NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No non-clinical studies have been conducted with JALYN. The following information is based on studies performed with dutasteride or tamsulosin.CarcinogenesisDutasteride: 2-year carcinogenicity study was conducted in B6C3F1 mice at doses of 3, 35, 250, and 500 mg/kg/day for males and 3, 35, and 250 mg/kg/day for females; an increased incidence of benign hepatocellular adenomas was noted at 250 mg/kg/day (290-fold the MRHD of 0.5-mg daily dose) in female mice only. Two of the major human metabolites have been detected in mice. The exposure to these metabolites in mice is either lower than in humans or is not known.In 2-year carcinogenicity study in Han Wistar rats, at doses of 1.5, 7.5, and 53 mg/kg/day in males and 0.8, 6.3, and 15 mg/kg/day in females, there was an increase in Leydig cell adenomas in the testes at 135-fold the MRHD (53 mg/kg/day and greater). An increased incidence of Leydig cell hyperplasia was present at 52-fold the MRHD (male rat doses of 7.5 mg/kg/day and greater). positive correlation between proliferative changes in the Leydig cells and an increase in circulating luteinizing hormone levels has been demonstrated with 5-alpha-reductase inhibitors and is consistent with an effect on the hypothalamic-pituitary-testicular axis following 5-alpha-reductase inhibition. At tumorigenic doses, luteinizing hormone levels in rats were increased by 167%. In this study, the major human metabolites were tested for carcinogenicity at approximately to times the expected clinical exposure.Tamsulosin: In rat carcinogenicity assay, no increases in tumor incidence was observed in rats administered up to times the MRHD of 0.8 mg/day (based on AUC of animal doses up to 43 mg/kg/day in males and up to 52 mg/kg/day in females), with the exception of modest increase in the frequency of mammary gland fibroadenomas in female rats receiving doses of 5.4 mg/kg or greater.In carcinogenicity assay, mice were administered up to times the MRHD of tamsulosin (oral doses up to 127 mg/kg/day in males and 158 mg/kg/day in females). There were no significant tumor findings in male mice. Female mice treated for years with the highest doses of 45 and 158 mg/kg/day had statistically significant increases in the incidence of mammary gland fibroadenomas (P<0.0001) and adenocarcinomas.The increased incidences of mammary gland neoplasms in female rats and mice were considered secondary to tamsulosin-induced hyperprolactinemia. It is not known if tamsulosin elevates prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known.MutagenesisDutasteride: Dutasteride was tested for genotoxicity in bacterial mutagenesis assay (Ames test), chromosomal aberration assay in Chinese hamster ovary (CHO) cells, and micronucleus assay in rats. The results did not indicate any genotoxic potential of the parent drug. Two major human metabolites were also negative in either the Ames test or an abbreviated Ames test.Tamsulosin: Tamsulosin produced no evidence of mutagenic potential in vitro in the Ames reverse mutation test, mouse lymphoma thymidine kinase assay, unscheduled DNA repair synthesis assay, and chromosomal aberration assays in CHO cells or human lymphocytes. There were no mutagenic effects in the in vivo sister chromatid exchange and mouse micronucleus assay.Impairment of FertilityDutasteride: Treatment of sexually mature male rats with dutasteride at 0.1 times the MRHD (animal doses of 0.05 mg/kg/day or greater for up to 31 weeks) based on mean serum concentration resulted in dose- and time-dependent decreases in fertility at all doses; reduced cauda epididymal (absolute) sperm counts but not sperm concentration (at 50 and 500 mg/kg/day); reduced weights of the epididymis, prostate, and seminal vesicles; and microscopic changes (cytoplasmic vacuolation of tubular epithelium in the epididymides and/or decreased cytoplasmic content of epithelium, consistent with decreased secretory activity in the prostate and seminal vesicles) in the reproductive organs at all doses in the absence of paternal toxicity. The fertility effects were reversed by Recovery Week at all doses, and sperm counts were normal at the end of 14-week recovery period. The microscopic changes were no longer present at Recovery Week 14 at 0.1 times the MRHD and were partly recovered in the remaining treatment groups. Low levels of dutasteride (0.6 to 17 ng/mL) were detected in the serum of untreated female rats mated to treated males (10 to 500 mg/kg/day for 29 to 30 weeks) which are 16 to 110 times the MRHD based on mean serum concentration. No feminization occurred in male offspring of untreated female rats mated to treated male rats even though detectable blood levels of dutasteride were observed in the female rats.In fertility study in female rats with dosing weeks prior to mating through early gestation, oral administration of dutasteride at doses of 0.05, 2.5, 12.5, and 30 mg/kg/day resulted in reduced litter size due to increased resorptions and in feminization of male fetuses (decreased anogenital distance) at to 10 times the MRHD (animal doses of 2.5 mg/kg/day or greater) based on mean serum concentration, in the presence of maternal toxicity (decreased body weight gain). Fetal body weights were also reduced at approximately 0.02 times the MRHD (rat dose of 0.05 mg/kg/day or greater) based on mean serum concentration, with no no-effect level, in the absence of maternal toxicity.Tamsulosin: Studies in rats revealed significantly reduced fertility in males dosed with single or multiple daily doses of 300 mg/kg/day of tamsulosin hydrochloride (AUC exposure in rats about 50 times the human exposure with the maximum therapeutic dose). The mechanism of decreased fertility in male rats is considered to be an effect of the compound on the vaginal plug formation possibly due to changes of semen content or impairment of ejaculation. The effects on fertility were reversible, showing improvement by days after single dose and weeks after multiple daily dosing. Effects on fertility in males were completely reversed within weeks after discontinuation of multiple daily dosing. Multiple doses of 10 and 100 mg/kg/day tamsulosin hydrochloride (1/5 and 16 times the anticipated human AUC exposure) did not significantly alter fertility in male rats. Effects of tamsulosin on sperm counts or sperm function have not been evaluated.Studies in female rats revealed significant reductions in fertility after single or multiple daily doses of 300 mg/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 daily doses of 10 or 100 mg/kg/day of the racemic mixture did not significantly alter fertility in female rats.. 13.2 Animal Toxicology and/or Pharmacology. Central Nervous System Toxicology StudiesDutasteride: 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.Rabbit Dermal AbsorptionIn rabbit dermal pharmacokinetics study, dermal absorption of dutasteride in CAPMUL (glyceryl oleate) in rabbits resulted in serum concentrations of 2.7 to 40.5 mcg/h/mL for doses of to 20 mg/mL, respectively, or 56% to 100% of applied dutasteride to be absorbed under occluded and prolonged conditions. JALYN soft gelatin capsules administered orally contain 0.5 mg dutasteride dissolved in mixture of mono-di-glycerides of caprylic/capric acid and butylated hydroxytoluene. Dutasteride in water was minimally absorbed in rabbits (2,000 mg/kg).