Approval date: February 20, 2007
Revision date: Mar. 24, 2008
March 15, 2009
May 21, 2010
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February 02, 2016
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Instructions for Bicalutamide Tablets
Please read the instructions carefully and use under the guidance of a physician.
【Drug name】.
Generic name: bicalutamide tablets
Trade name: CASODEX
English Name: Bicalutamide Tablets
Hanyu Pinyin: Bikalu’an Pian
Ingredients
The main ingredient of this product is bicalutamide
Chemical name: (±)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide
Chemical structure formula.
Molecular formula: C18H14N2O4F4S
Molecular weight: 430.37
【Properties】.
This product is a white film-coated tablet, which appears white after removing the coating.
Indications
50mg daily: Used in combination with luteinizing hormone-releasing hormone (LHRH) analogue or surgical orchiectomy for the treatment of advanced prostate cancer.
150mg Daily: For the treatment of patients with locally advanced prostate cancer without distant metastases who are unsuitable or unwilling to undergo surgical debulking or other medical treatment.
【Specifications】.
(1)50mg (2)150mg
【Dosage】 (1)50mg tablet
50mg tablet
Combined with luteinizing hormone-releasing hormone (LHRH) analogue or surgical orchiectomy for the treatment of advanced prostate cancer.
Adult Adult men including the elderly: One tablet (50mg) once a day. Treatment with this product should be started at least 3 days before starting treatment with LHRH analogues or at the same time as surgical orchiectomy.
Children This product is contraindicated in children.
Renal impairment No dose adjustment is required for patients with renal impairment.
Hepatic impairment No dose adjustment is necessary for patients with mild hepatic impairment. Drug accumulation may occur in patients with moderate to severe hepatic impairment (see [Precautions]).
150mg Tablets
For the treatment of patients with locally advanced, non-distant metastatic prostate cancer who are unsuitable or unwilling to undergo surgical debulking or other medical therapy.
Adult men including the elderly: Take by mouth, three 50 mg tablets once a day or one 150 mg tablet once a day.
This product should be continued for at least two years or until disease progression.
Renal impairment: No dose adjustment is required for patients with renal impairment.
Hepatic impairment: No dose adjustment is required for patients with mild hepatic impairment; drug accumulation may occur in patients with moderate to severe hepatic impairment (see [Precautions])
[Adverse Reactions].
1) 50 mg daily for use in combination with luteinizing hormone-releasing hormone (LHRH) analogs or surgical orchiectomy in the treatment of advanced prostate cancer.
Adverse reactions are defined in this section as follows: very common (≥1/10); common (≥1/100 and<1/10); occasional (≥1/1,000 and<1/100); rare (≥1/10,000 and<1/1,000); very rare (<1/10,000); unknown (cannot be assessed based on available data)
Table I
Frequency of adverse reactions
System Organ Classification Frequency Events Blood and lymphatic system disorders Very common Anemia Immune system disorders Occasional hypersensitivity reactions, angioedema and urticaria Metabolic and nutritional disorders Common decreased appetite Psychiatric disorders Common decreased libido, depression Neurological disorders Very common Dizziness Common drowsiness Cardiac disorders Common myocardial infarction (fatal outcome has been reported)4.
Heart failure4 unknown QT prolongation (see [Precautions] and [Drug Interactions]). Vascular disease very common flushed breathing, thoracic and mediastinal disease occasionally interstitial lung disease5
Fatal outcomes have been reported Gastrointestinal disorders are very common Abdominal pain
Constipation
Nausea common indigestion
Gastrointestinal gas and bloating Hepatobiliary disease common Hepatotoxicity, jaundice, elevated transaminases1 Rarely Hepatic failure2 Fatal outcome has been reported Skin and subcutaneous tissue disease common Hair loss
Hirsutism/hair regrowth
Dry skin
Pruritus
Rash rare photosensitivity reactions renal and urinary disorders very common hematuria genital and breast disorders very common male breast development and breast tenderness3 common erectile dysfunction systemic and medication localized disorders very common weakness
Edema common chest pain physical examination common weight gain
Liver function changes are rare and severe. These changes are mostly transient and may subside or improve with continued or discontinued treatment.
Hepatic failure is extremely rare in patients treated with bicalutamide, and a causal relationship has not been established. Care should be taken to check liver function regularly (see [Precautions]).
