Bicalutamide (Page 2 of 5)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of bicalutamide tablets. 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.

Respiratory disorders: Interstitial lung disease (some fatal) including interstitial pneumonitis and pulmonary fibrosis, most often at doses greater than 50 mg

Hemorrhage: Increased PT/INR due to interaction between coumarin anticoagulants and bicalutamide. Serious bleeding reported. [see Warnings and Precautions ( 5.2)]

Skin and subcutaneous tissue disorders: Photosensitivity

7 DRUG INTERACTIONS

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 co-administration of bicalutamide, mean midazolam (a CYP 3A4 substrate) levels may be increased 1.5 fold (for C max ) 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. PT/INR should be closely monitored in patients concomitantly receiving coumarin anticoagulants and bicalutamide. Adjustment of the anticoagulant dose may be necessary [see Warnings and Precautions ( 5.2) and Adverse Reactions ( 6.2)] .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Bicalutamide is contraindicated for use in pregnant women because it can cause fetal harm. Bicalutamide is not indicated for use in females. There are no human data on the use of bicalutamide in pregnant women. In animal reproduction studies, oral administration of bicalutamide to pregnant rats during organogenesis caused abnormal development of reproductive organs in male fetuses at exposures approximately 0.7 to 2 times the human exposure at the recommended dose (see Data).

Data

Animal Data

In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6-15, male fetuses had reduced anogenital distance at doses of 10 mg/kg/day and above (approximately 0.7 to 2 times the human exposure at the recommended dose).

In a pre-and post-natal development study, female rats were dosed from gestation day 7-16 and allowed to litter and rear their offspring to weaning. Male offspring of rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above, were observed to have reduced anogenital distance.

In a peri-and post-natal development study, female rats were dosed from gestation day 16 to lactation day 22 and allowed to litter and rear their offspring to weaning. Survival and weights of offspring during lactation were reduced for litters from maternal rats receiving doses of 250 mg/kg/day (approximately 2 times the human exposure at the recommended dose). Male offspring of rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above, were observed to have reduced anogenital distance, smaller secondary sex organs, cryptorchidism and hypospadias resulting in an inability to mate and impregnate their female partners. Female offspring of rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above had reduced pregnancy rates.

8.2 Lactation

Risk Summary

Bicalutamide is not indicated for use in pregnant women. There is no information available on the presence of bicalutamide in human milk, or on the effects on the breastfed infant or on milk production. Bicalutamide has been detected in rat milk.

8.3 Females and Males of Reproductive Potential

Contraception

Males

Antiandrogen therapy may cause morphological changes in spermatozoa [see Nonclinical Toxicology (13.1)]. Based on findings in animal reproduction studies and its mechanism of action, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 130 days after the final dose of bicalutamide [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1)].

Infertility

Males

Based on animal studies, bicalutamide can lead to inhibition of spermatogenesis and may impair fertility in males of reproductive potential. The long-term effects of bicalutamide on male fertility have not been studied [see Nonclinical Toxicology (13.1)].

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 ARIMIDEX ®$ (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/ARIMIDEX ®$ 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, anastrozole or other aromatase inhibitors

3. Median calculated as midpoint of 3 rd and 4 th ranked observations

4. 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 reduction 1
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%)
PT 2 (n=6) 10.3 -0.2 -2.6 3 (-7.2, 8.4) 4/6 (67%)
NPT 4 (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%)
PT 2 (n=6) -0.1 +0.7 -0.2 3 (-1.6, 3.5) 4/6 (67%)
NPT 4 (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 anastrozole 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.

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