text:
Label: BICALUTAMIDE- bicalutamide tablet, film coated
- NDC Code(s): 0093-0220-01, 0093-0220-56
- Packager: Teva Pharmaceuticals USA Inc
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: None
- Marketing Status: Abbreviated New Drug Application
Drug Label Information
Updated 08/12
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BICALUTAMIDE tablets USP for oral use
Initial U.S. Approval: 1995INDICATIONS AND USAGE
- Bicalutamide 50 mg is an androgen receptor inhibitor indicated for use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analog for the treatment of Stage D2 metastatic carcinoma of the prostate.
- Bicalutamide 150 mg daily is not approved for use alone or with other treatments. (1)
The recommended dose for bicalutamide therapy in combination with an LHRH analog is one 50 mg tablet once daily (morning or evening). (2)
50 mg tablets (3)
- Severe hepatic injury and fatal hepatic failure have been observed. Monitor serum transaminase levels prior to starting treatment with bicalutamide, at regular intervals for the first four months of treatment and periodically thereafter, and for symptoms or signs suggestive of hepatic dysfunction. Use bicalutamide with caution in patients with hepatic impairment. (5.1)
- Gynecomastia and breast pain have been reported during treatment with bicalutamide 150 mg when used as a single agent. (5.2)
- Bicalutamide is used in combination with a LHRH agonist. LHRH agonists have been shown to cause a reduction in glucose tolerance in males. Consideration should be given to monitoring blood glucose in patients receiving bicalutamide in combination with LHRH agonists. (5.3)
- Monitoring Prostate Specific Antigen (PSA) is recommended. Evaluate for clinical progression if PSA increases. (5.4)
Adverse reactions that occurred in more than 10% of patients receiving bicalutamide plus an LHRH-A were: hot flashes, pain (including general, back, pelvic and abdominal), asthenia, constipation, infection, nausea, peripheral edema, dyspnea, diarrhea, hematuria, nocturia and anemia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at tel: 1-888-838-2872, X6351 or email@example.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
- Pediatric patients: Efficacy has not been demonstrated for the treatment of familial male-limited precocious puberty (testotoxicosis).(8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 8/2012
Close - FULL PRESCRIBING INFORMATION: CONTENTS*
2.1 Dosage Adjustment in Renal Impairment
2.2 Dosage Adjustment in Hepatic Impairment
4.1 Hypersensitivity
4.2 Women
4.3 Pregnancy
5.1 Hepatitis
5.2 Gynecomastia and Breast Pain
5.3 Glucose Tolerance
5.4 Laboratory Tests
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Renal Impairment
8.8 Women
12.1 Mechanism of Action
12.3 Pharmacokinetics
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14.1 Bicalutamide 50 mg Daily in Combination With an LHRH-A
14.2 Safety Data From Clinical Studies Using Bicalutamide 150 mg
16.1 Storage and Handling
Bicalutamide Tablets 50 mg 100s Label Text
- *
- Sections or subsections omitted from the full prescribing information are not listed.
Bicalutamide tablets 50 mg daily are indicated for use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analog for the treatment of Stage D2 metastatic carcinoma of the prostate.
Bicalutamide tablets 150 mg daily are not approved for use alone or with other treatments [see Clinical Studies (14.2)].
Close - 2 DOSAGE AND ADMINISTRATION
The recommended dose for bicalutamide therapy in combination with an LHRH analog is one 50 mg tablet once daily (morning or evening), with or without food. It is recommended that bicalutamide tablets USP be taken at the same time each day. Treatment with bicalutamide tablets USP should be started at the same time as treatment with an LHRH analog.
2.1 Dosage Adjustment in Renal Impairment
No dosage adjustment is necessary for patients with renal impairment [see Use in Specific Populations (8.7)].
2.2 Dosage Adjustment in Hepatic Impairment
No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. In patients with severe liver impairment (n = 4), although there was a 76% increase in the half-life (5.9 and 10.4 days for normal and impaired patients, respectively) of the active enantiomer of bicalutamide no dosage adjustment is necessary [see Use in Specific Populations (8.6)].
4.1 Hypersensitivity
Bicalutamide tablets are contraindicated in any patient who has shown a hypersensitivity reaction to the drug or any of the tablet's components. Hypersensitivity reactions including angioneurotic edema and urticaria have been reported [see Adverse Reactions (6.2)].
4.2 Women
Bicalutamide tablets have no indication for women, and should not be used in this population.
4.3 Pregnancy
Bicalutamide tablets may cause fetal harm when administered to a pregnant woman. Bicalutamide tablets are contraindicated in women, including those who are or may become pregnant. There are no studies in pregnant women using bicalutamide tablets. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].
5.1 Hepatitis
Cases of death or hospitalization due to severe liver injury (hepatic failure) have been reported postmarketing in association with the use of bicalutamide tablets. Hepatotoxicity in these reports generally occurred within the first three to four months of treatment. Hepatitis or marked increases in liver enzymes leading to drug discontinuation occurred in approximately 1% of bicalutamide tablet patients in controlled clinical trials.
Serum transaminase levels should be measured prior to starting treatment with bicalutamide tablets, at regular intervals for the first four months of treatment, and periodically thereafter. If clinical symptoms or signs suggestive of liver dysfunction occur (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, jaundice, or right upper quadrant tenderness), the serum transaminases, in particular the serum ALT, should be measured immediately. If at any time a patient has jaundice, or their ALT rises above two times the upper limit of normal, bicalutamide tablets should be immediately discontinued with close follow-up of liver function.
5.2 Gynecomastia and Breast Pain
In clinical trials with bicalutamide 150 mg as a single agent for prostate cancer, gynecomastia and breast pain have been reported in up to 38% and 39% of patients, respectively.
5.3 Glucose Tolerance
A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycemic control in those with preexisting diabetes. Consideration should therefore be given to monitoring blood glucose in patients receiving bicalutamide in combination with LHRH agonists.
5.4 Laboratory Tests
Regular assessments of serum Prostate Specific Antigen (PSA) may be helpful in monitoring the patient's response. If PSA levels rise during bicalutamide therapy, the patient should be evaluated for clinical progression. For patients who have objective progression of disease together with an elevated PSA, a treatment-free period of antiandrogen, while continuing the LHRH analog, may be considered.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
6.1 Clinical Trials Experience
In patients with advanced prostate cancer treated with bicalutamide in combination with an LHRH analog, the most frequent adverse reaction was hot flashes (53%).
In the multicenter, double-blind, controlled clinical trial comparing bicalutamide 50 mg once daily with flutamide 250 mg three times a day, each in combination with an LHRH analog, the following adverse reactions with an incidence of 5% or greater, regardless of causality, have been reported.
Table 1. Incidence of Adverse Reactions (≥ 5% in Either Treatment Group) Regardless of Causality Body System: Adverse Reaction Treatment Group Number of Patients (%) Bicalutamide Plus LHRH Analog Flutamide Plus LHRH Analog (n = 401) (n = 407) Body as a Whole Pain (General) 142 (35) 127 (31) Back Pain 102 (25) 105 (26) Asthenia 89 (22) 87 (21) Pelvic Pain 85 (21) 70 (17) Infection 71 (18) 57 (14) Abdominal Pain 46 (11) 46 (11) Chest Pain 34 (8) 34 (8) Headache 29 (7) 27 (7) Flu Syndrome 28 (7) 30 (7) Cardiovascular Hot Flashes 211 (53) 217 (53) Hypertension 34 (8) 29 (7) Digestive Constipation 87 (22) 69 (17) Nausea 62 (15) 58 (14) Diarrhea 49 (12) 107 (26) Increased Liver Enzyme Test 30 (7) 46 (11) Dyspepsia 30 (7) 23 (6) Flatulence 26 (6) 22 (5) Anorexia 25 (6) 29 (7) Vomiting 24 (6) 32 (8) Hemic and Lymphatic Anemia 45 (11) 53 (13) Metabolic and Nutritional Peripheral Edema 53 (13) 42 (10) Weight Loss 30 (7) 39 (10) Hyperglycemia 26 (6) 27 (7) Alkaline Phosphatase Increased 22 (5) 24 (6) Weight Gain 22 (5) 18 (4) Musculoskeletal Bone Pain 37 (9) 43 (11) Myasthenia 27 (7) 19 (5) Arthritis 21 (5) 29 (7) Pathological Fracture 17 (4) 32 (8) Nervous System Dizziness 41 (10) 35 (9) Paresthesia 31 (8) 40 (10) Insomnia 27 (7) 39 (10) Anxiety 20 (5) 9 (2) Depression 16 (4) 33 (8) Respiratory System Dyspnea 51 (13) 32 (8) Cough Increased 33 (8) 24 (6) Pharyngitis 32 (8) 23 (6) Bronchitis 24 (6) 22 (3) Pneumonia 18 (4) 19 (5) Rhinitis 15 (4) 22 (5) Skin and Appendages Rash 35 (9) 30 (7) Sweating 25 (6) 20 (5) Urogenital Nocturia 49 (12) 55 (14) Hematuria 48 (12) 26 (6) Urinary Tract Infection 35 (9) 36 (9) Gynecomastia 36 (9) 30 (7) Impotence 27 (7) 35 (9) Breast Pain 23 (6) 15 (4) Urinary Frequency 23 (6) 29 (7) Urinary Retention 20 (5) 14 (3) Urinary Impaired 19 (5) 15 (4) Urinary Incontinence 15 (4) 32 (8) Other adverse reactions (greater than or equal to 2%, but less than 5%) reported in the bicalutamide-LHRH analog treatment group are listed below by body system and are in order of decreasing frequency within each body system regardless of causality.