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of dutasteride and tamsulosin from JALYN are comparable to the pharmacokinetics of dutasteride and tamsulosin when administered separately.AbsorptionThe pharmacokinetic parameters of dutasteride and tamsulosin observed after administration of JALYN in single-dose, randomized, 3-period, partial cross-over trial are summarized in Table below.Table 2. Arithmetic Means (SD) of Serum Dutasteride and Tamsulosin in Single-dose Pharmacokinetic Parameters under Fed Conditionsa Median (range). N 91.ComponentNAUC(0-t) (ng h/mL)Cmax (ng/mL)Tmax (h)a 1/2 (h)Dutasteride9239.6 (23.1)2.14 (0.77)3.00 (1.00-10.00)Tamsulosin92187.2 (95.7)11.3 (4.44)6.00 (2.00-24.00)13.5 (3.92)b Dutasteride: Following administration of single 0.5-mg dose of soft gelatin capsule, time to peak absolute bioavailability in healthy subjects is approximately 60% (range: 40% to 94%).Tamsulosin: Absorption of tamsulosin is essentially complete (>90%) following oral administration of 0.4-mg tamsulosin hydrochloride capsules under fasting conditions. Tamsulosin exhibits linear kinetics following single and multiple dosing, with achievement of steady-state concentrations by the fifth day of once-daily dosing.Effect of FoodFood does not affect the pharmacokinetics of dutasteride following administration of JALYN. However, mean 30% decrease in tamsulosin Cmax was observed when JALYN was administered with food, similar to that seen when tamsulosin monotherapy was administered under fed versus fasting conditions.DistributionDutasteride: Pharmacokinetic data following single and repeat oral doses show that dutasteride has large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma albumin (99.0%) and alpha-1 acid glycoprotein (AAG, 96.6%).In trial of healthy subjects (n 26) receiving dutasteride 0.5 mg/day for 12 months, semen dutasteride concentrations averaged 3.4 ng/mL (range: 0.4 to 14 ng/mL) at 12 months and, similar to serum, achieved steady-state concentrations at months. On average, at 12 months 11.5% of serum dutasteride concentrations partitioned into semen.Tamsulosin: The mean steady-state apparent volume of distribution of tamsulosin after intravenous administration to 10 healthy male adults was 16 L, which is suggestive of distribution into extracellular fluids in the body.Tamsulosin is extensively bound to human plasma proteins (94% to 99%), primarily AAG, with linear binding over wide concentration range (20 to 600 ng/mL). The results of 2-way in vitro studies indicate that the binding of tamsulosin to human plasma proteins is not affected by amitriptyline, diclofenac, glyburide, simvastatin plus simvastatin-hydroxy acid metabolite, warfarin, diazepam, or propranolol. Likewise, tamsulosin had no effect on the extent of binding of these drugs.MetabolismDutasteride: Dutasteride is extensively metabolized in humans. In vitro studies showed that dutasteride is metabolized by the CYP3A4 and CYP3A5 isoenzymes. Both of these isoenzymes produced the 4-hydroxydutasteride, 6-hydroxydutasteride, and the 6,4-dihydroxydutasteride metabolites. In addition, the 15-hydroxydutasteride metabolite was formed by CYP3A4. Dutasteride is not metabolized in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In human serum following dosing to steady state, unchanged dutasteride, major metabolites (4-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride), and minor metabolites (6,4-dihydroxydutasteride and 15-hydroxydutasteride), as assessed by mass spectrometric response, have been detected. The absolute stereochemistry of the hydroxyl additions in the and 15 positions is not known. In vitro, the 4-hydroxydutasteride and 1,2-dihydrodutasteride metabolites are much less potent than dutasteride against both isoforms of human 5-reductase. The activity of 6-hydroxydutasteride is comparable to that of dutasteride.Tamsulosin: There is no enantiomeric bioconversion from tamsulosin [R(-) isomer] to the S(+) isomer in humans. Tamsulosin is extensively metabolized by cytochrome P450 enzymes in the liver and less than 10% of the dose is excreted in urine unchanged. However, the pharmacokinetic profile of the metabolites in humans has not been established. In vitro studies indicate that CYP3A4 and CYP2D6 are involved in metabolism of tamsulosin as well as some minor participation of other CYP isoenzymes. Inhibition of hepatic drug-metabolizing enzymes may lead to increased exposure to tamsulosin [see Drug Interactions (7.1)]. The metabolites of tamsulosin undergo extensive conjugation to glucuronide or sulfate prior to renal excretion.Incubations with human liver microsomes showed no evidence of clinically significant metabolic interactions between tamsulosin and amitriptyline, albuterol, glyburide, and finasteride. However, results of the in vitro testing of the tamsulosin interaction with diclofenac and warfarin were equivocal.ExcretionDutasteride: Dutasteride and its metabolites were excreted mainly in feces. As percent of dose, there was approximately 5% unchanged dutasteride (approximately 1% to approximately 15%) and 40% as dutasteride-related metabolites (approximately 2% to approximately 90%). Only trace amounts of unchanged dutasteride were found in urine (<1%). Therefore, on average, the dose unaccounted for approximated 55% (range: 5% to 97%). The terminal elimination half-life of dutasteride is approximately weeks at steady state. The average steady-state serum dutasteride concentration was 40 ng/mL following 0.5 mg/day for year. Following daily dosing, dutasteride serum concentrations achieve 65% of steady-state concentration after month and approximately 90% after months. Due to the long half-life of dutasteride, serum concentrations remain detectable (greater than 0.1 ng/mL) for up to to months after discontinuation of treatment.Tamsulosin: On administration of the radiolabeled dose of tamsulosin to healthy volunteers, 97% of the administered radioactivity was recovered, with urine (76%) representing the primary route of excretion compared with feces (21%) over 168 hours.Following intravenous or oral administration of an immediate-release formulation, the elimination half-life of tamsulosin in plasma ranges from to hours. Because of absorption rate-controlled pharmacokinetics with tamsulosin hydrochloride capsules, the apparent half-life of tamsulosin is approximately to 13 hours in healthy volunteers and 14 to 15 hours in the target population.Tamsulosin undergoes restrictive clearance in humans, with relatively low systemic clearance (2.88 L/h).Specific PopulationsPediatric Patients: The pharmacokinetics of dutasteride and tamsulosin administered together have not been investigated in subjects younger than 18 years.Geriatric Patients: Dutasteride and tamsulosin pharmacokinetics using JALYN have not been studied in geriatric patients. The following