It may abate with combined depot treatment.
In pharmacoepidemiologic studies of prostate cancer treated with LHRH analogs with anti-androgens, an increased risk appeared to be observed when using this product 50 mg in combination with LHRH analogs, but no significant increase in risk was observed when this product 150 mg was used alone for the treatment of prostate cancer.
After reviewing the post-marketing data, it was added to the list as an adverse drug reaction. The frequency of occurrence is episodic and is based on the incidence of interstitial pneumonia adverse events reported during the treatment phase of Comstock 150 mg in the randomized clinical study EPC.
2) 150 mg daily for the treatment of patients with locally advanced, non-distant metastatic prostate cancer who are not candidates for or do not wish to undergo surgical debulking or other medical therapy.
Very common (≥ 1/10).
Male breast development, breast tenderness. Most patients receiving monotherapy with this drug have experienced gynecomastia and/or breast tenderness. This symptom was more severe in 5% of the patients in the clinical study. Gynecomastia may not return spontaneously after discontinuation of treatment, especially after prolonged drug use.
Common (≥1/100 and<1/10).
Flushing, pruritus, debility, alopecia, hair regrowth, dry skin, decreased libido, nausea, impotence, and weight gain.
Occasionally (≥1/1,000 and<1/100).
Abdominal pain, depression, dyspepsia, hematuria, and interstitial lung disease.
Allergic reactions, including angioneurotic edema and urticaria.
Liver function changes (elevated transaminases, cholestasis and jaundice), rarely severe. These changes are mostly transient and may gradually subside or improve with continued or discontinued treatment.
Hepatic failure is extremely rare in patients treated with bicalutamide, and a causal relationship has not been established. Care should be taken to check liver function regularly (see [Precautions]).
Unknown (not predictable based on available data) QT prolongation (see [Precautions] and [Drug Interactions]).
Suspected adverse reaction reporting
Reporting of suspected adverse reactions after drug approval is important. It allows continuous monitoring of the benefit/risk balance of the drug. Drug manufacturers, operators and medical institutions should report through the national adverse drug reaction monitoring system in a timely manner.
[Contraindications].
This product is contraindicated in women and children (see section [Use in Pregnant and Lactating Women]).
This product should not be used in patients who are hypersensitive to the active ingredient or any of the excipients.
This product should not be used in combination with terfenadine, astemizole or cisapride (see Drug Interactions).
Precautions]
Treatment should be initiated under direct professional supervision.
This product is extensively metabolized in the liver. Data suggest that drug clearance may be slowed in patients with severe liver damage, which may lead to accumulation. Therefore, this product should be used with caution in patients with moderate to severe hepatic impairment.
Cases of death or hospitalization due to severe liver injury (liver failure) have been reported in post-marketing use of this product (see [ADVERSE REACTIONS]). These hepatotoxicities usually occur during the first 3-4 months of treatment. In controlled clinical trials approximately 1% of patients discontinued the drug due to hepatitis or significant liver enzyme elevation.
Serum transaminase levels should be tested prior to initiation of treatment with this product and at regular intervals during the first 4 months of treatment and thereafter. Serum transaminase levels, especially ALT, should be tested immediately if clinical signs or symptoms suggestive of hepatic insufficiency develop, such as nausea, vomiting, abdominal pain, malaise, anorexia, flu-like symptoms, dark urine, jaundice, or right upper abdominal tenderness. any time a patient develops jaundice, or if ALT rises more than two times the upper limit of normal, the drug should be discontinued immediately and liver function should be monitored on a follow-up basis.
Reduced glucose tolerance has been observed in men receiving LHRH agonists. In patients who have diabetes themselves, this may manifest as diabetes or hyperglycemia that is not well controlled. Therefore, monitoring of blood glucose should be considered in patients receiving this product in combination with an LHRH agonist.
This product has been shown to inhibit cytochrome P450 (CYP3A4) activity, so caution should be exercised when combined with drugs that are primarily metabolized by CYP3A4 (see [Contraindications] and [Drug Interactions]).
Patients with hereditary galactose intolerance, Lapp lactase deficiency, or impaired glucose-galactose absorption should not take this product.
When 150 mg daily is used for the treatment of locally advanced, non-distant metastatic prostate cancer, discontinuation of the drug should be considered in patients who develop objective disease progression with elevated prostate-specific antigen (PSA).