Body as a Whole: Neoplasm; Neck Pain; Fever; Chills; Sepsis; Hernia; Cyst
Cardiovascular: Angina Pectoris; Congestive Heart Failure; Myocardial Infarct; Heart Arrest; Coronary Artery Disorder; Syncope
Digestive: Melena; Rectal Hemorrhage; Dry Mouth; Dysphagia; Gastrointestinal Disorder; Periodontal Abscess; Gastrointestinal Carcinoma
Metabolic and Nutritional: Edema; BUN Increased; Creatinine Increased; Dehydration; Gout; Hypercholesteremia
Musculoskeletal: Myalgia; Leg Cramps
Nervous: Hypertonia; Confusion; Somnolence; Libido Decreased; Neuropathy; Nervousness
Respiratory: Lung Disorder; Asthma; Epistaxis; Sinusitis
Skin and Appendages: Dry Skin; Alopecia; Pruritus; Herpes Zoster; Skin Carcinoma; Skin Disorder
Special Senses: Cataract specified
Urogenital: Dysuria; Urinary Urgency; Hydronephrosis; Urinary Tract Disorder
Abnormal Laboratory Test Values:
Laboratory abnormalities including elevated AST, ALT, bilirubin, BUN, and creatinine and decreased hemoglobin and white cell count have been reported in both bicalutamide-LHRH analog treated and flutamide-LHRH analog treated patients.
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of bicalutamide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Uncommon cases of hypersensitivity reactions, including angioneurotic edema and urticaria have been seen [seeContraindications (4.1)]. Cases of interstitial lung disease (some fatal), including interstitial pneumonitis and pulmonary fibrosis, have been reported with bicalutamide. Interstitial lung disease has been reported most often at doses greater than 50 mg. A few cases of fatal hepatic failure have been reported.
Reduction in glucose tolerance, manifesting as diabetes or a loss of glycemic control in those with preexisting diabetes, has been reported during treatment with LHRH agonists.
Clinical studies have not shown any drug interactions between bicalutamide and LHRH analogs (goserelin or leuprolide). There is no evidence that bicalutamide induces hepatic enzymes.
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. Clinical studies have shown that with coadministration of bicalutamide, mean midazolam (a CYP 3A4 substrate) levels may be increased 1.5 fold (for Cmax) and 1.9 fold (for AUC). Hence, caution should be exercised when bicalutamide is coadministered with CYP 3A4 substrates.
In vitro protein-binding studies have shown that bicalutamide can displace coumarin anticoagulants from binding sites. Prothrombin times should be closely monitored in patients already receiving coumarin anticoagulants who are started on bicalutamide and adjustment of the anticoagulant dose may be necessary.
Close - 8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Teratogenic Effects
Pregnancy category X
[See Contraindications (4.3)]. Based on its mechanism of action, bicalutamide may cause fetal harm when administered to a pregnant woman. Bicalutamide is contraindicated in women, including those who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
While there are no human data on the use of bicalutamide in pregnancy and bicalutamide is not for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus.
In animal reproduction studies, male offspring of rats receiving doses of 10 mg/kg/day (approximately 2/3 of clinical exposure at the recommended dose) and above, were observed to have reduced anogenital distance and hypospadias. These pharmacological effects have been observed with other antiandrogens. No other teratogenic effects were observed in rabbits receiving doses up to 200 mg/kg/day (approximately 1/3 of clinical exposure at the recommended dose) or rats receiving doses up to 250 mg/kg/day (approximately 2 times the clinical exposure at the recommended dose).
8.4 Pediatric Use
The safety and effectiveness of bicalutamide in pediatric patients have not been established.
Bicalutamide orodispersible tablet was studied in combination with anastrozole orodispersible tablet in an open-label, non-comparative, multi-center study that assessed the efficacy and safety of this combination regimen over 12 months in the treatment of gonadotropin-independent precocious puberty in boys with familial male-limited precocious puberty, also known as testotoxicosis. Patients were enrolled in the study if they had a baseline age ≥ 2 years and a diagnosis of testotoxicosis based on clinical features of progressive precocious puberty, symmetrical testicular enlargement, advanced bone age, pubertal levels of serum testosterone, prepubertal pattern of gonadotropin secretion following a GnRH stimulation test, and absence of other clinical and biochemical causes of testosterone excess. Thirteen out of the 14 patients enrolled completed 12 months of combination treatment (one patient was lost to follow-up). If central precocious puberty (CPP) developed an LHRH analog was to be added. Four patients were diagnosed with CPP during the 12 month study and received LHRH analog treatment and 2 additional patients were diagnosed at the end of the 12 months and received treatment subsequently. Mean ± SD characteristics at baseline were as follows: chronological age: 3.9 ± 1.9 years; bone age 8.8 ± 2.5; bone age/chronological age ratio: 2.06 ± 0.51; growth rate (cm/yr): 10.81 ± 4.22; growth rate standard deviation score (SDS): 0.41 ± 1.36.
The starting bicalutamide dose was 12.5 mg. Bicalutamide was titrated in each patient until steady-state R-bicalutamide (the active isomer of bicalutamide) trough plasma concentration reached 5 to 15 mcg/mL, which is the range of therapeutic concentrations achieved in adults with prostate cancer following the administration of the currently approved bicalutamide dose of 50 mg. The starting daily dose of anastrozole was 0.5 mg. Anastrozole was independently titrated in each patient until it reached at steady-state a serum estradiol concentration of < 10 pmol/L (2.7 pg/mL). The following ascending doses were used for bicalutamide: 12.5 mg, 25 mg, 50 mg, and 100 mg. For anastrozole there were two ascending doses: 0.5 mg and 1 mg. At the end of the titration phase 1 patient was on 12.5 mg bicalutamide, 8 patients were on 50 mg bicalutamide, and 4 patients were on 100 mg bicalutamide; 10 patients were on 0.5 mg anastrozole and 3 patients were on 1 mg anastrozole. In the majority of patients, steady-state trough concentrations of R-bicalutamide appeared to be attained by Day 21 with once daily dosing. Steady-state trough plasma anastrozole concentrations appeared to be attained by Day 8.
The primary efficacy analysis of the study was to assess the change in growth rate after 12 months of treatment, relative to the growth rate during the ≥ 6 months prior to entering the study. Pre-study growth rates were obtained retrospectively. There was no statistical evidence that the growth rate was reduced during treatment. During bicalutamide/anastrozole treatment the mean growth rate (cm/yr) decreased by 1.6 cm/year, 95% CI (-4.7 to 1.5) p = 0.28; the mean growth rate SDS decreased by 0.1 SD, 95% CI (–1.2 to 1) p = 0.88. Table 2 shows descriptive data for growth rates for the overall population and for subgroups defined by history of previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors.
Table 2. Growth Rates - *
- 1 Change compared to pre-study growth rate
- †
- 2 PT = Previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrazole or other aromatase inhibitors
- ‡
- 4Median calculated as midpoint of 3 rd and 4 th ranked observations
- §
- 3 NPT = no previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors
Endpoint Analysis Population Pre-study Mean Change From Pre-study to 12 Months % Patients With Growth Reduction1* Mean Median (Min, Max) Growth rate (cm/yr) All treated (n = 13) 10.8 -1.6 -2.8 (-7.4, 8.4) 9/13 (69%) PT2† (n = 6) 10.3 -0.2 -2.64‡ (-7.2, 8.4) 4/6 (67%) NPT3§ (n = 7) 11.2 -2.8 -2.8 (-7.4, 1.1) 5/7 (71%) Growth rate (SD units) All treated (n = 13) 0.4 -0.1 -0.4 (-2.7, 3.5) 9/13 (69%) PT2† (n = 6) -0.1 +0.7 -0.24‡ (-1.6, 3.5) 4/6 (67%) NPT3§ (n = 7) 0.8 -0.7 -0.4 (-2.7, 0.5) 5/7 (71%) Total testosterone concentrations increased by a mean of 5 mmol/L over the 12 months of treatment from a baseline mean of 10 mmol/L. Estradiol concentrations were at or below the level of quantification (9.81 pmol/L) for 11 of 12 patients after 12 months of treatment. Six of the 12 patients started treatment at an estradiol concentration below the level of quantification.
There were no deaths, serious adverse events, or discontinuations due to adverse events during the study. Of the 14 patients exposed to study treatment, 13 (92.9%) experienced at least one adverse event. The most frequently reported (> 3 patients) adverse events were gynecomastia (7/14, 50%), central precocious puberty (6/14, 43%), vomiting (5/14, 36%), headache (3/14, 21%), pyrexia (3/14, 21%) and upper respiratory tract infection (3/14, 21%). Adverse reactions considered possibly related to bicalutamide by investigators included gynecomastia (6/14, 43%), central precocious puberty (2/14, 14%), breast tenderness (2/14, 14%), breast pain (1/14, 7%), asthenia (1/14, 7%), increased alanine aminotransferase [ALT] (1/14, 7%), increased aspartate aminotransferase [AST] (1/14, 7%), and musculoskeletal chest pain (1/14, 7%). Headache was the only adverse reaction considered possibly related to anastrazole by investigators. For the patient who developed elevated ALT and AST, the elevation was < 3X ULN, and returned to normal without stopping treatment; there was no concomitant elevation in total bilirubin.
8.5 Geriatric Use
In two studies in patients given 50 or 150 mg daily, no significant relationship between age and steady-state levels of total bicalutamide or the active R-enantiomer has been shown.
8.6 Hepatic Impairment