text reflects information for the individual components. Dutasteride: No dosage adjustment is necessary in the elderly. The pharmacokinetics and pharmacodynamics of dutasteride were evaluated in 36 healthy male subjects aged between 24 and 87 years following administration of single 5-mg dose of dutasteride. In this single-dose trial, dutasteride half-life increased with age (approximately 170 hours in men aged 20 to 49 years, approximately 260 hours in men aged 50 to 69 years, and approximately 300 hours in men older than 70 years). Tamsulosin: Cross-study comparison of tamsulosin overall exposure (AUC) and half-life indicate that the pharmacokinetic disposition of tamsulosin may be slightly prolonged in geriatric males compared with young, healthy male volunteers. Intrinsic clearance is independent of tamsulosin binding to AAG, but diminishes with age, resulting in 40% overall higher exposure (AUC) in subjects aged 55 to 75 years compared with subjects aged 20 to 32 years.Male and Female Patients:Dutasteride: Dutasteride is contraindicated in females who are pregnant and is not indicated for use in females [see Contraindications (4), Warnings and Precautions (5.6)]. The pharmacokinetics of dutasteride in females have not been studied. Tamsulosin: Tamsulosin is not indicated for use in females. No information is available on the pharmacokinetics of tamsulosin in females.Racial and Ethnic Groups: The effect of race on the pharmacokinetics of dutasteride and tamsulosin administered together or separately has not been studied.Patients with Renal Impairment: The effect of renal impairment on dutasteride and tamsulosin pharmacokinetics has not been studied using JALYN. The following text reflects information for the individual components. Dutasteride: The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of steady-state 0.5-mg dose of dutasteride is recovered in human urine, so no adjustment in dosage is anticipated for patients with renal impairment. Tamsulosin: The pharmacokinetics of tamsulosin have been compared in subjects with mild-moderate (30<= CLcr <70 mL/min/1.73 m2) or moderate-severe (10<= CLcr <30 mL/min/1.73 m2) renal impairment and normal subjects (CLcr >90 mL/min/1.73 m2). While change in the overall plasma concentration of tamsulosin was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin, as well as the intrinsic clearance, remained relatively constant. Therefore, patients with renal impairment do not require an adjustment in tamsulosin dosing. However, patients with end-stage renal disease (CLcr <10 mL/min/1.73 m2) have not been studied.Patients with Hepatic Impairment: The effect of hepatic impairment on dutasteride and tamsulosin pharmacokinetics has not been studied using JALYN. The following text reflects information available for the individual components. Dutasteride: The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients. Tamsulosin: The pharmacokinetics of tamsulosin have been compared in subjects with moderate hepatic impairment (Child-Pugh classification: Grades and B) and normal subjects. While change in the overall plasma concentration of tamsulosin was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin does not change significantly with only modest (32%) change in intrinsic clearance of unbound tamsulosin. Therefore, patients with moderate hepatic impairment do not require an adjustment in tamsulosin dosage. Tamsulosin has not been studied in patients with severe hepatic impairment.Drug Interaction StudiesThere have been no drug interaction studies using JALYN. The following text reflects information available for the individual components.Cytochrome P450 Inhibitors:Dutasteride: No clinical drug interaction trials have been performed to evaluate the impact of CYP3A enzyme inhibitors on dutasteride pharmacokinetics. However, based on in vitro data, blood concentrations of dutasteride may increase in the presence of inhibitors of CYP3A4/5 such as ritonavir, ketoconazole, verapamil, diltiazem, cimetidine, troleandomycin, and ciprofloxacin.Dutasteride does not inhibit the in vitro metabolism of model substrates for the major human cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentration of 1,000 ng/mL, 25 times greater than steady-state serum concentrations in humans. Tamsulosin: Strong and Moderate Inhibitors of CYP3A4 or CYP2D6: The effects of ketoconazole (a strong inhibitor of CYP3A4) at 400 mg once daily for days on the pharmacokinetics of single tamsulosin hydrochloride capsule 0.4-mg dose was investigated in 24 healthy volunteers (age range: 23 to 47 years). Concomitant treatment with ketoconazole resulted in increases in the Cmax and AUC of tamsulosin by factors of 2.2 and 2.8, respectively. The effects of concomitant administration of moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of tamsulosin have not been evaluated.The effects of paroxetine (a strong inhibitor of CYP2D6) at 20 mg once daily for days on the pharmacokinetics of single tamsulosin capsule 0.4-mg dose was investigated in 24 healthy volunteers (age range: 23 to 47 years). Concomitant treatment with paroxetine resulted in increases in the Cmax and AUC of tamsulosin by factors of 1.3 and 1.6, respectively. similar increase in exposure is expected in poor metabolizers (PM) of CYP2D6 as compared with extensive metabolizers (EM). fraction of the population (about 7% of whites and 2% of African-Americans) are CYP2D6 PMs. Since CYP2D6 PMs cannot be readily identified and the potential for significant increase in tamsulosin exposure exists when tamsulosin 0.4 mg is coadministered with strong CYP3A4 inhibitors in CYP2D6 PMs, tamsulosin 0.4-mg capsules should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole).The effects of concomitant administration of moderate CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of tamsulosin have not been evaluated.The effects of coadministration of both CYP3A4 and CYP2D6 inhibitor with tamsulosin capsules have not been evaluated. However, there is potential for significant increase in tamsulosin exposure when tamsulosin 0.4 mg is coadministered with combination of both CYP3A4 and CYP2D6 inhibitors.Cimetidine: The effects of cimetidine at the highest recommended dose (400 mg every hours for days) on the pharmacokinetics of single tamsulosin capsule 0.4-mg dose was investigated in 10 healthy volunteers (age range: 21 to 38 years). Treatment with cimetidine resulted in significant decrease (26%) in the clearance of tamsulosin hydrochloride, which resulted in moderate increase in tamsulosin hydrochloride AUC (44%).Alpha-adrenergic Antagonists:Dutasteride: In single-sequence, crossover trial in healthy volunteers, the administration of tamsulosin or terazosin in combination with dutasteride had no effect on the steady-state pharmacokinetics of either alpha-adrenergic antagonist. Although the effect of administration of tamsulosin or terazosin on dutasteride pharmacokinetic parameters was not evaluated, the percent change in DHT concentrations was similar for dutasteride, alone or in combination with tamsulosin or terazosin.Warfarin: Dutasteride: In trial of 23 healthy