Bicalutamide 150mg Film-Coated Tablets

Document: spc-doc_PL 31774-0019 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 the 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

Bicalutamide150 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

Posology

Paediatric population

Bicalutamide Bluefish is not indicated in children and adolescents. 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.

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 is contra-indicated in female and children(see section 4.6). Bicalutamide 150 mg must not be given to any patient who has shown a hypersensitivity reaction to the active substance or to any of the excipients listed in section 6.1

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

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 150 mg 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 150 mg and fatal outcomes have been reported (see section 4.8). Bicalutamide therapy should be discontinued if changes are severe.

As there is no experience with the use of bicalutamide in patients with severe renal impairment (creatinine clearance < 30ml/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 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). 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 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 coadministration 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 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 administering bicalutamide to patients taking medicinal products that inhibit the oxidation processes in the liver, 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. It is therefore recommended that if bicalutamide is started in patients who are already receiving coumarin anticoagulants, prothrombin time should be closely monitored.

4.6 Fertility, pregnancy and lactation

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

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 form the available data).

Table 1 Frequency of Adverse Reactions

System Organ Class	Frequency	Event
Blood and the lymphatic system disorders	Common	Anaemia
	Very rare	Thromb ocytopeni a
Immune system disorders	Uncommon	Hypersensitivity, angioedema and urticaria
Metabolism and nutrition disorders	Common	Decreased appetite, diabetes mellitus
	Uncommon	Hyperglycaemia, weight loss
Psychiatric disorders	Common	Decreased libido, depression
Nervous system disorders	Common	Dizziness, somnolence, insomnia
Cardiac disorders	Very rare	Angina, conduction defects including PR and QT interval prolongation, arrhythmias and non specific ECG changes
Vascular disorders	Common	Hot flush
Respiratory, thoracic and mediastinal disorders	Uncommon	Interstitial lung disease^e (fatal outcomes have been reported).
	Uncommon	Dyspnoea
Gastrointestinal disorders	Common	Abdominal pain, constipation, dyspepsia, flatulence, nausea, diarrhoea
	Uncommon	Dry mouth
	Rare	Vomiting
Hepato-biliary disorders	Common	Hepatotoxicity, jaundice, bilirubinemia, hepatomegaly, cholestasis, hypertransaminasaemia^a
	Rare	Hepatic failure^d (fatal outcomes have been reported).
Skin and subcutaneous tissue disorders	Very common	Rash
	Common	Alopecia, hirsuitism/hair re-growth, dry skin^c, pruritis, sweating
Renal and urinary disorders	Common	Haematuria

	Uncommon	Nocturia
Reproductive system and breast disorders	Very common	Gynaecomastia and breast tenderness^b
	Common	Erectile dysfunction, impotence
General disorders and administration site conditions	Very common	Asthenia
	Common	Chest pain, oedema, general pain, pelvic pain, chills
	Uncommon	Headache, pain in the back, neck pain
Investigations	Common	Weight increased

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

b. 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 .

c. 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.

d. 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.

e. 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.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

There is no human experience of over dosage. 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, antiadrogen, ATC code: L02BB03.

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 associated with the (R)- enantiomer.

Bicalutamide 150mg was studied as a treatment for patients with localized (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 8,113 patients, where the product was given as immediate hormone therapy or as adjuvant to radical prostatectomy or radiotherapy (primarily external beam radiation). At 7.4 years median followup, 27.4 % of all bicalutamide-treated patients and 30.7 % of all placebo-treated patients 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% confidence interval 0.91 to 1.09). However some trends were apparent for patients 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	ocally 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-bicalutamide 99.6%) 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. . Target organ changes, including tumour induction (Leydig cells, thyroid, liver in animals are clearly related to the primary and secondary pharmacological action of bicalutamide. Enzyme induction has not been observed in man and none of these findings is considered to have relevance to the treatment of patients with 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 (Type A)

Magnesium Stearate Film-Coating:

Opadry OY-S-9622 consisting of:

Hypromellose 5 Cp (E464)

Titanium dioxide (E171)

Propylene Glycol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 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

14, 28, 30, 90, 98, 100 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

Bluefish Pharmaceuticals AB Torsgatan 11, SE-111 23 Stockholm Sweden

8 MARKETING AUTHORISATION NUMBER(S)

PL 31774/0019

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

21/01/2014

10 DATE OF REVISION OF THE TEXT

21/04/2015