Bicalutamide should be used with caution in patients with moderate-to-severe hepatic impairment. Bicalutamide is extensively metabolized by the liver. Limited data in subjects with severe hepatic impairment suggest that excretion of bicalutamide may be delayed and could lead to further accumulation. Periodic liver function tests should be considered for hepatic-impaired patients on long-term therapy [see Warnings and Precautions (5.1)].
No clinically significant difference in the pharmacokinetics of either enantiomer of bicalutamide was noted in patients with mild-to-moderate hepatic disease as compared to healthy controls. However, the half-life of the R-enantiomer was increased approximately 76% (5.9 and 10.4 days for normal and impaired patients, respectively) in patients with severe liver disease (n = 4).
8.7 Renal Impairment
Renal impairment (as measured by creatinine clearance) had no significant effect on the elimination of total bicalutamide or the active R-enantiomer.
Long-term clinical trials have been conducted with dosages up to 200 mg of bicalutamide daily and these dosages have been well tolerated. A single dose of bicalutamide that results in symptoms of an overdose considered to be life threatening has not been established.
There is no specific antidote; treatment of an overdose should be symptomatic.
In the management of an overdose with bicalutamide, vomiting may be induced if the patient is alert. It should be remembered that, in this patient population, multiple drugs may have been taken. Dialysis is not likely to be helpful since bicalutamide is highly protein bound and is extensively metabolized. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.
Close - 11 DESCRIPTION
Bicalutamide tablets USP contain 50 mg of bicalutamide USP, a non-steroidal androgen receptor inhibitor with no other known endocrine activity. The chemical name is propanamide, N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-,(+-). The structural formula is:
The pKa' is approximately 12. Bicalutamide USP is a fine white to off-white powder which is practically insoluble in water at 37°C (5 mg per 1000 mL), slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and soluble in acetone and tetrahydrofuran.
Bicalutamide tablets USP are a racemate with their antiandrogenic activity being almost exclusively exhibited by the R-enantiomer of bicalutamide USP; the S-enantiomer is essentially inactive.
The inactive ingredients of bicalutamide tablets USP are: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol 4000, povidone, sodium lauryl sulfate, and titanium dioxide.
Close - 12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Bicalutamide is a non-steroidal androgen receptor inhibitor. It competitively inhibits the action of androgens by binding to cytosol androgen receptors in the target tissue. Prostatic carcinoma is known to be androgen sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen.
When bicalutamide is combined with luteinizing hormone-releasing hormone (LHRH) analog therapy, the suppression of serum testosterone induced by the LHRH analog is not affected. However, in clinical trials with bicalutamide as a single agent for prostate cancer, rises in serum testosterone and estradiol have been noted.
In a subset of patients who have been treated with bicalutamide and an LHRH agonist, and who discontinue bicalutamide therapy due to progressive advanced prostate cancer, a reduction in Prostate Specific Antigen (PSA) and/or clinical improvement (antiandrogen withdrawal phenomenon) may be observed.
12.3 Pharmacokinetics
Bicalutamide is well-absorbed following oral administration, although the absolute bioavailability is unknown. Coadministration of bicalutamide with food has no clinically significant effect on rate or extent of absorption.
Bicalutamide is highly protein-bound (96%) [see Drug Interactions (7)].
Bicalutamide undergoes stereospecific metabolism. The S (inactive) isomer is metabolized primarily by glucuronidation. The R (active) isomer also undergoes glucuronidation but is predominantly oxidized to an inactive metabolite followed by glucuronidation. Both the parent and metabolite glucuronides are eliminated in the urine and feces. The S-enantiomer is rapidly cleared relative to the R-enantiomer, with the R-enantiomer accounting for about 99% of total steady-state plasma levels.
Pharmacokinetics of the active enantiomer of bicalutamide in normal males and patients with prostate cancer are presented in Table 3.
Table 3 Parameter Mean Standard Deviation Normal Males (n = 30) Apparent Oral Clearance (L/hr) 0.320 0.103 Single Dose Peak Concentration (mcg/mL) 0.768 0.178 Single Dose Time to Peak Concentration (hours) 31.3 14.6 Half-life (days) 5.8 2.29 Patients with Prostate Cancer (n = 40) Css (mcg/mL) 8.939 3.504 - 13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Two-year oral carcinogenicity studies were conducted in both male and female rats and mice at doses of 5, 15 or 75 mg/kg/day of bicalutamide. A variety of tumor target organ effects were identified and were attributed to the antiandrogenicity of bicalutamide, namely, testicular benign interstitial (Leydig) cell tumors in male rats at all dose levels (the steady-state plasma concentration with the 5 mg/kg/day dose is approximately 2/3 human therapeutic concentrations*) and uterine adenocarcinoma in female rats at 75 mg/kg/day (approximately 1 1/2 times the human therapeutic concentrations*). There is no evidence of Leydig cell hyperplasia in patients; uterine tumors are not relevant to the indicated patient population.
A small increase in the incidence of hepatocellular carcinoma in male mice given 75 mg/kg/day of bicalutamide (approximately 4 times human therapeutic concentrations*) and an increased incidence of benign thyroid follicular cell adenomas in rats given 5 mg/kg/day (approximately 2/3 human therapeutic concentrations*) and above were recorded. These neoplastic changes were progressions of non-neoplastic changes related to hepatic enzyme induction observed in animal toxicity studies. Enzyme induction has not been observed following bicalutamide administration in man. There were no tumorigenic effects suggestive of genotoxic carcinogenesis.
A comprehensive battery of both in vitro and in vivo genotoxicity tests (yeast gene conversion, Ames, E. coli, CHO/HGPRT, human lymphocyte cytogenetic, mouse micronucleus, and rat bone marrow cytogenetic tests) has demonstrated that bicalutamide does not have genotoxic activity.
Administration of bicalutamide may lead to inhibition of spermatogenesis. The long-term effects of bicalutamide on male fertility have not been studied.
In male rats dosed at 250 mg/kg/day (approximately 2 times human therapeutic concentrations*), the precoital interval and time to successful mating were increased in the first pairing but no effects on fertility following successful mating were seen. These effects were reversed by 7 weeks after the end of an 11 week period of dosing.
No effects on female rats dosed at 10, 50 and 250 mg/kg/day (approximately 2/3, 1 and 2 times human therapeutic concentrations, respectively*) or their female offspring were observed. Administration of bicalutamide to pregnant females resulted in feminization of the male offspring leading to hypospadias at all dose levels. Affected male offspring were also impotent.
*Based on a maximum dose of 50 mg/day of bicalutamide for an average 70 kg patient.
14.1 Bicalutamide 50 mg Daily in Combination With an LHRH-A
In a multicenter, double-blind, controlled clinical trial, 813 patients with previously untreated advanced prostate cancer were randomized to receive bicalutamide 50 mg once daily (404 patients) or flutamide 250 mg (409 patients) three times a day, each in combination with LHRH analogs (either goserelin acetate implant or leuprolide acetate depot).
In an analysis conducted after a median follow-up of 160 weeks was reached, 213 (52.7%) patients treated with bicalutamide-LHRH analog therapy and 235 (57.5%) patients treated with flutamide-LHRH analog therapy had died. There was no significant difference in survival between treatment groups (see Figure 1). The hazard ratio for time to death (survival) was 0.87 (95% confidence interval 0.72 to 1.05).
Figure 1 - The Kaplan-Meier Probability of Death for Both Antiandrogen Treatment Groups.
There was no significant difference in time to objective tumor progression between treatment groups (see Figure 2). Objective tumor progression was defined as the appearance of any bone metastases or the worsening of any existing bone metastases on bone scan attributable to metastatic disease, or an increase by 25% or more of any existing measurable extraskeletal metastases. The hazard ratio for time to progression of bicalutamide plus LHRH analog to that of flutamide plus LHRH analog was 0.93 (95% confidence interval, 0.79 to 1.10).
Figure 2 - Kaplan-Meier Curve for Time to Progression for Both Antiandrogen Treatment Groups.
Quality of life was assessed with self-administered patient questionnaires on pain, social functioning, emotional well being, vitality, activity limitation, bed disability, overall health, physical capacity, general symptoms, and treatment related symptoms. Assessment of the Quality of Life questionnaires did not indicate consistent significant differences between the two treatment groups.
14.2 Safety Data From Clinical Studies Using Bicalutamide 150 mg
Bicalutamide 150 mg is not approved for use either alone or with other treatments.
Two identical multicenter, randomized, open-label trials comparing bicalutamide 150 mg daily monotherapy to castration were conducted in patients that had locally advanced (T3-4, NX, MO) or metastatic (M1) prostate cancer.