volunteers, weeks of treatment with dutasteride 0.5 mg/day did not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time when administered with warfarin. Tamsulosin: definitive drug-drug interaction trial between tamsulosin and warfarin was not conducted. Results from limited in vitro and in vivo studies are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and tamsulosin.Nifedipine, Atenolol, Enalapril:Tamsulosin: In trials in hypertensive subjects (age range: 47 to 79 years) whose blood pressure was controlled with stable doses of nifedipine extended-release, atenolol, or enalapril for at least months, tamsulosin hydrochloride capsules 0.4 mg for days followed by tamsulosin hydrochloride capsules 0.8 mg for another days (n 8 per trial) resulted in no clinically significant effects on blood pressure and pulse rate compared with placebo (n 4 per trial). Therefore, dosage adjustments are not necessary when tamsulosin is administered concomitantly with nifedipine extended-release, atenolol, or enalapril.Digoxin and Theophylline:Dutasteride: In trial of 20 healthy volunteers, dutasteride did not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at dose of 0.5 mg/day for weeks. Tamsulosin: In trials in healthy volunteers (n 10 per trial; age range: 19 to 39 years) receiving tamsulosin capsules 0.4 mg/day for days, followed by tamsulosin capsules 0.8 mg/day for to days, single intravenous doses of digoxin 0.5 mg or theophylline mg/kg resulted in no change in the pharmacokinetics of digoxin or theophylline. Therefore, dosage adjustments are not necessary when tamsulosin capsule is administered concomitantly with digoxin or theophylline.Furosemide:Tamsulosin: The pharmacokinetic and pharmacodynamic interaction between tamsulosin hydrochloride capsules 0.8 mg/day (steady-state) and furosemide 20 mg intravenously (single dose) was evaluated in 10 healthy volunteers (age range: 21 to 40 years). Tamsulosin had no effect on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an 11% to 12% reduction in tamsulosin Cmax and AUC, these changes are expected to be clinically insignificant and do not require dose adjustment for tamsulosin.Calcium Channel Antagonists:Dutasteride: In population pharmacokinetics analysis, decrease in clearance of dutasteride was noted when coadministered with the CYP3A4 inhibitors verapamil (-37%, = 6) and diltiazem (-44%, = 5). In contrast, no decrease in clearance was seen when amlodipine, another calcium channel antagonist that is not CYP3A4 inhibitor, was coadministered with dutasteride (+7%, = 4). The decrease in clearance and subsequent increase in exposure to dutasteride in the presence of verapamil and diltiazem is not considered to be clinically significant. No dosage adjustment is recommended.Cholestyramine:Dutasteride: Administration of single 5-mg dose of dutasteride followed hour later by 12 cholestyramine did not affect the relative bioavailability of dutasteride in 12 normal volunteers.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryJALYN is contraindicated for use in pregnancy because it may cause harm to the male fetus [see Contraindications (4)]. JALYN is not indicated for use in females.Dutasteride, component of JALYN, is 5-alpha-reductase inhibitor that prevents conversion of testosterone to dihydrotestosterone (DHT), hormone necessary for normal development of male genitalia. Abnormalities in the genitalia of male fetuses is an expected physiological consequence of inhibition of this conversion. These results are similar to observations in male infants with genetic 5-alpha-reductase deficiency. In animal reproduction studies, dutasteride inhibited normal development of external genitalia in male offspring when given to rats or rabbits during organogenesis at less than the maximum recommended human dose (MRHD) of 0.5 mg daily, in the absence of maternal toxicity. At 15 times the MRHD, prolonged pregnancy, decreased reproductive organ weights, and delayed puberty in male offspring were observed in rats, with no-effect levels less than the MRHD of 0.5 mg daily. Increased placental weights in rabbits were also observed, with no-effect levels less than the MRHD of 0.5 mg daily (see Data). Although dutasteride is secreted into human semen, the drug concentration in the human female partner is approximately 100 times less than concentrations producing abnormalities of male genitalia in animal studies (see Data). In monkeys dosed during organogenesis at blood concentrations comparable to or above levels to which human female partner is estimated to be exposed, male offspring external genitalia was not adversely affected. No feminization occurred in male offspring of untreated female rats mated to treated male rats even though detectable blood levels of dutasteride were observed in the female rats [see Nonclinical Toxicology (13.1)]. No adverse developmental effects were observed in animal studies in which tamsulosin hydrochloride was administered to rats or rabbits during the period of organogenesis (see Data).DataHuman Data:Dutasteride: The highest measured semen concentration of dutasteride in treated men was 14 ng/mL. Although dutasteride is detected in semen, assuming exposure of 50-kg female to mL of semen and 100% absorption, the females expected dutasteride blood concentration through semen would be about 0.0175 ng/mL. This concentration is approximately 100 times less than blood concentrations producing abnormalities of male genitalia in animal studies. Dutasteride is highly protein bound in human semen (greater than 96%), which may reduce the amount of dutasteride available for vaginal absorption.Animal Data:Dutasteride: In an embryo-fetal development study in rats, oral administration of dutasteride at 10 times less than the MRHD of 0.5 mg daily (based on average blood levels in men) resulted in feminization of male genitalia in the fetus (decreased anogenital distance at 0.05 mg/kg/day with lack of no-effect level) in the absence of maternal toxicity. In addition, nipple development, hypospadias, and distended preputial glands occurred in fetuses of dams treated at doses of 2.5 mg/kg/day or greater (approximately 15 times the MRHD). Reduced fetal body weight and associated delayed ossification in the presence of maternal toxicity (decreased body weight gain) were observed at maternal exposure approximately 15 times the MRHD (dose of 2.5 mg/kg/day or greater). An increase in stillborn pups was observed in dams treated at 30 mg/kg/day (approximately 111 times the MRHD), with no-effect level of 12.5 mg/kg/day.In rabbit embryo-fetal development study, doses 28 times the MRHD (doses of 30 mg/kg/day or greater), based on average blood levels in men, were administered orally on Gestation Days to 29 (during organogenesis and the late period of external genitalia development). Histological evaluation of the genital papilla of fetuses revealed evidence of feminization of the male fetus as well as fused skull bones and increased placental weights at all doses in the absence of maternal toxicity. second embryo-fetal development study in rabbits dosed throughout pregnancy (organogenesis and later period of external genitalia development [Gestation Days to 29]) at 0.3 times the MRHD (doses of 0.05 mg/kg/day or greater, with no no-effect level), also produced evidence of feminization of the genitalia in male fetuses and increased placental weights at all doses in the absence of maternal toxicity.In an embryo-fetal development study, pregnant rhesus monkeys were exposed intravenously during organogenesis (Gestation Days 20 to 100) to dutasteride blood level comparable to or above the estimated dutasteride exposure of human female partner. Dutasteride was administered on Gestation Days 20 to 100 (during organogenesis) at doses of 400, 780, 1,325, or 2,010 ng/day (12 monkeys/group). No feminization of male external genitalia of monkey offspring was observed. Reduction of fetal adrenal weights, reduction in fetal prostate weights, and increases in fetal ovarian and testis weights were observed at the highest dose tested. Based on the highest measured semen concentration of dutasteride in treated men (14 ng/mL), these doses in the monkey represent up to 16 times the potential maximum exposure of 50-kg human female to mL of semen daily from dutasteride-treated male, assuming 100% absorption. The dose levels (on ng/kg basis) administered to monkeys in this study are 32 to 186 times the nominal (ng/kg) dose to which female would potentially be exposed via the semen. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites.In an oral pre- and post-natal development study in rats, feminization of the male genitalia was observed. Decreased anogenital distance was observed at 0.05 times the MRHD and greater (0.05 mg/kg/day and greater), with lack of no-effect level, based on average blood levels in men as an estimation of AUC. Hypospadias and nipple development were observed at 2.5 mg/kg/day or greater (14 times the MRHD or greater, with no-effect level at 0.05 mg/kg/day). Doses of 2.5 mg/kg/day and greater also resulted in prolonged gestation in the parental females, an increase in time to balano-preputial separation in male offspring, decrease in time to vaginal patency for female offspring, and decrease in prostate and seminal vesicle weights in male offspring. Increased stillbirths and decreased neonatal viability in offspring were noted at 30 mg/kg/day (102 times the MRHD in the presence of maternal toxicity [decreased body weights]). Tamsulosin: Administration of tamsulosin hydrochloride to pregnant female rats during the period of organogenesis (Gestation Days to 17) at dose levels up to approximately 50 times the human therapeutic AUC exposure (300 mg/kg/day) revealed no evidence of harm to the fetus. Administration of tamsulosin hydrochloride to pregnant rabbits during the period of organogenesis (Gestation Days to 18) at dose levels up to 50 mg/kg/day produced no evidence of fetal harm.

SPL PATIENT PACKAGE INSERT SECTION.

PHARMACIST DETACH HERE AND GIVE INSTRUCTIONS TO PATIENTPATIENT INFORMATIONJALYN (JAY-lin)(dutasteride and tamsulosin hydrochloride)capsulesJALYN is for use by men only.What is JALYNJALYN is prescription medicine that contains medicines: dutasteride and tamsulosin. JALYN is used to treat the symptoms of benign prostatic hyperplasia (BPH) in men with an enlarged prostate. The medications in JALYN work in different ways to improve symptoms of BPH. Dutasteride shrinks the enlarged prostate and tamsulosin relaxes muscles in the prostate and neck of the bladder. These medications, when used together, can improve symptoms of BPH better than either medication when used alone. Do not take JALYNif you are:opregnant or may be pregnant. JALYN may harm your unborn baby. Pregnant females should not touch JALYN capsules. If female who is pregnant with male baby gets enough JALYN in her body by swallowing or touching JALYN, the male baby may be born with sex organs that are not normal. If pregnant female comes in contact with leaking JALYN capsules, the contact area should be washed immediately with soap and water.oallergic to dutasteride, tamsulosin, or any of the ingredients in JALYN. See the end of this leaflet for complete list of ingredients in JALYN.otaking another medicine that contains an alpha-blocker.oallergic to other 5-alpha-reductase inhibitors, for example, PROSCAR (finasteride) tablets.Before you take JALYN, tell your healthcare provider about all of your medical conditions, including if you:ohave history of low blood pressureotake medicines to treat high blood pressureoplan to have cataract or glaucoma surgeryohave liver problemsoare allergic to sulfa medicationsohave any other medical conditionsTell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. JALYN and other medicines may affect each other, causing side effects. JALYN may affect the way other medicines work, and other medicines may affect how JALYN works.Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take JALYNoTake JALYN exactly as your healthcare provider tells you to take it.oSwallow JALYN capsules whole. Do not crush, chew, or open JALYN capsules because the contents of the capsule may irritate your lips, mouth, or throat.oTake your JALYN time each day, about 30 minutes after the same meal every day. For example, you may take JALYN 30 minutes after dinner every day.oIf you miss dose, you can take it later that same day, 30 minutes after meal. Do not take JALYN capsules in the same day. If you stop or forget to take JALYN for several days, talk with your healthcare provider before starting again.oIf you take too much JALYN, call your healthcare provider or go to the nearest hospital emergency room right away.What should avoid while taking JALYNoAvoid driving, operating machinery, or other dangerous activities when starting treatment with JALYN until you know how JALYN affects you. JALYN can cause sudden drop in your blood pressure, especially at the start of treatment. sudden drop in blood pressure may cause you to faint, feel dizzy or lightheaded.oYou should not donate blood while taking JALYN or for months after you have stopped JALYN. This is important to prevent pregnant females from receiving JALYN through blood transfusions.What are the possible side effects of JALYNJALYN may cause serious side effects including:oDecreased blood pressure. JALYN may cause sudden drop in your blood pressure upon standing from sitting or lying position, especially at the start of treatment. Symptoms of low blood pressure may include:ofaintingodizzinessofeeling lightheaded oRare and serious allergic reactions, including:oswelling of your face, tongue, or throatodifficulty breathingoserious skin reactions, such as skin peeling Get medical help right away if you have these serious allergic reactions.oHigher chance of more serious form of prostate cancer.oEye problems during cataract or glaucoma surgery. During cataract or glaucoma surgery, condition called Intraoperative Floppy Iris Syndrome (IFIS) can happen if you take or have taken JALYN in the past. If you need to have cataract or glaucoma surgery, tell your surgeon if you take or have taken JALYN.oA painful erection that will not go away. Rarely, JALYN can cause painful