Rarely, photosensitivity reactions have been reported in patients taking Comstat 150 mg. Patients should be advised to avoid direct exposure to excessive sunlight or ultraviolet light while taking Comstat 150mg and to consider applying sunscreen. If photosensitivity reactions are prolonged and/or more severe, symptomatic treatment should be administered.
Androgen deprivation therapy may prolong the QT interval.
For patients with a history of QT interval prolongation, or with risk factors for QT interval prolongation, and for patients being treated with medications that may prolong the QT interval (see [Drug Interactions]), physicians should evaluate the benefit-risk ratio, including the possibility of tip-twisting ventricular tachycardia, prior to initiation of Comstock.
Effects on the ability to drive and operate machinery
This product does not affect the patient’s ability to drive or operate machinery. However, caution should be taken in patients who have experienced such effects as drowsiness may occasionally occur.
Pregnant women and nursing mothers
This product is contraindicated in women, and should not be used in pregnant women or nursing mothers.
For Children
This product is contraindicated in children. Please refer to the detailed description in the [Dosage] section.
Geriatric use
Please refer to the detailed description in [Dosage] section.
Drug Interactions
There are no pharmacodynamic or pharmacokinetic interactions between this product and LHRH analogs.
In vitro tests have shown that R-bicalutamide is an inhibitor of CYP3A4 and has a minor inhibitory effect on CYP2C9, 2C19 and 2D6 activity.
Although no evidence of a potential drug interaction with this product was found in clinical studies using antipyrine as a marker of cytochrome P450 (CYP) activity, the mean midazolam exposure level (AUC) increased by 80% after 28 days of combination use of this product. For drugs with a small therapeutic index range, the magnitude of this increase can be relevant. Therefore, the combination of terfenadine, astemizole or cisapride is contraindicated (see [Contraindications]) and caution should be exercised when this product is combined with cyclosporine and calcium channel blockers. Doses of these drugs may need to be reduced, especially if there are signs of increased efficacy or adverse drug reactions. For cyclosporine, close monitoring of plasma concentrations and clinical status is recommended at the beginning or end of treatment with cyclosporine.
Caution should be exercised when this product is used concomitantly with other drugs that inhibit drug oxidation, such as cimetidine and ketoconazole. This could theoretically cause an increase in plasma concentrations of the drug, which could theoretically increase the side effects of the drug.
In vitro studies have shown that this product can compete with coumarin-based anticoagulants, e.g., warfarin, for their protein binding sites. It is therefore recommended that prothrombin time should be closely monitored in patients already receiving coumarin-based anticoagulants if this product is started.
Because androgen deprivation therapy may prolong the QT interval, careful evaluation should be performed for the combination of Comstock with drugs known to prolong the QT interval or to induce tip-twisting ventricular tachycardia, such as class IA (e.g., quinidine, propyzamide) or class III (e.g., amiodarone, sotalol, dofetilide, ibrit) antiarrhythmic agents, methadone, moxifloxacin, and antipsychotics (see [ Precautions]).
Pediatric population
Interaction studies have been conducted only in adults.
Drug overdose]
There is no experience with overdose in humans, there is no specific antidote, and it should be treated symptomatically. Dialysis may not be helpful because the product is highly protein bound and excreted in the urine in a non-native form. However, general supportive therapy is needed, which includes close monitoring of vital signs.
Clinical trials]
1. 50 mg daily in combination with luteinizing hormone-releasing hormone (LHRH) analogue in advanced prostate cancer
In a multicenter, double-blind, controlled clinical trial, 813 patients with previously untreated advanced prostate cancer were randomly assigned to receive bicalutamide 50 mg administered once daily (404 patients) or flutamide 250 mg administered three times daily (409 patients) in combination with an LHRH analogue (goserelin acetate implant or leuprolide acetate long-acting formulation) in both groups. When analyzed after a median follow-up of 160 weeks, 213 cases (52.7%) in the bicalutamide group and 235 cases (57.5%) in the flutamide group died. There was no significant difference in survival between the two groups (HR=0.87, 95% CI: 0.72-1.05). There was also no significant difference in objective time to disease progression between the two groups (HR=0.93, 95% CI: 0.79-1.10). There was also no significant difference in quality of life assessment and treatment-related symptoms between the two groups.