Monotherapy — M1 Group
Bicalutamide 150 mg daily is not approved for use in patients with M1 cancer of the prostate. Based on an interim analysis of the two trials for survival, the Data Safety Monitoring Board recommended that bicalutamide treatment be discontinued in the M1 patients because the risk of death was 25% (HR 1.25, 95% CI 0.87 to 1.81) and 31% (HR 1.31, 95% CI 0.97 to 1.77) higher in the bicalutamide treated group compared to that in the castrated group, respectively.
Locally Advanced (T3-4, NX, MO) Group
Bicalutamide 150 mg daily is not approved for use in patients with locally advanced (T3-4, NX, MO) cancer of the prostate. Following discontinuation of all M1 patients, the trials continued with the T3-4, NX, MO patients until study completion. In the larger trial (N = 352), the risk of death was 25% (HR 1.25, 95% CI 0.92 to 1.71) higher in the bicalutamide group and in the smaller trial (N = 140), the risk of death was 36% (HR 0.64, 95% CI, 0.39 to 1.03) lower in the bicalutamide group.
In addition to the above two studies, there are three other on-going clinical studies that provide additional safety information for bicalutamide 150 mg, a dose that is not approved for use. These are three multicenter, randomized, double-blind, parallel group trials comparing bicalutamide 150 mg daily monotherapy (adjuvant to previous therapy or under watchful waiting) with placebo, for death or time to disease progression, in a population of 8113 patients with localized or locally advanced prostate cancer.
Bicalutamide 150 mg daily is not approved for use as therapy for patients with localized prostate cancer who are candidates for watchful waiting. Data from a planned subgroup analysis of two of these trials in 1627 patients with localized prostate cancer who were under watchful waiting, revealed a trend toward decreased survival in the bicalutamide arm after a median follow-up of 7.4 years. There were 294 (37.7%) deaths in the bicalutamide treated patients versus 279 (32.9%) deaths in the placebo treated patients (localized watchful waiting group) for a hazard ratio of 1.16 (95% CI 0.99 to 1.37).
Bicalutamide tablets USP are available as follows:
50 mg - white to off-white, film-coated, round tablets, debossed with "93" on one side and "220" on the other side, in bottles of 30 and 100.
16.1 Storage and Handling
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
Patients should be informed that therapy with bicalutamide and the LHRH analog should be started at the same time and that they should not interrupt or stop taking these medications without consulting their physician.
During treatment with bicalutamide, somnolence has been reported, and those patients who experience this symptom should observe caution when driving or operating machines.
Patients should be informed that diabetes, or loss of glycemic control in patients with preexisting diabetes has been reported during treatment with LHRH agonists. Consideration should therefore be given to monitoring blood glucose in patients receiving bicalutamide in combination with LHRH agonists.
Manufactured In Israel By:
Jerusalem, 91010, Israel
Manufactured For:
Sellersville, PA 18960
Rev. D 5/2012
Close - PATIENT PACKAGE INSERT
Patient Information
Bicalutamide Tablets USP
Read the Patient Information that comes with bicalutamide tablets before you start taking them and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment.
What are bicalutamide tablets?
Bicalutamide tablets are a prescription medicine called an androgen receptor inhibitor, used in combination with luteinizing hormone-releasing hormone (LHRH) medicines to treat stage D2 metastatic prostate cancer. It is not known if bicalutamide tablets are safe and effective in children.
Who should not take bicalutamide tablets?
Do not take bicalutamide tablets if:
- you are a woman.
- you are allergic to any of the ingredients in bicalutamide tablets. See the end of this leaflet for a complete list of ingredients.
What should I tell my healthcare provider before taking bicalutamide tablets?
Before you take bicalutamide tablets, tell your healthcare provider about all your medical conditions including if you:
- are a woman (see "Who should not take bicalutamide tablets?").
- are pregnant or think you may be pregnant.
- have liver problems.
- take a medicine to thin your blood. Ask your healthcare provider or pharmacist if you are not sure if your medicine is a blood thinner.
- have diabetes (poor blood sugar control has been reported in people taking bicalutamide tablets in combination with LHRH medicines).
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Bicalutamide tablets and other medicines may affect each other causing side effects. Bicalutamide tablets may affect the way other medicines work, and other medicines may affect how bicalutamide tablets work.
Know the medicines you take. Keep a list of your medicines with you to show your healthcare providers when you get a new medicine.
How should I take bicalutamide tablets?
- Take bicalutamide tablets exactly as prescribed.
- Take bicalutamide tablets at the same time everyday.
- Your treatment with bicalutamide tablets should start at the same time as your treatment with the LHRH medicine.
- If you miss a dose do not take an extra dose, take the next dose at your regular time. Do not take 2 doses at the same time.
- Bicalutamide tablets can be taken with or without food.
- If you take too many bicalutamide tablets, call your healthcare provider or Poison Control Center or go to the nearest hospital emergency room right away.
- Do not stop taking bicalutamide tablets unless your healthcare provider tells you.
- Your healthcare provider may do blood tests while you take bicalutamide tablets.
- Your prostate cancer may get worse while taking bicalutamide tablets in combination with LHRH medicines. Regular monitoring of your prostate cancer with your healthcare provider is important to determine if your disease is worse.
What should I avoid while taking bicalutamide tablets?
Driving and operating machinery. Do not drive, operate machinery, or do other dangerous activities until you know how bicalutamide tablets affect you.
What are the possible side effects of bicalutamide tablets?
Bicalutamide tablets can cause serious side effects.
Get medical help right away, if you have:
- Trouble breathing with or without a cough or fever. Some people who take bicalutamide tablets get an inflammation in the lungs called interstitial lung disease.
- An allergic reaction. Symptoms of an allergic reaction include: itching of the skin, hives (raised bumps), swelling of the face, lips, tongue, throat, or trouble swallowing.
- Yellowing of the skin and eyes (jaundice), dark urine, right upper stomach pain, nausea, vomiting, tiredness, loss of appetite, chills, fever, whole body pain. These may be symptoms of liver damage.
- Poor blood sugar control can happen in people who take bicalutamide tablets in combination with LHRH medicines.
- Enlargement of breast (gynecomastia) and breast pain.
The most common side effects of bicalutamide tablets include:
- hot flashes, or short periods of feeling warm and sweating
- whole body pain in your back, pelvis, stomach
- feeling weak
- constipation
- infection
- nausea
- swelling in your ankles, legs or feet
- diarrhea
- blood in your urine
- waking from sleep to urinate at night
- a decrease in red blood cells (anemia)
- feeling dizzy
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of bicalutamide tablets. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Store bicalutamide tablets between 20°C to 25°C (68°F to 77°F).
Keep bicalutamide tablets and all medicines out of the reach of children.
General information about the safe and effective use of bicalutamide tablets.
Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use bicalutamide tablets for a condition for which they were not prescribed. Do not give bicalutamide tablets to other people, even if they have the same symptoms that you have. They may harm them.
This patient information leaflet summarizes the most important information about bicalutamide tablets. If you would like more information about bicalutamide tablets talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about bicalutamide tablets that is written for health professionals. For more information call 1-888-838-2872, MEDICAL AFFAIRS.
What are the ingredients in bicalutamide tablets USP?
Active ingredients include: bicalutamide.
Inactive ingredients include: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol 4000, povidone, sodium lauryl sulfate, and titanium dioxide.
Manufactured In Israel By:
Jerusalem, 91010, Israel
Manufactured For:
Sellersville, PA 18960
Rev. B 9/2010
Close - PRINCIPAL DISPLAY PANEL
Bicalutamide Tablets 50 mg 100s Label Text
Tablets USP
50 mg
Rx only
bicalutamide tablet, film coatedProduct Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0093-0220 Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BICALUTAMIDE (BICALUTAMIDE) BICALUTAMIDE 50 mg Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE CROSCARMELLOSE SODIUM HYPROMELLOSES LACTOSE MONOHYDRATE MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE POLYDEXTROSE POLYETHYLENE GLYCOL 4000 POVIDONE SODIUM LAURYL SULFATE TITANIUM DIOXIDE Product Characteristics Color WHITE (white to off-white) Score no score Shape ROUND Size 7mm Flavor Imprint Code 93;220 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0093-0220-56 30 in 1 BOTTLE 2 NDC:0093-0220-01 100 in 1 BOTTLE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076932 07/06/2009 Labeler - Teva Pharmaceuticals USA Inc (118234421)


