D (animal doses of 10 and 100mg/kg/day tamsulosin hydrochloride) did not significantly alter fertility in male rats. Effects of tamsulosin on sperm counts or sperm function have not been eva luated.
Studies in female rats revealed significant reductions in fertility after single or multiple dosing with 300mg/kg/day of the R-isomer or racemic mixture of tamsulosin hydrochloride, respectively. In female rats, the reductions in fertility after single doses were considered to be associated with impairments in fertilization. Multiple dosing with 10 or 100mg/kg/day of the racemic mixture did not significantly alter fertility in female rats.
Estimates of exposure multiples comparing animal studies to the MRHD for dutasteride are based on clinical serum concentration at steady state.
Estimates of exposure multiples comparing animal studies to the MRHD for tamsulosin are based on AUC.
13.2 Animal Toxicology and/or Pharmacology
Central Nervous System Toxicology Studies:Dutasteride: In rats and dogs, repeated oral administration of dutasteride resulted in some animals showing signs of non-specific, reversible, centrally-mediated toxicity without associated histopathological changes at exposures 425- and 315-fold the expected clinical exposure (of parent drug), respectively.
14 CLINICAL STUDIES
The trial supporting the efficacy of JALYN was a 4-year multicenter, randomized, double-blind, parallel-group study (CombAT study) investigating the efficacy of the coadministration of dutasteride 0.5mg/day and tamsulosin hydrochloride 0.4mg/day (n=1,610) compared with dutasteride alone (n=1,623) or tamsulosin alone (n=1,611). Subjects were at least 50years of age with a serum PSA ≥1.5ng/mL and <10ng/mL and BPH diagnosed by medical history and physical examination, including enlarged prostate (≥30cc) and BPH symptoms that were moderate to severe according to the International Prostate Symptom Score (IPSS). Eighty-eight percent (88%) of the enrolled study population was Caucasian. Approximately 52% of subjects had previous exposure to 5 alpha-reductase inhibitor or alpha adrenergic antagonist treatment. Of the 4,844subjects randomly assigned to receive treatment, 69% of subjects in the coadministration group, 67% in the dutasteride group, and 61% in the tamsulosin group completed 4years of double-blind treatment.
Effect on Symptom Score: Symptoms were quantified using the first 7questions of the International Prostate Symptom Score (IPSS). The baseline score was approximately 16.4units for each treatment group. Coadministration therapy was statistically superior to each of the monotherapy treatments in decreasing symptom score at Month24, the primary time point for this endpoint. At Month24, the mean changes from baseline (±SD) in IPSS total symptom scores were -6.2 (±7.14) for the coadministration group, -4.9 (±6.81) for dutasteride, and -4.3 (±7.01) for tamsulosin, with a mean difference between coadministration and dutasteride of -1.3units (P<0.001; [95% CI: -1.69, -0.86]), and between coadministration and tamsulosin of -1.8units (P<0.001; [95% CI: -2.23, -1.40]). A significant difference was seen by Month9 and continued through Month48. At Month 48 the mean changes from baseline (±SD) in IPSS total symptom scores were -6.3 (±7.40) for coadministration, -5.3 (±7.14) for dutasteride, and -3.8 (±7.74) for tamsulosin, with a mean differe |
