Bicalutamide Kabi Trusted Generics: Total Care

ONCOLOGY

Bicalutamide Kabi Film-Coated Tablets Fresenius Kabi Deutschland GmbH Deutschland Kabi Fresenius

F HO O O F H Therapeutic class N S F Antiandrogen O

F Indications N 50 mg: Treatment of advanced prostate cancer in combination with LHRH analogue therapy or surgical castration. 150 mg: Bicalutamide Kabi 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. It is also indicated for the management of patients with locally advanced, non-metastatic prostate cancer for whom surgical castration or other medical intervention is not considered appropriate or acceptable.

Composition 50 mg: each film-coated tablet contains 50 mg bicalutamide 150 mg: each film-coated tablet contains 150 mg bicalutamide

Available Fresenius Kabi dosage forms Strength is denoted by color 50 mg film-coated tablets supplied in a strip of 10 or 14 tablets 150 mg film-coated tablets supplied in a strip of 10 or 14 tablets

Pack Size Bicalutamide Kabi 50mg: 28 / 30 / 90 tablets Bicalutamide Kabi 150 mg: 28 / 30 / 50 / 60 / 90 / 98 / 100 tablets Trusted Generics: Total Care

Bicalutamide in focus • Bicatulamide Kabi is the most frequently applied non-storoidal anti-androgen • Proven andorogen receptor inhibitor • Steady plasma concentrations maintained for 24 hours • Highly protein bound (96%) • Orally well absorbed and undergoes stereo specific metabolism

Survival curve

1.0 Clinical benefits of Bicalutamide compared with Flutamide in 0.9 combined androgen blockade for patients with advanced 0.8 prostatic carcinoma: final report 0.7 of double-blind, randomized, multicenter trial.

0.6 Paul F. Schellhammer, Roohollah Sharifi, Norman L. Block, Mark 0.5 S. Soloway, Peter M. Venner, 0.4 A. Lynn Patterson, Michael F. Sarosdy, Nicholas J. Vogelzang, 0.3 Julie Jones Schellenger, Geert J. C. M. Kolvenbag. For the Casodex Proportion surviving 0.2 Combination Study Group. Urology  Bicalutamide plus LHRH-A 50 (3), 1997. 0.1  Flutamide plus LHRH-A

0 0 365 730 1095 1450 1825 Day Kaplan-Meier distributions of survival time. LHRH-A = luteinizing hormone-releasing hormone analogue.

Dosage and administration Adult males including the elderly: 50 mg or 150 mg; one tablet once a day. Treatment with Bicalutamide Kabi 50 mg film-coated tablets should be started at least 3 days before commencing treatment with an LHRH analogue, or at the same time as surgical castration. Bicalutamide Kabi 150 mg tablets should be taken continuously for at least 2 years or until disease progression.

Storage and handling • Bicalutamide Kabi tablets should be stored at room temperature (15–30°C) • No special instructions for handling are required

Shelf-life 2 years Abridged SPC of Bicalutamide Kabi 50 mg Film-Coated Tablets Composition: Each tablet contains 50 mg bicatulamide. Also contains lactose monohydrate. Therapeutic Indications: Treatment of advanced prostate cancer in combination with LHRH analogue therapy or surgical castration. Posology and method of administration: Adult males including the elderly: one tablet (50 mg) once a day. Treatment with Bicalutamide 50 mg Film-Coated Tablets should be started at least 3 days before commencing treatment with an LHRH analogue, or at the same time as surgical castration. Children: Bicalutamide is contra-indicated in children. 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. Contraindications: Bicalutamide is contra-indicated in females and children. Bicalutamide must not be given to any patient who has shown a hypersensitivity reaction to bicalutamide or its excipients. Co-administration of terfenadine, astemizole or cisapride with bicalutamide is contra-indicated. Special warnings and precautions for use: 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 50 mg Film-Coated Tablets 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 have been observed rarely with bicalutamide. Bicalutamide therapy should be discontinued if changes are severe. 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. 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 contra-indicated and 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 cyclosporin, 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. It is therefore recommended that if Bicalutamide 50 mg Film-Coated Tablets treatment is started in patients who are already receiving coumarin anticoagulants, prothrombin time should be closely monitored.Abridged SPC of Bicalutamide 150 mg Film-Coated Tablets. Pregnancy and lactation: Bicalutamide is contra-indicated in females and must not be given to pregnant women or nursing mothers. 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. Any affected patients should exercise caution. Undesirable effects: The evaluation of adverse reactions is based on the following definition of frequency: 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). Very common  10%: Reproductive system and breast disorders: Breast tenderness. Gynaecomastia. General disorders: Hot flushes.Common 1% and  10%: Gastrointestinal disorders: Diarrhoea. Nausea. Hepato-biliary disorders: Hepatic changes (elevated levels of transaminases, cholestasis and jaundice). General disorders: Asthenia. Pruritus. Uncommon  0.1% and  1%: Immune system disorders: Hypersensitivity reactions, including angioneurotic oedema and urticaria. Respiratory, thoracic and mediastinal disorders: Interstitial lung disease. Rare  0.01% and  0.1%: Gastrointestinal disorders: Vomiting. Skin and subcutaneous tissue disorders: Dry skin. Hepato- biliary disorders: Hepatic failure. 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. List of excipients: Bicalutamide Film-Coated Tablets includes the following excipients: Tablet core: Lactose monohydrate, Sodium starch glycolate, Colloidal silicon dioxide, Povidone, Magnesium stearate. Film-coating: Opadry White Y-1-7000 (hypromellose, polyethylene glycol and titanium dioxide). Incompatibilities: None known. Shelf life: 2 years. Special precautions for storage: Do not store above 30 °C. Keep blister in the outer carton to protect from light.