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1 | Hi yes its correct but no need to wipe any things... Hi if your rom is deodex you can... You have odex rom?? Goodluck Armin. Sent from my GT-I9100 using xda premium Hi, i am on stock, guess it is odex... I will find a deod... | View... |
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subset: commoncrawl


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Red Bull driver David Coulthard takes his RB7 racing machine on a tour through NJ's suburban neighborhoods before speeding through NYC's Lincoln Tunnel. Nothing ends a victorious run through one of NYC's most congested traffic channels like burning some donuts with Lady Liberty in the background.
Moto Video
So This is What it Looks Like Taking a Race Car Through the Lincoln Tunnel
From Around the Web


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Future Fund boosts infrastructure, property
PUBLISHED: 28 Jan 2011 16:40:47 | UPDATED: 02 Feb 2011 16:01:47PRINT EDITION: 28 Jan 2011The Future Fund more than doubled its exposure to infrastructure and direct property in 2010 as it further reduced its stake in telecoms behemoth Telstra.
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Companies | Telstra Corporation. |
People | David Murray |
Topics | Financial Services Industry, Financial Markets, Politics /Federal Politics |


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Guide: Day Hikers' Ten Essentials If you're just getting into hiking, everyone is going to recommend that you pack the 10 Essentials when you go for a hike. Then they list about 30 pieces of gear that you should bring with you, but they never… Permalink
Running Tips By: John Sahadi – Buyer While road-runners are getting lighter with their footwear choices; the trend is "hitting the trails" too. Before your next trail run , stop by one of our locations and try a pair on! When running trails,… Permalink


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Need Help? Call 877-778-7845
MULTI-Level, MULTI-Play, and MULTI-Purpose!
The most powerful, all-in-one percussion pad that suits anyone from a beginner to an expert, accommodating different levels of playing, a wide variety of playing styles and performance situations.
DTX-MULTI 12 equips the 12 pads which are easy to be distinguished even at the dark stage. You can use the DTX-MULTI 12 in a variety of ways, such as using the percussion pad in combination with acoustic drums and percussion to accent music with a rich variety of voices, transferring data to the connected computer where you can compose music with the included "Cubase AI 5" program, and connecting a kick pedal (sold separately) to create as a compact drum set
Pad section
Tone generator
Trigger section
The System Requrements of Cubase AI is Here (www.steinberg.net)
MAT1 Attachment to combine DTX-MULTI12 and PS940
PS940 Stand for DTX-MULTI12 (PS940 requires MAT1 for mounting MAT1)
HH65 Hi-hat controller which can produce a full range of hi-hat effects such as full open, full closed, half open, and foot splash.
KP65 Large rubber kick pad which is big enough for a double foot pedal setup. Plays quietly with very natural feel.
FC7 For those electronic keyboards with an input jack labeled "FOOT CONTROLLER", the FC7 is used as Volume, Expression and Assignable controller. FC7 also has a fortissimo function, which enables you to accent certain parts of your performance.Also, the pedal angle is adjustable for seated or standing performance.
Cubase AI 5 Cubase AI 5 is a special, compact version of Steinberg's famed music production system.


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"The harder you work, the luckier you get." by Gary Player
Below is the poem entitled Bridge which was written by poet Miyuki Akimitsu. Please feel free to comment on this poem. However, please remember, PoetrySoup is a place of encouragement and growth.
Read Poems by Miyuki Akimitsu
Best Miyuki Akimitsu Poems
1 am in the morning No noises fill the air Sitting on the bridge He thinks Remembering everything He has ever done The street lights Glowing from a distance He stands up Climbs over the side Of the bridge Stands there He breathes in His last memory stuck in his head He lifts one foot And jumps his body hits the river Water drowning his lungs What he felt at that moment No one could understand Sinking to the bottom of the river The man tied a concrete block To his back His eyes wide open The last thing he saw was water The last memory he had Was of his daughter Living life like this is sad But if you have no help Who do you turn to?