erection (priapism), which cannot be relieved by having sex. If this happens, get medical help right away. If priapism is not treated, there could be lasting damage to your penis, including not being able to have an erection.The most common side effects of JALYN include:oejaculation problemsotrouble getting or keeping an erection (impotence)oa decrease in sex drive (libido)odizzinessoenlarged or painful breasts. If you notice breast lumps or nipple discharge, you should talk to your healthcare provider.orunny noseSome of these events may continue after you stop taking JALYN.Depressed mood has been reported in patients receiving dutasteride, an ingredient of JALYN.Dutasteride, an ingredient of JALYN, has been shown to reduce sperm count, semen volume, and sperm movement. However, the effect of JALYN on male fertility is not known.Prostate-Specific Antigen (PSA) Test: Your healthcare provider may check you for other prostate problems, including prostate cancer before you start and while you take JALYN. blood test called PSA (prostate-specific antigen) is sometimes used to see if you might have prostate cancer. JALYN will reduce the amount of PSA measured in your blood. Your healthcare provider is aware of this effect and can still use PSA to see if you might have prostate cancer. Increases in your PSA levels while on treatment with JALYN (even if the PSA levels are in the normal range) should be evaluated by your healthcare provider.These are not all the possible side effects with JALYN. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store JALYNoStore JALYN capsules at room temperature (59 to 86F or 15 to 30C).oJALYN capsules may become deformed and/or discolored if kept at high temperatures.oDo not use or touch JALYN if your capsules are deformed, discolored, or leaking.oSafety throw away medicines that is no longer needed.Keep JALYN and all medicines out of the reach of children.General information about the safe and effective use of JALYN.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use Jalyn for condition for which it was not prescribed. Do not give Jalyn to other people, even if they have the same symptoms that you have. It may harm them.You can ask your healthcare provider or pharmacist for information about Jalyn that is written for health professionals.For more information call 1-888-825-5249.What are the ingredients in JALYNActive ingredient: dutasteride and tamsulosin hydrochlorideInactive ingredients: black ink, butylated hydroxytoluene, carrageenan, FD&C yellow 6, ferric oxide (yellow), gelatin (from certified BSE-free bovine sources), glycerin, hypromellose, iron oxide red, methacrylic acid copolymer dispersion, microcrystalline cellulose, mono-di-glycerides of caprylic/capric acid, potassium chloride, talc, titanium dioxide, and triethyl citrate.Manufactured for:GlaxoSmithKlineResearch Triangle Park, NC 27709JALYN is trademark owned by or licensed to the GSK group of companies.The other brand listed is trademark owned by or licensed to its owner and is not owned by or licensed to the GSK group of companies. The maker of this brand is not affiliated with and does not endorse the GSK group of companies or its products.(C)2020 GSK group of companies or its licensor.JLN:11PILThis Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 12/2020. opregnant or may be pregnant. JALYN may harm your unborn baby. Pregnant females should not touch JALYN capsules. If female who is pregnant with male baby gets enough JALYN in her body by swallowing or touching JALYN, the male baby may be born with sex organs that are not normal. If pregnant female comes in contact with leaking JALYN capsules, the contact area should be washed immediately with soap and water.. oallergic to dutasteride, tamsulosin, or any of the ingredients in JALYN. See the end of this leaflet for complete list of ingredients in JALYN.. otaking another medicine that contains an alpha-blocker.. oallergic to other 5-alpha-reductase inhibitors, for example, PROSCAR (finasteride) tablets.. ohave history of low blood pressure. otake medicines to treat high blood pressure. oplan to have cataract or glaucoma surgery. ohave liver problems. oare allergic to sulfa medications. ohave any other medical conditions. oTake JALYN exactly as your healthcare provider tells you to take it.. oSwallow JALYN capsules whole. Do not crush, chew, or open JALYN capsules because the contents of the capsule may irritate your lips, mouth, or throat.. oTake your JALYN time each day, about 30 minutes after the same meal every day. For example, you may take JALYN 30 minutes after dinner every day.. oIf you miss dose, you can take it later that same day, 30 minutes after meal. Do not take JALYN capsules in the same day. If you stop or forget to take JALYN for several days, talk with your healthcare provider before starting again.. oIf you take too much JALYN, call your healthcare provider or go to the nearest hospital emergency room right away.. oAvoid driving, operating machinery, or other dangerous activities when starting treatment with JALYN until you know how JALYN affects you. JALYN can cause sudden drop in your blood pressure, especially at the start of treatment. sudden drop in blood pressure may cause you to faint, feel dizzy or lightheaded.. oYou should not donate blood while taking JALYN or for months after you have stopped JALYN. This is important to prevent pregnant females from receiving JALYN through blood transfusions.. oDecreased blood pressure. JALYN may cause sudden drop in your blood pressure upon standing from sitting or lying position, especially at the start of treatment. Symptoms of low blood pressure may include:ofaintingodizzinessofeeling lightheaded ofainting. odizziness. ofeeling lightheaded. oRare and serious allergic reactions, including:oswelling of your face, tongue, or throatodifficulty breathingoserious skin reactions, such as skin peeling. oswelling of your face, tongue, or throat. odifficulty breathing. oserious skin reactions, such as skin peeling. Get medical help right away if you have these serious allergic reactions.. oHigher chance of more serious form of prostate cancer.. oEye problems during cataract or glaucoma surgery. During cataract or glaucoma surgery, condition called Intraoperative Floppy Iris Syndrome (IFIS) can happen if you take or have taken JALYN in the past. If you need to have cataract or glaucoma surgery, tell your surgeon if you take or have taken JALYN.. oA painful erection that will not go away. Rarely, JALYN can cause painful erection (priapism), which cannot be relieved by having sex. If this happens, get medical help right away. If priapism is not treated, there could be lasting damage to your penis, including not being able to have an erection.. oejaculation problems. otrouble getting or keeping an erection (impotence). oa decrease in sex drive (libido). odizziness. oenlarged or painful breasts. If you notice breast lumps or nipple discharge, you should talk to your healthcare provider.. orunny nose. oStore JALYN capsules at room temperature (59 to 86F or 15 to 30C).. oJALYN capsules may become deformed and/or discolored if kept at high temperatures.. oDo not use or touch JALYN if your capsules are deformed, discolored, or leaking.. oSafety throw away medicines that is no longer needed.