Last Updated on eMC 25-08-2015 View medicine  | Zentiva Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.8 - Undesirable effects - how to report a side effect

Date of revision of text on the SPC:11-06-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Prac reccomendation on AT interval prolongation due to long term use

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data

Date of revision of text on the SPC:28-10-2013

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

In Section 4.2       Posology and method of administration

 

           Adult males including the elderly

One 50 mg tablet once a day.

 

The tablets should be swallowed whole with liquid.

 

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.

 

Children and adolescents

Bicalutamide is contranot indicated in children and adolescents.

 

Renal impairment

No dose adjustment is necessary for patients with renal impairment. There is no experience with the use of bicalutamide in patients with severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.4).

 

Hepatic impairment

No dose adjustment is necessary for patients with mild hepatic impairment. Increased accumulation may occur The medicinal product may accumulate in patients with moderate to severe hepatic impairment (see section 4.4).

 

In Section 4.3       Contraindications

 

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

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

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

 

In Section 4.4        Special warnings and precautions for use

 

Initiation of treatment should be under the direct supervision of a specialist and subsequently patients should be kept under regular surveillance.

 

Bicalutamide is extensively metabolised in the liver. Data Research results suggests that itbicalutamide’s 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.

 

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

 

Periodic liver function testing should be considered is warranted in order to find out about possible hepatic changes. The majority of changes are expected to occur within the first 6 months of bicalutamide therapy.

 

As there is no experience with the use of bicalutamide in patients with severe renal impairment (creatinine clearance < 30 ml/min), bicalutamide should only be used with caution in these patients.

 

Periodical monitoring of cardiac function is advisable in patients with heart disease.

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 (CYP 3A4), as such caution should be exercised when co-administered with drugs metabolised predominantly by CYP 3A4 (see sections 4.3 and 4.5).

 

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


In Section 4.6       Fertility, pregnancy and lactation

 

           Not applicable, since this medicinal product is not used in women.

 

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.

This medicinal product is contraindicated in women and must not be given to pregnant and nursing mothers.

 

In Section 4.7       Effects on ability to drive and use machines

 

Bicalutamide is unlikely to impair No studies on the effects on the ability of patients to drive or operate machinery. and use machines have been performed. However, it should be noted that occasionally dizziness or somnolence may occur (see section 4.8). Any affected patients should exercise caution.

 

In Section 4.8       Undesirable effects

 

In this section, undesirable effects are defined as follows: vVery 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).

 

System Organ Class

Frequency

Undesirable effectEvent

Blood and lymphatic system disorders

Very common

Anaemia

Immune system disorders

Uncommon

Hypersensitivity, angioeodema reactions (including angioneurotic oedema  and urticaria)

Metabolism and nutrition disorders

Common

Decreased appetiteAnorexia

Psychiatric disorders

Common

Decreased libido

Depression

Nervous system disorders

Very common

Dizziness

Common

Somnolence

Cardiac disorders

Common

Myocardial infarction (fatal outcomes have been reported)1, cardiac failure1

Vascular disorders

Very common

Hot flush

Respiratory, thoracic and mediastinal disorders

Uncommon

Interstitial lung disease2

(fFatal outcomes have been reported)

Gastrointestinal disorders

Very common

Abdominal pain

Constipation

Nausea

Common

Dyspepsia

Flatulence

Hepato-biliary disorders

Common

Hepatic changes (including elevated levels of transaminases, jaundice)/hepato-biliary disorders1 Hepatotoxicity, jaundice, hypertransaminasaemia3

Rare

Hepatic failure42

(fFatal outcomes have been reported)

Skin and subcutaneous tissue disorders

Common

Alopecia

Hirsuiitism/hair re-growth

Dry skin

Pruritis

Rash

Renal and urinary disorders

Very common

Haematuria

Reproductive system and breast disorders

Very common

Gynaecomastia and breast tenderness53

Common

Erectile dysfunctionImpotence

General disorders and administration site conditions

Very common

Asthenia

Oedema

Common

Chest pain

Investigations

Common

Weight increasedgain


1 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.