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Documentation |
Unmeasured output disturbance model
outdist = getoutdist(MPCobj)
[outdist,channels] = getoutdist(MPCobj)
outdist = getoutdist(MPCobj) retrieves the model of output disturbances used by the Model Predictive Controller object MPCobj. The output model, outdist, is a discrete-time, delay-free, LTI state-space (ss) object.
This command is most useful when a default output disturbance model is being used and you want to review its structure. This model, in combination with the intput disturbance model (if any), governs how well the controller compensates for unmeasured disturbances and prediction errors. You can override the controller's default behavior using the setoutdist command. For details on the role of disturbance modeling in Model Predictive Control, see Controller State Estimation.
If the controller employs an output disturbance model, it must have ny outputs, where ny is the number of plant outputs defined in MPCobj.Model.Plant. All input signals to outdist are unit-variance white noise. If you specify the output disturbance model, the number of inputs is your choice. For the default, the number of inputs depends upon the number of measured outputs, the input disturbance model (if any), and the need to maintain observability of the controller's state variables. For more details, see "State Estimation".
For details about the overall model used in the MPC algorithm for state estimation purposes, see Controller State Estimation.
[outdist,channels] = getoutdist(MPCobj) also returns the output channels to which integrated white noise has been added by default as an output disturbance model. If you have specified a custom output disturbance model using setoutdist, channels is empty.
getEstimator | getindist | mpc | setEstimator | setoutdist


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I love reporting on good franchise business news. I just found this story...a good franchise business news story-online. It's the first I heard of it, and felt it was worth sharing. Maybe you'll be motivated to take a shot at becoming a franchise owner yourself after reading it. _______________________________________________________________ Since opening in 2011, Bob Rosedale's franchise ... Read More
New LinkedIn Group Started: How To Buy A Franchise
Are you interested in owning a franchise? Or, are you interested in at least learning about becoming a franchise owner? If so, I just started something that I hope you'll find useful. And, it's free for you to get involved with. New LinkedIn Group Started: How To Buy A Franchise I just started a group on LinkedIn. It's the... How To Buy A Franchise ... Read More
Please Take This Short Franchise Ownership Survey
So, you're thinking that franchise ownership could be the route for you to take. Why? Why do you want to buy a franchise? When would you like to be in business-in a perfect world? What types of franchises are you going to investigate? Please Take This Short Franchise Ownership Survey I'm in franchising. Have been for a long time. I have my own take on franchising as an industry. I ... Read More
Maybe You Should Look At Buying An Existing Franchise
One option-if you're on the hunt for a franchise to buy, is to buy an existing franchise. An already-operating franchise business. It's one way to go, and there are definite advantages. In a moment, I'll show you a few advantages of *buying an existing franchise. *I recently asked subscribers of my free VIP Franchise Newsletter for their suggestions on what they'd like me to write about here. ... Read More
New Fitness Franchise Opportunity Is Well Positioned For Explosive Growth
(Sponsored Post) This post was written by Ray Haiber As an experienced franchise professional, every once in a while I get invited to help bring a new concept to the market that I know intuitively has all the right ingredients to become a bona fide success. This is exactly what happened when I was introduced to TapouT Fitness late last year. Due to the exploding mainstream popularity of the ... Read More
Franchise Ownership Fact: Most People Are Too Frightened To Start A Business
It's true. Most people are too risk-averse to start their own business. It's not a bad thing...not at all. But, it's a fact. It's the reason most people don't buy franchises-or any other type of business. Do you consider yourself to be risk-averse? Are you frightened with the idea of owning your own business? If so, and pardon my bluntness here, but why are you spending your time on The ... Read More
3 New Franchise Books Have Been Released And They're The Shortest Ones Ever Written
It's been a while since a new book on franchising has been written and released. But, all that has changed this year, because of one intrepid indie book publisher. The Publisher: FranBiz Press. About FranBiz Press FranBiz Press was launched in the summer of 2014 by an Alaskan entrepreneur by the name of Para Salin. Salin, the former CEO of a medium size business book ... Read More
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Own a Business? Get Listed for free!
Hosting an Event? Get Listed for free!
Categories: |
Mozart's Overture to the Marriage of Figaro and Mozart's Requiem combined with the Allentown Symphony Chorus; Christine Lamprea, winner of the 2013 Schadt String Competition, featured in Barber's Cello Concerto. www.millersymphonyhall.org.
Music Style | Classical |


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Shine A Light Gallery
Shine A Light is a concert film by Martin Scorsese that seeks to capture a moment in time, as well as pay tribute to the ongoing brilliance of the Rolling Stones in live form. The main bulk of proceedings is focused upon capturing them live and, in all, there are 22 tracks recorded during two memorable nights at New York's Beacon Theatre in 2006. Check out some photos…
Roll your mouse over the left and right-hand sides of the image and then click to view more pictures.
6 of 6
Read our review of the soundtrack to Shine A Light or the film itself
Recent Galleries:
- Disney's Frozen Fever Photo Gallery
- Focus - Margot Robbie Photo Gallery
- Focus (Will Smith/Margot Robbie) Photo Gallery
- The Second Best Exotic Marigold Hotel Photo Gallery
- Spectre: Rome Photo Call (Daniel Craig and Monica Bellucci)
- The Second Best Exotic Marigold Hotel Royal Film Performance Photo Gallery
- The Man From U.N.C.L.E. (Henry Cavill/Armie Hammer) First-look Photo Gallery
- Focus (Will Smith/Margot Robbie) UK Premiere Photo Gallery
- Daughter of God (Keanu Reeves) First-look Photo Gallery
- The Cobbler (Adam Sandler/Dustin Hoffman) First-look Photo Gallery


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Home > Science Fiction
Jeapes Japes collects all of Jeapes published short fiction, plus one story unique to the collection. The majority of the stories were published in Interzone while some appeared in other venues including The Magazine of Fantasy & Science Fiction. Themes of artificial intelligence and time travel run throughout the book.
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Here's a video recording of the keynote from XP2013 – Make Impacts, Not Software. This is a theme I challenged myself to present at plenty of conferences this year and refine and add material for each one. It's shaping up pretty nicely now, so I'm happy to share this version.
I'm Gojko Adzic, author of Impact Mapping and Specification by Example. My latest book is Fifty Quick Ideas to Improve Your User Stories. To learn about discounts on my books, conferences and workshops, sign up for Impact or follow me on Twitter. Join me at these conferences and workshops:
Specification by Example Workshops
- Rijswijk, NL, 12-13 March
- Stockholm, SE, 15-16 April
- Vienna, AT, 20-21 April
- Istanbul, TR, 7-8 May
- Wrocław, PL, 11 May
Impact Mapping Workshops
- Product Owner Survival Camp, Vienna, AT, 19-20 March
Conference talks and workshops
- ScanAgile, Helsinki, FI, 10-11 March
- Kravdagen 2015 Stockholm, SE, 26 March
- VOXXED Days, Instanbul, TR, 9 May
- Testing Cup, Wroclaw, PL, 11-13 May


