Bicalutamide 150mg Film-Coated Tablets

Document: spc-doc_PL 15413-0018 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Bicalutamide 150 mg film-coated tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 150 mg bicalutamide.

Excipient(s): One tablet contains 188.0 mg lactose monohydrate For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

White, round, biconvex, film coated tablets, with diameter of 10.5mm, and a score line on one side. The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Bicalutamide 150 mg is indicated either alone or as adjuvant to radical prostatectomy or radiotherapy in patients with locally advanced prostate cancer at high risk for disease progression (see section 5.1).

4.2 Posology and method of administration

Adult males including the elderly: one film-coated tablet (150mg) daily with or without food.

Route: Oral

The tablets should be swallowed whole with liquid.

Treatment with Bicalutamide should be taken continuously for at least 2 years or until disease progression.

Children and adolescents: Bicalutamide is not indicated in children and adolescents.

Renal impairment: no dosage 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 dosage adjustment is necessary for patients with mild hepatic impairment. The medicinal product may accumulate in patients with moderate to severe hepatic impairment (see Section 4.4).

4.3. Contraindications

Bicalutamide 150 mg is contra-indicated in women children and adolescents (see Section 4.6).

Bicalutamide 150 mg is contraindicated in patients with hypersensitivity to the active substance or any of the excipients of this product.

Co-administration of terfenadine, astemizole or cisapride with Bicalutamide 150 mg is contra-indicated (see section 4.5).

4.4. Special warnings and precautions for use

Bicalutamide is extensively metabolised in the liver. Research results 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.

Severe hepatic changes have been observed rarely with Bicalutamide 150 mg 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 due to the possibility of 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.

For patients who have an objective progression of disease together with elevated PSA, cessation of bicalutamide therapy should be considered.

Bicalutamide 150 mg-contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

In vitro studies have shown that the R-enantiomer of bicalutamide is an inhibitor of CYP 3A4 with lesser inhibitory effects on CYP 2C9, 2C19 and 2D6 activity.

Although in vitro studies have indicated the possibility of bicalutamide inhibiting cytochrome 3A4, a number of clinical studies show that the scale of this inhibition for most drugs metabolized by cytochrome P450 is probably not clinically significant. Nonetheless, for drugs with a narrow therapeutic index metabolized in the liver, the CYP 3A4 inhibition caused by bicalutamide could be of relevance. As such, concomitant use of terfenadine, astemizole and cisapride is contra-indicated.

Caution should be exercised with the co-administration of bicalutamide with compounds such as cyclosporin and calcium channel blockers. Dosage reduction may be required for these drugs particularly if there is evidence of enhanced or adverse drug effect. For cyclosporine, it is recommended that plasma concentrations and clinical condition are closely monitored following initiation or cessation of bicalutamide therapy.

Caution should be exercised when administering bicalutamide to patients taking medicinal products that inhibit the oxidation processes in the liver, e.g. cimetidine and ketoconazole. 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 site. It is therefore recommended that prothrombin time is closely monitored if bicalutamide is started in patients who are already receiving coumarin anticoagulants.

4.6 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.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive 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.

4.8. Undesirable effects

The pharmacological action of bicalutamide may give rise to certain undesirable effects. These include the following:

System Organ Class	Frequency	Bicalutamide 50 mg (+ LHRH analogue)	Bicalutamide 150 mg (monotherapy)
Blood and Lymphatic system disorder	Very common	Anaemia
	Common		Anaemia
Nervous System Disorders	Very common	Dizziness
	Common	Somnolence	Dizziness, somnolence
Vascular disorders	Very common	Hot flush
	Common		Hot flush
Gastrointestinal disorders	Very common	Abdominal pain, constipation, nausea
	Common	Dyspepsia, flatulence	Abdominal pain, constipation, dyspepsia, flatulence, nausea
Skin and subcutaneous tissue disorders	Very common		Rash
	Common	Alopecia, hirsutism/ hair re-growth, rash, dry skin, pruritus	Alopecia, hirsutism/ hair re-growth, dry skin^d, pruritus
Renal and urinary disorders	Very common	Haematuria
	Common		Haematuria
Reproductive system and breast disorders	Very common	Gynaecomastia and breast tenderness^b	Gynaecomastia and breast tenderness^a
	Common	Erectile dysfunction	Erectile dysfunction
General disorders and administration site conditions	Very common	Asthenia, oedema	Asthenia
	Common	Chest pain	Chest pain, oedema
Metabolism and nutrition disorders	Common	Decreased appetite	Decreased appetite
Psychiatric disorders	Common	Decreased libido, depression	Decreased libido, depression
Cardiac disorders	Common	Myocardial infarction (fatal outcomes have been reported)^g ,Cardiac failure^g
Hepatobiliary disorders	Common	Hepatotoxicitiy, jaundice, hypertransaminasaemia^c	Hepatotoxicitiy, jaundice, hypertransaminasaemia^c

	Rare	Hepatic failure^f (fatal outcomes have been reported)	Hepatic failure^f (fatal outcomes have been reported)
Investigations	Common	Weight increased	Weight increased
Immune system disorders	Uncommon	Hypersensitivity, angioedema, and urticaria	Hypersensitivity, angioedema, and urticaria
Respiratory, thoracic and mediastinal disorders	Uncommon	Interstitial lung disease^e(fatal outcomes have been reported)	Interstitial lung disease^e(fatal outcomes have been reported)

The majority of patients receiving Bicalutamide 150 mg as monotherapy experience gynaecomastia and/or breast pain. In studies these symptoms were considered to be severe in up to 5% of the patients. Gynaecomastia may not resolve spontaneously following cessation of therapy, particularly after prolonged treatment.