2. 150 mg daily as a single agent in the treatment of patients with locally advanced prostate cancer without distant metastases
The results of three placebo-controlled, double-blind studies with 8113 patients in which 150 mg of this product was used for the treatment of limited (T1-T2, N0 or NX, M0) or locally advanced (T3-T4, any N; or any T, N+) non-metastatic prostate cancer (all M0) were combined and analyzed in studies in which this product was used as first-line hormonal therapy or as adjuvant therapy after prostatectomy or radiotherapy. At a median follow-up period of 9.7 years, objective disease progression was observed in 36.6% and 38.17% of patients treated with this product and placebo, respectively.
A decreased risk of disease progression was observed between most patient groups, but was particularly evident in those patients at high risk of disease progression, so clinicians should determine the best treatment option for patients at low risk of disease progression and should probably delay hormone therapy until symptoms of disease progression occur.
At a median follow-up of 9.7 years, no difference in overall survival was seen, with a mortality rate of 31.4% (HR=1.01; 95% CI 0.94 to 1.09). However, certain trends were seen in an exploratory analysis of some subgroups of patients receiving this product as monotherapy.
Patients with limited disease who received this product as monotherapy did not show a difference in progression-free survival compared with the placebo group. No difference in overall survival was also shown for patients who received bicalutamide as adjuvant therapy after radiotherapy (HR=0.98; 95% CI 0.80 to 1.20) or as adjuvant therapy after radical prostate cancer surgery (HR=1.03; 95% CI 0.85 to 1.25), while there was a trend toward decreased survival in the watchful waiting subgroup (HR=1.15; 95% CI of 1.00 to 1.32). In light of this, the risk-benefit ratio for the use of this product was not considered favorable for patients with limited disease.
Patients in the locally advanced watchful waiting subgroup receiving this product as monotherapy showed a trend toward improved survival compared with the placebo group (HR=0.81; 95% CI 0.66 to 1.01). Progression-free survival and overall survival data for patients with locally advanced prostate cancer can be seen in the following table.
Progression-free survival (PFS) data table for patients with locally advanced disease
Analysis population Treatment group 3-year PFS (%) 5-year PFS (%) 7-year PFS (%) 10-year PFS (%) Watchful waiting (n=657) Bicalutamide 150 mg 19.7% 36.3% 52.1% 73.2% Placebo 39.8% 59.7% 70.7% 79.1% Radiotherapy (n=305) Bicalutamide 150 mg 13.9% 33.0% 42.1% 62.7% placebo 30.7% 49.4% 58.6% 72.2% radical prostate cancer surgery (n=1719) bicalutamide 150mg 7.5% 14.4% 19.8% 29.9% placebo 11.7% 19.4% 23.2% 30.9%
Overall survival (OS) data table for patients with locally advanced disease
Analysis Population Treatment group 3-year OS (%) 5-year OS (%) 7-year OS (%) 10-year OS (%) Watchful waiting (n=657) Bicalutamide 150mg 14.2% 29.4% 42.2% 65.0% Placebo 17.0% 36.4% 53.7% 67.5% Radiotherapy (n=305) Bicalutamide 150mg 8.2% 20.9% 30.0%48.5% placebo12.6%23.1%38.1%53.3% radical prostate cancer surgery (n=1719)bicalutamide 150mg4.6%10.0%14.6%22.4% placebo4.2%8.7%12.6%20.2%
In another research project, the efficacy of bicalutamide 150 mg in treating patients with locally advanced non-metastatic prostate cancer (who were ordered to undergo immediate debulking surgery) was demonstrated by a combined analysis of two studies enrolling 480 patients with untreated locally advanced non-metastatic (M0) prostate cancer. At 56% mortality and a median follow-up period of 6.3 years, there was no significant difference in survival between treatment with this product compared with debulking surgery (HR=1.05; CI 0.81 to 1.36), but the two treatments could not yet be considered statistically equivalent.
A combined analysis of two studies enrolling 805 patients with untreated metastatic (M1) prostate cancer that reached a 43% mortality rate showed that treatment with Benadryl 150 mg was less effective than denervation surgery in terms of survival metrics (HR=1.30; CI 1.04 to 1.65), with an expected difference in time to death of 42 days (6 weeks) over a median survival period of 2 years .