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Maksim Chmerkovskiy Announces 'Dancing With the Stars' Departure
UPDATED: On the eve of his reunion with former partner Kristie Alley for the ABC series' upcoming "All-Stars" season, the controversial pro says his time in the ballroom is coming to an end.
It looks like 15 may be the charm for Maksim Chmerkovskiy.
The veteran Dancing With the Stars pro, who has never won the mirrorball in his 13 cycles participating on the ABC competition, has said that he'll leave the series when his contract expires next year, making the upcoming All-Stars cycle will be his last.
"What else do I have to do there after 15 seasons?" he told The New York Post. "It makes total sense. The audience can't expect for me to want to stick around, and the producers can't expect for me to want to stick around."
PHOTOS: 'Dancing With the Stars: All-Stars' Official Cast Portraits
The 32-year-old joined the series in its second season, making him one of the longest participants. And his tenure on the show has given it some of its most memorable moments, most notably in his frequent clashes with the judges.
ABC and BBC Worldwide Productions don't comment on the status of current and future Dancing With the Stars cast members, and Chmerkovskiy's personal rep did not immediately respond to The Hollywood Reporter's request for comment.
Chmerkovskiy is one of the few dancers who is actually reuniting with a past partner. When the season premieres on Monday, he'll once again dance with friend and twelfth season runner-up Kirstie Alley.
PHOTOS: Broadcast TV's Returning Shows for 2012-13 Season
As for his non-Dancing plans, Chmerkovskiy says that he's secured a lead role in a "major studio movie" that's set to begin filming in January.
Chmerkovskiy made it clear on Twitter that words of his departure were not taken out of context.
"With nothing but love, gratitude and respect to all that played a part in that amazing aspect of my life," he wrote Friday morning, linking the Post story.
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Holdays.net Home
It's all about the nails, are you worth it......
Beauty Warning:side effects;admiring glances, compliments & attention.
I also have some lovely ideas for your toes - see my other listings.
Beautifulset of crystals to be applied to your own nails or acrylics.
Set comprises of
200 mixed round AB crystals (2 & 3mm), (same coating as used on Swarovski crystals)
10 large round ab crystals (5mm),
Instructions: all you need is a little time & patience.
1 Cover your nail in clear varnish.
2. Then coat in clear varnish again and start adding the crystals.
3.You can use nail glue if you prefer.
Only the best quality crystals used.
See other listing foracrylic nails, lashes, hair extensions& nail decals & NEW IN YOUNGER LOOKING EYES - non surgical eyelid lift.
I ship overseas & combine postal charges.
Payment within three days please.
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Internet Screamers
Part of a series on Trolling. [View Related Entries]
[View Related Sub-entries]
Internet Screamers, also known as Jumpscares, are practical jokes that are meant to scare the viewer by abruptly flashing a disturbing image or playing a loud, frightening noise. Screamers are often used as a bait and switch type of trolling in online forums.
The earliest known screamer Kikia began circulating on the Taiwanese web in 2003, which features a poorly drawn boy sitting in a field and walking in a market place before the screen turns white and a frightening face from the video game Fatal Frame II is abruptly flashed on the screen (shown below).
Also in 2003, the Scary Maze Game was released online by developer Jeremy Winterrowd. Upon completion of the flash game's third level, the player is greeted by a large picture of the character Regan McNeil (played by Linda Blair) in the 1973 horror film The Exorcist.
In July 2005, the German beverage company K-Fee released a commercial known as "Ghost Car" in which a zombie abruptly pops up on the screen during peaceful footage of a car driving through an idyllic scene (shown below).
In 2011, the South Korean horror webcomic The Bong-Chon Dong Ghost was released, which contained a jump scarein two parts of the comic. In February 2013, the flash Anne.jpg[4] was released on the website Akk.li intended to fool users with a fake filename hyperlink. Instead of a static image, the site instantly pops-up and flashes with an image of the creepypasta character Jeff The Killer along with a loud scream.
Related Memes
Reaction Videos
Scary prank reactions are video recordings of people tricked into viewing an Internet screamer.


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Propellerhead announces Reason 7 for Mac
Propellerhead has announced Reason 7, the latest version of its digital audio workstation software.
New features include the External MIDI Instrument device, which brings MIDI out support to Reason 7, letting you connect your favorite external MIDI gear right into Reason.
Audio editing has been improved with automatic slicing into single notes or hits -- making perfect timing a cinch -- and exporting those slices into Dr. Octo Rex Loop Player, Reason's samplers or the Kong Drum Designer.
For mixing, Reason 7 has taken some of that functionality into the Reason rack, added new bus channels and the new Spectrum EQ: a powerful spectrum analyzer with a graphic EQ overlay.
Additionally, Reason 7 comes with an expanded sound bank to inspire your creativity as well as new audio import formats, like MP3, WMA and AAC, making it easier to bring your own loops or music into Reason.
Finally, Reason 7 introduces the Audiomatic Retro Transformer. Propellerhead says the Audiomatic Retro Transformer is "a future‑retro effect unit with plenty of personality. Add Audiomatic to any channel or group and select a snapshot to instantly change the sound of your track. More details about the Audiomatic Retro Transformer are coming soon." And we look forward to them.
Reason 7 will be available soon, and if you purchase or upgrade to the current version of Reason (6.5 -- which we took a look at last year) after March 1st, you'll get a free upgrade to Reason 7.
Check out all the details here.
Software Updates
more updates- Apple Remote Desktop updated with Yosemite support
- OS X Yosemite 10.10.2, iOS 8.1.3 updates now available
- Sports Illustrated 120 SPORTS channel comes to Apple TV
- Logic Pro X update brings AirDrop support, new effects, tools, and more
- Parallels Access 2.5 released, adds file manager, computer-to-computer remote access
- The Google Translate iOS app is about to get a lot smarter


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20 Types of Guys You've Dated From Sex and the City
by Tara Block
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20 Types of Guys You've Dated From Sex and the City
Ready to feel old? This weekend is the 10th anniversary of the Sex and the City finale, when we discovered the fate of the Manolo-wearing Carrie, Samantha, Miranda, and Charlotte (before the movies, of course). But the gang's glam fashion was only one aspect of the show's claim to fame. It was really the relationships — the good, the bad, and the frightening — that had has hooked. And whether you were Team Big or Team Aidan, there was at least a handful of the quartet's love interests that ring a bell for us all. I've rounded up 20 types of former flames from the TV show that we can all relate to in our dating past. Whether it's a mama's boy, a fetish-obsessed fella, or a wedding hookup, you're sure to see a guy you've dated in this group.
4 years
Well done my lady! Loved looking back at SATC. Excited for cosmos and next weeks premiere!
Link Love
- 10 things guests want to see at your wedding — HuffPost Weddings
- 7 reasons to be a bride who wears flats — Glamour
- These doughnut cakes might be better than any wedding cake — Wedding Chicks
- The 10 best wedding Instagrams of the week — Brides
- This intimate mountaintop wedding is seriously stunning — Style Me Pretty
- Your dog will be so cute with this DIY floral wreath — Green Wedding Shoes
- The ultimate wedding registry for the modern couple — Equally Wed
- 26 stunning engagement rings that cost under $50 — POPSUGAR Smart Living
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NHL NY Rangers vs. New Jersey, 05/25/2012 20:00 New Jersey -110 MLB San Diego vs. NY Mets, 05/25/2012 19:10 NY Mets -116 MLB San Diego vs. NY Mets, 05/25/2012 19:10 Over 7/-120 MLB Kansas City vs. Baltimore, 05/25/2012 19:05 Baltimore -122 MLB NY Yankees vs. Oakland, 05/25/2012 22:05 NY Yankees -142 MLB LA Angels vs. Seattle, 05/25/2012 22:10 LA Angels -122 To see more of superseed619's plays click here.
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Good Luck seed - we match up on most of those baseball plays....hope we have a great night!!
GL Superseed :)