May be reduced by concomitant castration.

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

Due to the coding conventions used in the EPC studies, adverse events of ‘dry skin’ were coded under the COSTART term of ‘rash’. No separate frequency descriptor can therefore be determined for the 150 mg Bicalutamide dose however the same frequency as the 50 mg dose is assumed.

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.

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.

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.

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 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: Hormone antagonists and related agents, antiandrogens. ATC code: L02BB03.

Bicalutamide is 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 associated with the ( R )-enantiomer.

Bicalutamide (Bicalutamide) 150 mg was studied as a treatment for patients with localised (T1-T2, N0 or NX, M0) or locally advanced (T3-T4, any N, M0; T1-T2, N+, M0) non-metastatic prostate cancer in a combined analysis of 3 placebo controlled double-blind studies in 8113 patients, where bicalutamide was given as immediate hormonal therapy or as adjuvant to radical prostatectomy or radiotherapy, (primarily external beam radiation). At 7.4 years median follow up, 27.4% and 30.7% of all bicalutamide and placebo-treated patients, respectively, had experienced objective disease progression.

A reduction in risk of objective disease progression was seen across most patient groups but was most evident in those at highest risk of disease progression.

Therefore, clinicians may decide that the optimum medical strategy for a patient at low risk of disease progression, particularly in the adjuvant setting following radical prostatectomy, may be to defer hormonal therapy until signs that the disease is progressing.

No overall survival difference was seen at 7.4 years median follow up with 22.9% mortality (HR=0.99; 95% CI 0.91 to1.09). However, some trends were apparent in exploratory subgroup analyses.

Progression-free survival and overall survival data for patients with locally advanced disease are summarised in the following tables:

Table 1 Progression-free survival in locally advanced disease by therapy

sub-group

Analysis population	Events (%) in bicalutamide patients	Events (%) in placebo patients	Hazard ratio (95% CI)
Watchful waiting	193/335 (57.6)	222/322 (68.9)	0.60 (0.49 to 0.73)
Radiotherapy	66/161 (41.0)	86/144 (59.7)	0.56 (0.40 to 0.78)
Radical prostatectomy	179/870 (20.6)	213/849 (25.1)	0.75 (0.61 to 0.91)
Table 2 Overall survival in locally advanced disease by therapy sub-group

Analysis population	Deaths (%) in bicalutamide patients	Deaths (%) in placebo patients	Hazard ratio (95% CI)
Watchful waiting	164/335 (49.0)	183/322 (56.8)	0.81 (0.66 to 1.01)
Radiotherapy	49/161 (30.4)	61/144 (42.4)	0.65 (0.44 to 0.95)
Radical prostatectomy	137/870 (15.7)	122/849 (14.4)	1.09 (0.85 to 1.39)

For patients with localised disease receiving bicalutamide alone, there was no significant difference in progression free survival. In these patients there was also a trend toward decreased survival compared with placebo patients (HR=1.16; 95% CI 0.99 to 1.37). In view of this, the benefit-risk profile for the use of bicalutamide is not considered favourable in this group of patients

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.

Following a long-term administration of bicalutamide, the peak concentration of the (R)-enantiomer accumulates to about 10 fold in plasma as compared to the levels measured after a single dose of 50mg of Bicalutamide.

A dosing scheme of 150mg Bicalutamide daily will result in a steady-state concentration of the R-enantioner of 22 microgram/ml and as a consequence of its half-life, steady state is reached after approximately 1 month of therapy

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.

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 bicalutamide 150 mg was 4.9 microgram/ml. The amount of bicalutamide potentially delivered to a female partner during intercourse is low and equates to approximately 0.3 microgram/kg. This is below that required to induce changes in offspring of laboratory animals.

5.3 Preclinical safety data

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 liver. This enzyme induction observed in animals has not been observed in humans. Target organ changes in animals are clearly related to the primary and secondary pharmacological action of bicalutamide. These comprise involution of androgen-dependent tissues; thyroid follicular adenomas, hepatic and leydig cell hyperplasias and neoplasias or cancer; disturbance of male offspring sexual differentiation; reversible impairment of fertility in males. -None of these findings in preclinical testing are considered to have relevance to the treatment of patients with advanced prostate cancer.

Atrophy of seminiferous tubules is a predicted class effect with antiandrogens and has been observed for all species examined. Full reversal of testicular atrophy was 24 weeks after a 12 - month repeated dose toxicity study in rats, although functional reversal was evident in reproduction studies 7 weeks after the end of an 11 week dosing period. A period of subfertility or infertility should be assumed in man. Genotoxicity studies did not reveal any mutagenic potential of bicalutamide.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Lactose monohydrate Povidone K- 25 Sodium starch glycolate Magnesium Stearate

Film-Coating:

Opadry OY-S-9622 consisting of: Hypromellose Titanium dioxide (E171) Propylene Glycol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

48 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

PVC/PVDC/Aluminium blisters

10, 28, 30 & 90 tablets contained in a carton. Not all pack sizes may be marketed

6.6 Special precautions for disposal

No special requirements.

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

7 MARKETING AUTHORISATION HOLDER

Hikma Farmaceutica S.A., Estrada do Rio da Mo 8, 8A e 8B - Ferven9a, 2705-906, Terrugem SNT, Portugal

8 MARKETING AUTHORISATION NUMBER(S)

PL 15413/0018

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 09/10/2008 Renewal of the authorisation: 09/10/2013

10 DATE OF REVISION OF THE TEXT

13/09/2016