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryJALYN is contraindicated for use in pregnancy because it may cause harm to the male fetus [see Contraindications (4)]. JALYN is not indicated for use in females.Dutasteride, component of JALYN, is 5-alpha-reductase inhibitor that prevents conversion of testosterone to dihydrotestosterone (DHT), hormone necessary for normal development of male genitalia. Abnormalities in the genitalia of male fetuses is an expected physiological consequence of inhibition of this conversion. These results are similar to observations in male infants with genetic 5-alpha-reductase deficiency. In animal reproduction studies, dutasteride inhibited normal development of external genitalia in male offspring when given to rats or rabbits during organogenesis at less than the maximum recommended human dose (MRHD) of 0.5 mg daily, in the absence of maternal toxicity. At 15 times the MRHD, prolonged pregnancy, decreased reproductive organ weights, and delayed puberty in male offspring were observed in rats, with no-effect levels less than the MRHD of 0.5 mg daily. Increased placental weights in rabbits were also observed, with no-effect levels less than the MRHD of 0.5 mg daily (see Data). Although dutasteride is secreted into human semen, the drug concentration in the human female partner is approximately 100 times less than concentrations producing abnormalities of male genitalia in animal studies (see Data). In monkeys dosed during organogenesis at blood concentrations comparable to or above levels to which human female partner is estimated to be exposed, male offspring external genitalia was not adversely affected. No feminization occurred in male offspring of untreated female rats mated to treated male rats even though detectable blood levels of dutasteride were observed in the female rats [see Nonclinical Toxicology (13.1)]. No adverse developmental effects were observed in animal studies in which tamsulosin hydrochloride was administered to rats or rabbits during the period of organogenesis (see Data).DataHuman Data:Dutasteride: The highest measured semen concentration of dutasteride in treated men was 14 ng/mL. Although dutasteride is detected in semen, assuming exposure of 50-kg female to mL of semen and 100% absorption, the females expected dutasteride blood concentration through semen would be about 0.0175 ng/mL. This concentration is approximately 100 times less than blood concentrations producing abnormalities of male genitalia in animal studies. Dutasteride is highly protein bound in human semen (greater than 96%), which may reduce the amount of dutasteride available for vaginal absorption.Animal Data:Dutasteride: In an embryo-fetal development study in rats, oral administration of dutasteride at 10 times less than the MRHD of 0.5 mg daily (based on average blood levels in men) resulted in feminization of male genitalia in the fetus (decreased anogenital distance at 0.05 mg/kg/day with lack of no-effect level) in the absence of maternal toxicity. In addition, nipple development, hypospadias, and distended preputial glands occurred in fetuses of dams treated at doses of 2.5 mg/kg/day or greater (approximately 15 times the MRHD). Reduced fetal body weight and associated delayed ossification in the presence of maternal toxicity (decreased body weight gain) were observed at maternal exposure approximately 15 times the MRHD (dose of 2.5 mg/kg/day or greater). An increase in stillborn pups was observed in dams treated at 30 mg/kg/day (approximately 111 times the MRHD), with no-effect level of 12.5 mg/kg/day.In rabbit embryo-fetal development study, doses 28 times the MRHD (doses of 30 mg/kg/day or greater), based on average blood levels in men, were administered orally on Gestation Days to 29 (during organogenesis and the late period of external genitalia development). Histological evaluation of the genital papilla of fetuses revealed evidence of feminization of the male fetus as well as fused skull bones and increased placental weights at all doses in the absence of maternal toxicity. second embryo-fetal development study in rabbits dosed throughout pregnancy (organogenesis and later period of external genitalia development [Gestation Days to 29]) at 0.3 times the MRHD (doses of 0.05 mg/kg/day or greater, with no no-effect level), also produced evidence of feminization of the genitalia in male fetuses and increased placental weights at all doses in the absence of maternal toxicity.In an embryo-fetal development study, pregnant rhesus monkeys were exposed intravenously during organogenesis (Gestation Days 20 to 100) to dutasteride blood level comparable to or above the estimated dutasteride exposure of human female partner. Dutasteride was administered on Gestation Days 20 to 100 (during organogenesis) at doses of 400, 780, 1,325, or 2,010 ng/day (12 monkeys/group). No feminization of male external genitalia of monkey offspring was observed. Reduction of fetal adrenal weights, reduction in fetal prostate weights, and increases in fetal ovarian and testis weights were observed at the highest dose tested. Based on the highest measured semen concentration of dutasteride in treated men (14 ng/mL), these doses in the monkey represent up to 16 times the potential maximum exposure of 50-kg human female to mL of semen daily from dutasteride-treated male, assuming 100% absorption. The dose levels (on ng/kg basis) administered to monkeys in this study are 32 to 186 times the nominal (ng/kg) dose to which female would potentially be exposed via the semen. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites.In an oral pre- and post-natal development study in rats, feminization of the male genitalia was observed. Decreased anogenital distance was observed at 0.05 times the MRHD and greater (0.05 mg/kg/day and greater), with lack of no-effect level, based on average blood levels in men as an estimation of AUC. Hypospadias and nipple development were observed at 2.5 mg/kg/day or greater (14 times the MRHD or greater, with no-effect level at 0.05 mg/kg/day). Doses of 2.5 mg/kg/day and greater also resulted in prolonged gestation in the parental females, an increase in time to balano-preputial separation in male offspring, decrease in time to vaginal patency for female offspring, and decrease in prostate and seminal vesicle weights in male offspring. Increased stillbirths and decreased neonatal viability in offspring were noted at 30 mg/kg/day (102 times the MRHD in the presence of maternal toxicity [decreased body weights]). Tamsulosin: Administration of tamsulosin hydrochloride to pregnant female rats during the period of organogenesis (Gestation Days to 17) at dose levels up to approximately 50 times the human therapeutic AUC exposure (300 mg/kg/day) revealed no evidence of harm to the fetus. Administration of tamsulosin hydrochloride to pregnant rabbits during the period of organogenesis (Gestation Days to 18) at dose levels up to 50 mg/kg/day produced no evidence of fetal harm.. 8.2 Lactation Risk SummaryJALYN is not indicated for use in females.. 