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Environment Events
Global Trends, Local Stories: New Films on India and Ethiopia
March 24, 2015 // 12:00pm — 2:00pm
Environmental Change and Security Program
On March 24, the DC Environmental Film Festival comes to the Wilson Center for the Washington, DC, premieres of two new short documentaries from ECSP, "Broken Landscape" and "Paving the Way." Filmmaker and ECSP Multimedia Producer Sean Peoples will describe his journey from the eroded gullies of Ethiopia to the rat-hole mines of northeastern India during a panel discussion led by the Wilson Center's Roger-Mark De Souza, with observations from Sierra Club's Kim Lovell and World Resources Institute's Ferzina Banaji.
The Opening Session of the Advancing Climate-Resilient Development Symposium
March 16, 2015 // 9:00am — 11:45am
Environmental Change and Security Program
You are welcome to attend the opening session of the Advancing Climate-Resilient Development Symposium. Hosted by USAID's Global Climate Change Office, this panel discussion is kicking-off a four-day long symposium that will be held in Washington, D.C., March 16-19, 2015. Seating for the opening session is limited, so register soon to guarantee your spot.
Resilience for Peace: A New Agenda
March 02, 2015 // 3:00pm — 4:30pm
Environmental Change and Security Program
From Asia's mushrooming urban centers to the remote highlands of Ethiopia, a new agenda for peace is emerging. By helping local communities build resilience to shared global challenges, we can forge bonds of trust that can help prevent conflict and pave the road to peace. Join us on Monday, March 2 to mark the launch of the Resilience for Peace Project, a collaboration between the Wilson Center and USAID's Office of Conflict Management and Mitigation.
The Precarious State of Our Oceans
February 25, 2015 // 3:00pm — 5:00pm
Brazil Institute
In the inaugural event in 2015, the Managing Our Planet series returns to discuss the state of our oceans.
High Stakes: How This Year's Climate Negotiations Will Impact National Security
February 12, 2015 // 9:00am — 10:30am
Environmental Change and Security Program
Join us in a discussion with Nick Mabey, chief executive of the environmental NGO E3G, who will present new analysis on the relationship between successful climate diplomacy and national security.
The Year Ahead in Environment and Energy
January 23, 2015 // 3:00pm — 5:00pm
Environmental Change and Security Program
With the Obama Administration moving forward on emissions reductions, the deadline for drafting the Sustainable Development Agenda, and a highly anticipated global climate summit in Paris, 2015 promises to be a crucial year for climate policy. "In many ways, last year was the year of building momentum, and this is the year of getting the work done," said Lisa Friedman, deputy editor of ClimateWire, at the Wilson Center on January 5.
Scaling the Mountain: Women, Health, and the Environment in Nepal
January 07, 2015 // 3:00pm — 5:00pm
Environmental Change and Security Program
From the mountains and foothills of the Himalayas to the Terai plains, climate change is rapidly changing life in Nepal. Many communities however, are not strangers to environmental stress; for decades, rapid population growth alongside agriculture and fuelwood collection have degraded land and diminished forests.
The Russian Far East: A New Arena for Great Power Contests in the Asia Pacific?
December 05, 2014 // 9:00am — 10:30am
Kennan Institute
Russia's Far East (RFE), Northeast Asia's geographic and strategic heartland, is crucial to an understanding of Asia-Pacific power games, and is a potential focal point of geopolitical competition. A region two-thirds the size of the United States, the RFE possesses enormous natural wealth and a vital strategic location on the north Pacific, where the interests of several major powers – China, Japan, the Koreas and the United States – intersect and interact.
Living Through Extremes: Building Livelihood Resilience Across Sectors and Countries
December 04, 2014 // 12:00pm — 2:00pm
Environmental Change and Security Program
As climate change upends established patterns of life, resilience – the ability of social and ecological systems to mitigate, endure, and adapt to short-term shocks and long-term stressors – has become a buzzword in development and humanitarian circles.
India Energy: The Struggle For Power
December 03, 2014 // 4:00pm — 5:30pm
Asia Program
Much has been said in recent years about India's rising global clout. Considerably less has been said about India and a different type of power: The kind that electrifies households, fires up factories, lights up buildings—and, overall, sustains nations and their economies. This event marks the launch of India Energy: The Struggle for Power, written by Raymond E. Vickery, a foremost expert on India's energy situation.


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Map and Directions
Welcome to Taylor's Auto Max Volkswagen of Great Falls! We provide high quality and dependable new and used automobiles to all of Montana including Helena Volkswagen shoppers. Get your oil changed, tires rotated, and brakes repaired at our certified service department. Whether you're looking for the latest models, or are interested in a certified pre-owned vehicle Taylor's Auto Max Volkswagen of Great Falls has you covered.
We offer competitive rates on all our models and have online specials. We are here to meet your automotive needs! Browse our entire inventory online today for price comparisons and model details. Contact us with our easy-to-use online form if you have any questions. Taylor's Auto Max Volkswagen of Great Falls is the automotive provider you can trust. We serve all Havre and Butte Volkswagen shoppers an excellent selection of new and used cars.
Taylor's Auto Max Volkswagen of Great Falls proudly serves as a Montana Volkswagen dealership. We have all of the new Volkswagen models available on site, including the Golf and Passat. Our state-of-the-art online search tool allows you to search for the specific vehicle that can meet your needs.
Check out our new and used inventory, and then contact our team for more information. Our dealership offers stress-free auto financing services to ensure you get the vehicle you want. We serve Great Falls and Helena Volkswagen shoppers and work hard to meet all your needs. We'd like to thank you for visiting our website, and look forward to demonstrating why more Helena Volkswagen customers are making the trip to Taylor's Auto Max Volkswagen of Great Falls for all of their sales and service needs.
Taylor's Auto Max Volkswagen of Great Falls is conveniently located at 4100 10th Avenue South. We are in the heart of Great Falls, Montana making us the premier destination for all of our Helena used cars shoppers.
If you're looking for a Butte or Helena Volkswagen dealership, choose Taylor's Auto Max Volkswagen of Great Falls and find that right vehicle today. For more information, visit our hours and directions page today, or contact us and our team will be happy to assist you in reaching Taylor's Auto Max Volkswagen of Great Falls today!
Does your current vehicle need routine maintenance or repairs? Need to order parts? Don't wait until it's too late! Come visit our Great Falls Volkswagen service center today for the Carefree Maintenance you need. Our team of certified professionals at Taylor's Auto Max Volkswagen of Great Falls is available Monday through Friday to get the job the done for our Helena and Lewistown Volkswagen customers.
Schedule a service appointment or order parts for your vehicle today using our online forms or contact Taylor's Auto Max Volkswagen of Great Falls directly at 1-888-412-6895 and we'll be happy to talk with you about bringing new life to the Volkswagen you love.
The Volkswagen Passat continues to gain praise and prestigious awards from across the automobile industry. This vehicle is spacious, has class-leading rear legroom and a variety of premium features, the new Passat blends comfort, style, and technology where other cars fail. Taylor's Auto Max Volkswagen of Great Falls has a full inventory of the Passat on-site. Use our online form to get a quote, and when you're ready to take this impressive vehicle for a spin, contact us. Taylor's Auto Max Volkswagen of Great Falls will make sure you're first in line for the test drive you've been waiting for.


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Mass Effect 3 ! These were the three words going round and round our heads this morning in the aftermath of Bioware's latest info-bomb. Knowing which characters will be returning makes me even more glad that I didn't kill them off.
Moving swiftly from one awesome sci-fi universe to another, we got a longer look at Space Marine . Then returned to Dead Island for some more screenshots. Oh, and Minecraft's getting a release date.
But there's still more happening in the world of PC gaming. Don't panic. We're on the case. Just calmly proceed to the list below for today's hit of PC gaming news.
Today in the PC Gamer office: conspiracies. The Secret World trailer threatened to confirm all of our worst fears. Maybe we are all programs in a Matrix style simulation designed to keep our minds calm while machines suck the energy from our immobile bodies. We'd be perfectly fine with this, but if that's the case, where can we download Kung Fu into our brains? And why can't we FLY? Deus Ex, May Payne, do you have any favourite gaming conspiracies?


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Microsoft Bing Director: Search Not a Zero Sum Game vs. Google
Microsoft Bing Director Stefan Weitz said Microsoft is fine not catching up to Google in traditional keyword search. However, Bing expects to differentiate by offering e-commerce-related verticals that ease consumers' transactions. Weitz pointed to areas such as event-driven tasks, commercial queries and knowledge-type queries as Bing's strengths and advantages over Google and any other challenger. For example, users searching for events in a city will be connected immediately to theater showings and other happenings. Users can then easily purchase tickets.
Microsoft's Bing search engine has been gaining market share at a solid clip, growing from roughly 8 percent in June 2009 to 11.5 percent through February, according to comScore. Still, that growth won't make people confuse Bing with Google, the U.S. leader at 65 percent (and greater abroad), anytime soon.Mar 29, 2010 at 2:00 p.m. Eastern / 11:00 a.m. Pacific (60 minutes). Join us for a free eSeminar sponsored by IBM