Abridged SPC of Bicalutamide Kabi 150 mg Film-Coated Tablets Composition: Each tablet contains 150 mg bicatulamide. Also contains lactose monohydrate. 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. It is also indicated for the management of patients with locally advanced, non-metastatic prostate cancer for whom surgical castration or other medical intervention is not considered appropriate or acceptable. Posology and method of administration: Adult males including the elderly: one film-coated tablet 150 mg to be taken orally once a day with or without food.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). 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. Contraindications: Bicalutamide 150mg is contra-indicated in women, children and adolescents, in patients with hypersensitivity to the active substance or any of the excipients. Co-administration of terfenadine, astemizole or cisapride with Bicalutamide 150 mg is contraindicated. 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 suggest 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. 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 < 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 has been shown to inhibit cytochrome P450 (CYP 3A4), as such, caution should be exercised when co-administered with drugs metabolized predominantly by CYP 3A4. Bicalutamide 150 mg contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactosemalabsorption should not take this medicine.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 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 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. 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 150 mg is started in patients who are already receiving coumarin anticoagulants, prothrombin time should be closely monitored. Pregnancy and lactation: Bicalutamide is contra-indicated in females and must not be given to pregnant women or nursing mothers. 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. Any affected patients should exercise caution. Undesirable effects: The evaluation of adverse reactions is based on the following definition of frequency: 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). Very common  10%: Reproductive system and breast disorders: Breast tenderness. Gynaecomastia. General disorders: Hot flushes.Common 1% and  10%: Gastrointestinal disorders: Diarrhoea. Nausea. Hepato-biliary disorders: Hepatic changes (elevated levels of transaminases, cholestasis and jaundice). Skin and subcutaneous tissue disorders: Alopecia Hirsuitism/hair regrowth. Dry Skin. Renal and urinary disorders: Haematuria. Psychiatricdisorders: Decreased libido, Depression General disorders: Asthenia. Pruritus. Uncommon  0.1% and  1%: Immune system disorders: Hypersensitivity reactions, including angioneurotic oedema and urticaria. Respiratory, thoracic and mediastinal disorders: Interstitial lung disease. Rare  0.01% and  0.1%: Gastrointestinal disorders: Vomiting. Hepato-biliary disorders: Hepatic failure. 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. List of excipients: Bicalutamide Film- Coated Tablets includes the following excipients: Tablet core: Lactose monohydrate, Sodium starch glycolate, Colloidal silicon dioxide, Povidone, Magnesium Fresenius Kabi Deutschland GmbH Deutschland Kabi Fresenius stearate. Film-coating: Opadry White Y-1-7000 (hypromellose, polyethylene glycol and titanium dioxide). Incompatibilities: None known. Shelf life: 2 years.

Registered Product Information may differ in your country. For further information and before prescribing refer to the nationally approved SmPC. May 2010

Fresenius Kabi Deutschland GmbH Else-Kröner-Straße 1 61352 Bad Homburg v.d.H. Germany Phone: +49 (0) 61 72 686-0