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 interstitial pneumonia

in the randomised treatment period of the 150 mg EPC studies.

3Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy.

2 Hepatic failure has occurred rarely in patients treated with bicalutamide, but a causal relationship has not been established with certainty. Periodic liver function testing should be considered (see also section 4.4).

4 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.

53 May be reduced by concomitant castration.

 

In addition, cardiac failure was reported in clinical trials (as a possible adverse drug reaction in the opinion of investigating clinicians, with a frequency of > 1%) during treatment with bicalutamide plus an LHRH analogue. There is no evidence of a causal relationship with drug treatment.

 

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.

Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

 

In Section 4.9              Overdose

 

No case of overdose has been reported. Since bicalutamide belongs to the anilide compounds there is a theoretical risk of the development of methaemoglobinaemia. Methaemoglobinaemia has been observed in animals after an overdose. Accordingly, a patient with an acute intoxication can be cyanotic. There is no specific antidote; treatment should be symptomatic. Dialysis is unlikely to 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.


In Section 5.1       Pharmacodynamic properties

 

Pharmacotherapeutic group: Hormone antagonists and related agents, anti- androgens.

ATC code: L02BB03.

 

Bicalutamide is a non-steroidal anti-androgen, devoid of other endocrine activity. It binds to the wild type or normal 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 the “anti-androgen withdrawal syndrome” in a subset of patients.

 

Bicalutamide is a racemate with its anti-androgenic activity being almost exclusively associated with the (R)-enantiomer

 

In Section 5.2       Pharmacokinetic properties

 

Bicalutamide is well absorbed following oral administration. There is no evidence of any clinically relevant effect of food on bioavailability.

 

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 9µg/ml are observed during daily administration of 50mg doses of bicalutamide. At steady state the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers.

 

The pharmacokinetics of the (R)-enantiomer are unaffected by age, renal impairment or mild to moderate hepatic impairment. There is evidence that the (R)-enantiomer is more slowly eliminated from plasma in patients with severe hepatic impairment.

 

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.

 

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


In Section 5.3       Preclinical safety data

 

Bicalutamide is a potent anti-androgen and a mixed function oxidase enzyme inducer in animals. Target organ changes, including tumour induction, in animals, are related to these activities. None of the findings in the preclinical testing is considered to have relevance to the treatment of advanced prostate cancer patients.

Bicalutamide is a pure and potent androgen receptor antagonist in experimental animals and humans.

 

The main secondary pharmacological action is induction of CYP450 dependent mixed function oxidases in the liver. Target organ changes, including tumour induction (Leydig cells, thyroid, liver), observed in animals, are clearly related to the primary and secondary pharmacological action of bicalutamide. The enzymatic induction was not observed in man and none of these findings was considered to have relevance to the treatment of advanced prostate cancer patients. The atrophy of seminiferous tubules is a predictable class effect of anti-androgens and has been observed in all the examined species. The total reversion of the testicles atrophy occurred 24 weeks after a toxicity study of repeated dose of 12 months in rats, although the function reversion has been evident in the reproduction studies of 7 weeks, after the end of an administration period of 11 weeks. In the man a period of sub-fertility or infertility should be considered.

 

Genotoxicity studies did not reveal any mutagenic potential of bicalutamide.



Reasons for adding or updating:

  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:23-07-2013

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

This is an updated SPC following licence renewal.  The only change is Revision of Text date

Reasons for adding or updating:

  • Change to section 7 - Marketing Authorisation Holder

Date of revision of text on the SPC:09-09-2011

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

 Section 7. Change in the name of MAH in UK.  Addition of an alternative trading style to our MA in the UK only.  The legal entities remail the same

Reasons for adding or updating:

  • Change to section 6. 3 - Shelf Life

Date of revision of text on the SPC:22-11-2010

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

SPC updated in line with innovator SPC.

There are been an increase to section 6.3- shelf life of tablets has been increased from 3 years to 5 years.

Reasons for adding or updating:

  • New SPC for eMC ie an SPC for an existing product, but one that is new for the eMC

Date of revision of text on the SPC:01-01-0001

Legal Category:POM

Black Triangle (CHM): NO