad, Dabhel, Daman 396210
(India).

Bicalutamide 50mg Film-coated Tablets Taj Pharma
Bicalutamide 150mg Film-coated Tablets Taj Pharma

Package leaflet: Information for the user

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

1. What Bicalutamide is and what it is used for
   2. What you need to know before you take Bicalutamide
   3. How to take Bicalutamide
   4. Possible side effects
   5. How to store Bicalutamide
   6. Contents of the pack and other information
2. What Bicalutamide is and what it is used for

Bicalutamide contains a medicine called bicalutamide. This belongs to a group of medicines called ‘anti-androgens’.

• Bicalutamide is used to treat prostate cancer.
• It works by blocking the effects of male hormones such as testosterone.

2. What you need to know before you take Bicalutamide

Do not take Bicalutamide:

• if you are allergic to bicalutamide or any of the other ingredients of this medicine (listed in section 6).
• if you are already taking a medicine called cisapride or certain anti-histamine medicines (terfenadine or astemizole).
• if you are a woman.

Do not take Bicalutamide if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking Bicalutamide.

Bicalutamide must not be given to children.

Warnings and precautions

Talk to your doctor or pharmacist before taking Bicalutamide:

• if you have any of the following: any heart or blood vessel conditions, including heart rhythm problems (arrhythmia), or are being treated with medicines for these conditions. The risk of heart rhythm problems may be increased when using Bicalutamide.
• if you are taking blood thinners or medicines to prevent blood clots.
• if you have problems with your liver.
• if you have diabetes and are already taking an ‘LHRH analogue’. These include goserelin, buserelin, leuprorelin and triptorelin.
• if you go into hospital, tell the medical staff that you are taking Bicalutamide.
• if you are taking Bicalutamide, you and/or your partner should use birth control while you are taking Bicalutamide and for 130 days after stopping Bicalutamide. Talk to your doctor if you have any questions about birth control.

Other medicines and Bicalutamide

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without a prescription and herbal medicines. This is because Bicalutamide can affect the way other medicines work. Also some other medicines can affect the way Bicalutamide works.

Do not take Bicalutamide if you are already taking any of the following medicines:

• Cisapride (used for some types of indigestion).
• Certain anti-histamine medicines (terfenadine or astemizole).

Bicalutamide might interfere with some medicines used to treat heart rhythm problems (e.g. quinidine, procainamide, amiodarone and sotalol) or might increase the risk of heart rhythm problems when used with some other drugs [e.g. methadone (used for pain relief and part of drug addiction detoxification), moxifloxacin (an antibiotic)], antipsychotics used for serious mental illnesses.

Also, tell your doctor or pharmacist if you are taking any of the following medicines:

• Medicines taken by mouth to prevent blood clots (oral anti-coagulants) e.g. warfarin. Blood thinners or medicines to prevent blood clots.
• Ciclosporin (to suppress your immune system).
• Calcium channel blockers (to treat high blood pressure or some heart conditions).
• Cimetidine (for stomach problems).
• Ketoconazole (to treat infections caused by a fungus).

Pregnancy, breast-feeding and fertility

Bicalutamide must not be taken by women, including pregnant women or mothers who are breast-feeding their babies.

Bicalutamide may have an effect on male fertility which could be reversible.

Driving and using machines

Bicalutamide is not likely to affect you being able to drive or use any tools or machines.

However, if you feel sleepy take care with these activities.

Bicalutamide contains lactose

Bicalutamide contains lactose monohydrate, which is a type of sugar. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

3. How to take Bicalutamide

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

• The recommended dose for an adult is one tablet each day.
• Swallow the tablet whole with a drink of water.
• Try to take your tablet at the same time each day.
• Do not stop taking this medicine even if you feel well, unless your doctor tells you to.

If you take more Bicalutamide than you should

If you take more Bicalutamide than prescribed by your doctor, talk to a doctor or go to a hospital straight away.

If you forget to take Bicalutamide

• If you forget to take a dose, skip the missed dose and take the next dose as usual.
• Do not take a double dose (two doses at the same time) to make up for a forgotten dose.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Allergic reactions

These are uncommon (may affect up to 1 in 100 people):

The symptoms can include sudden onset of:

• Rash, itching or hives on the skin.
• Swelling of the face, lips, tongue, throat or other parts of the body.
• Shortness of breath, wheezing or trouble breathing.

If this happens to you, see a doctor straight away.

Also tell your doctor straight away if you notice any of the following:

Very common (may affect more than 1 in 10 people):

• Pain in your abdomen.
• Blood in your urine.

Common (may affect up to 1 in 10 people):

• Yellowing of the skin or whites of your eyes (jaundice). These may be signs of liver problems or in rare cases (may affect up to 1 in 1,000 people) liver failure.

Uncommon (may affect up to 1 in 100 people):

• Serious shortness of breath or shortness of breath which suddenly gets worse. This may be with a cough or high temperature (fever). These may be signs of an inflammation of the lungs called ‘interstitial lung disease’.

Not known (frequency cannot be estimated from the available data):

• Changes in ECG (QT prolongation).

Other possible side effects:

Very common (may affect more than 1 in 10 people)

• Dizziness.
• Constipation.
• Feeling sick (nausea).
• Swelling and tenderness of your breasts.
• Hot flushes.
• Feeling weak.
• Swelling.
• Low levels of red blood cells (anaemia). This may make you feel tired or look pale.

Common (may affect up to 1 in 10 people)

• Loss of appetite.
• Reduced sex drive.
• Depression.
• Feeling sleepy.
• Indigestion.
• Wind (flatulence).
• Hair loss.
• Hair re-growth or growth of extra hair.
• Dry skin.
• Itching.
• Skin rash.
• Being unable to get an erection (impotence).
• Weight gain.
• Chest pain.
• Reduced heart function.
• Heart attack.

Rare (may affect up to 1 in 1,000 people)

• Increased skin sensitivity to sunlight.

Your doctor may do blood tests to check for any changes to your blood.

Do not be concerned by this list of possible side effects. You may not get any of them.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

5. How to store Bicalutamide

• Keep your tablets in the container they came in.
• Do not store above 30°C.
• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiry date which is stated on the carton. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Bicalutamide 50 mg Film-coated Tablets contains

a) Each film-coated tablet contains:
Bicalutamide USP                              50mg
Excipients                                             q.s.
Colour: Titanium Dioxide USP

b) Each film-coated tablet contains:
Bicalutamide USP                              150mg
Excipients                                             q.s.
Colour: Titanium Dioxide USP

The other ingredients are lactose monohydrate, magnesium stearate, hypromellose, macrogol, povidone, sodium starch glycolate and titanium dioxide.

What Bicalutamide 50 mg Film-coated Tablets look like and contents of the pack

Packed in Plastic Box.30 Film-Coated Tablets per pack.

7.Manufactured in India by:
Taj Pharmaceuticals Ltd.
at:Survey No.188/1 to, 190/1 to 4,
Athiyawad, Dabhel, Daman 396210
(India).