The registered clinical trial in China was a randomized, open, multicenter study evaluating the efficacy and safety of bicalutamide 150 mg alone compared with drug depot treatment alone in 58 patients with TNM staging of T3 or T4, any N, M0 and PSA ≥10 μg/L for prostate cancer. The results showed that bicalutamide 150 mg monotherapy for 12 weeks resulted in 62.2% PSA suppression and 36.3% prostate volume reduction; similar efficacy compared to the current standard depot treatment. The overall safety profile of bicalutamide 150 mg was good, with no serious adverse events during treatment, and no subjects were suspended or withdrawn from the study due to adverse events. 2 drug-related adverse events were reported, mainly breast pain and gynecomastia.
Pharmacology and Toxicology
Pharmacological effects
It binds to androgen receptors without activating gene expression, thereby inhibiting the androgen stimulation that leads to prostate tumor shrinkage. Clinical discontinuation of this product can cause anti-androgen withdrawal syndrome in some patients.
It is a racemic substance, and its anti-androgenic effect occurs only on the (R)-structure enantiomer.
Toxicological studies
Bicalutamide is a potent antiandrogenic drug and is a mixed function oxidase inducer in animals. Changes in animal target organs, including tumor induction in animals (mesenchymal cells, thyroid, liver) have been associated with these effects. In humans, enzyme-inducing effects have not been found. Results from preclinical trials are not considered relevant for the treatment of patients with advanced prostate cancer. Atrophy of the fine seminiferous tubules is an effect that can be expected from anti-androgenic drugs and has been observed in test animals of all species. Testicular atrophy was fully restored in rats 24 weeks after 12 months of repeated dosing toxicity studies, and in reproduction studies, function was restored 7 weeks after 11 weeks of dosing. Therefore, a sub-fertility or non-fertility period was inferred in males.
Pharmacokinetics]
Absorption
This product is well absorbed by oral administration. There is no evidence of any clinically relevant effect of food on its bioavailability.
Distribution
The product is highly protein bound (96% racemization
(R)-enantiomer>99%) and is extensively metabolized (by oxidation and glucuronidation), and its metabolites are eliminated by the kidney and bile in almost equal proportions.
Biotransformation
The (S)-enantiomer is eliminated more rapidly than the (R)-enantiomer, which has a plasma clearance half-life of 1 week.
At daily (50 mg and 150 mg) doses of this product, the (R)-enantiomer accumulates in plasma approximately 10-fold due to its long half-life.
The steady-state plasma concentration of (R)-enantiomers was about 9 μg/ml when 50 mg of this product was administered daily, and the effective (R)-enantiomers accounted for 99% of the total circulating dose at steady state.
The steady-state plasma concentration of the (R)-enantiomer was approximately 22 μg/ml when 150 mg of this product was administered daily.
At steady state the effective (R)-enantiomer accounts for 99% of the total circulating dose.
Elimination
The mean concentration of R-bicalutamide in the semen of men treated with 150 mg of this drug was 4.9 μg/ml, and the amount reaching women through sexual intercourse was low at approximately 0.3 μg/kg. animal studies have shown that this concentration is insufficient to affect the offspring.
Special Populations
The pharmacokinetics of (R)-enantiomers are not affected by age, renal impairment or mild to moderate hepatic impairment. There is evidence of slower plasma clearance of (R)-enantiomers in cases of severe hepatic impairment.
Storage】Keep below 30°C
Storage
Package】Aluminum-plastic blister package, 28 tablets/box.
Expiration date
50mg tablet 60 months
150mg tablet 48 months
Execution Standard
Imported drug registration standard JX20140033
Imported drug registration number
50mg tablet H20140720
150mg tablet H20130043
Manufacturer
Manufacturer name: CORDEN PHARMA GMBH
Address of manufacturer: OTTO HAHN STRASSE, PLANKSTADT, D-68723, Germany
Name of packaging company: AstraZeneca UK Limited
Address of packaging company: Silk Road Business Park, Macclesfield, Cheshire, SK10 2NA, UK
China Liaison Office Address: No. 2 Huangshan Road, Wuxi New District, Jiangsu Province
Zip code: 214028
Quality complaint phone number: 400 828 1755, 800-828-1755
Product Information Toll Free: 800-820-8116, 400 820 8116
Fax number: 021-38723255
AstraZeneca’s website: http://www.astrazeneca.com.cn