8.3 Females and Males of Reproductive Potential. InfertilityDutasteride:Males: The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in normal volunteers aged 18 to 52 years (n 27 dutasteride, = 23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, the mean percent reductions from baseline in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. Sperm concentration and sperm morphology were unaffected. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower than baseline. While mean values for all semen parameters at all timepoints remained within the normal ranges and did not meet predefined criteria for clinically significant change (30%), subjects in the dutasteride group had decreases in sperm count of greater than 90% from baseline at 52 weeks, with partial recovery at the 24-week follow-up. The clinical significance of these effects on semen characteristics for an individual patients fertility is not known [see Warnings and Precautions (5.11)].Tamsulosin:Males: Abnormal ejaculation including ejaculation failure, ejaculation disorder, retrograde ejaculation, and decreased ejaculation has been associated with tamsulosin hydrochloride. Studies in rats revealed significantly reduced fertility in males, considered to be due to impairment of ejaculation, which was reversible [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use. JALYN is not indicated for use in pediatric patients. Safety and effectiveness of JALYN in pediatric patients have not been established.. 8.5 Geriatric Use. Of 1,610 male subjects treated with coadministered dutasteride and tamsulosin in the CombAT trial, 58% of enrolled subjects were aged 65 years and older and 13% of enrolled subjects were aged 75 years and older. No overall differences in safety or efficacy were observed between these subjects and younger subjects but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)].. 8.6 Renal Impairment. The effect of renal impairment on dutasteride and tamsulosin pharmacokinetics has not been studied using JALYN. Because no dosage adjustment is necessary for dutasteride or tamsulosin in patients with moderate-to-severe renal impairment (10<= CLcr <30 mL/min/1.73 m2), no dosage adjustment is necessary for JALYN in patients with moderate-to-severe renal impairment. However, patients with end-stage renal disease (CLcr<10 mL/min/1.73 m2) have not been studied [see Clinical Pharmacology (12.3)].. 8.7 Hepatic Impairment. The effect of hepatic impairment on dutasteride and tamsulosin pharmacokinetics has not been studied using JALYN. The following text reflects information available for the individual components.DutasterideThe effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients. However, in clinical trial where 60 subjects received mg (10 times the therapeutic dose) daily for 24 weeks, no additional adverse events were observed compared with those observed at the therapeutic dose of 0.5 mg [see Clinical Pharmacology (12.3)].TamsulosinPatients with moderate hepatic impairment do not require an adjustment in tamsulosin dosage. Tamsulosin has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions, reported in >=1% of subjects treated with coadministered dutasteride and tamsulosin are ejaculation disorders, impotence, decreased libido, dizziness, and breast disorders. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. The clinical efficacy and safety of coadministered dutasteride and tamsulosin, which are individual components of JALYN, have been evaluated in multicenter, randomized, double-blind, parallel group trial (the Combination with Alpha-Blocker Therapy, or CombAT, trial). Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trial of another drug and may not reflect the rates observed in practice.oThe most common adverse reactions reported in subjects receiving coadministered dutasteride and tamsulosin were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders, and dizziness. Ejaculation disorders occurred significantly more in subjects receiving coadministration therapy (11%) compared with those receiving dutasteride (2%) or tamsulosin (4%) as monotherapy.oTrial withdrawal due to adverse reactions occurred in 6% of subjects receiving coadministered dutasteride and tamsulosin, and in 4% of subjects receiving dutasteride or tamsulosin as monotherapy. The most common adverse reaction in all treatment arms leading to trial withdrawal was erectile dysfunction (1% to 1.5%).In the CombAT trial, over 4,800 male subjects with BPH were randomly assigned to receive 0.5 mg dutasteride, 0.4 mg tamsulosin hydrochloride, or coadministration therapy (0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride) administered once daily in 4-year double-blind trial. Overall, 1,623 subjects received monotherapy with dutasteride; 1,611 subjects received monotherapy with tamsulosin; and 1,610 subjects received coadministration therapy. The population was aged 49 to 88 years (mean age: 66 years) and 88% were white. Table summarizes adverse reactions reported in at least 1% of subjects receiving coadministration therapy and at higher incidence than subjects receiving either dutasteride or tamsulosin as monotherapy.Table 1. Adverse Reactions Reported over 48-Month Period in >=1% of Subjects and More Frequently in the Coadministration Therapy Group than the Dutasteride or Tamsulosin Monotherapy Group (CombAT) by Time of Onseta Coadministration AVODART 0.5 mg once daily plus tamsulosin 0.4 mg once daily. Includes anorgasmia, retrograde ejaculation, semen volume decreased, orgasmic sensation decreased, orgasm abnormal, ejaculation delayed, ejaculation disorder, ejaculation failure, and premature ejaculation. These sexual adverse reactions are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse reactions may persist after treatment discontinuation. The role of dutasteride in this persistence is unknown. Includes erectile dysfunction and disturbance in sexual arousal. Includes libido decreased, libido disorder, loss of libido, sexual dysfunction, and male sexual dysfunction. Includes breast enlargement, gynecomastia, breast swelling, breast pain, breast tenderness, nipple pain, and nipple swelling.Adverse ReactionAdverse Reaction Time of OnsetYear 1Year 2Year 3Year 4Months 0-6 Months 7-12 Coadministrationa (n 1,610)(n 1,527)(n 1,428)(n 1,283)(n 1,200) Dutasteride(n 1,623)(n 1,548)(n 1,464)(n 1,325)(n 1,200) Tamsulosin (n 1,611)(n 1,545)(n 1,468)(n 1,281)(n 1,112)Ejaculation disordersb,c Coadministration7.8%1.6%1.0%0.5%<0.1% Dutasteride1.0%0.5%0.5%0.2%0.3% Tamsulosin2.2%0.5%0.5%0.2%0.3%Impotencec,d Coadministration5.4%1.1%1.8%0.9%0.4% Dutasteride4.0%1.1%1.6%0.6%0.3% Tamsulosin2.6%0.8%1.0%0.6%1.1%Decreased libidoc,e Coadministration4.5%0.9%0.8%0.2%0.0% Dutasteride3.1%0.7%1.0%0.2%0.0% Tamsulosin2.0%0.6%0.7%0.2%<0.1%Breast disordersf Coadministration1.1%1.1%0.8%0.9%0.6% Dutasteride0.9%0.9%1.2%0.5%0.7% Tamsulosin0.4%0.4%0.4%0.2%0.0%Dizziness Coadministration1.1%0.4%0.1%<0.1%0.2% Dutasteride0.5%0.3%0.1%<0.1%<0.1% Tamsulosin0.9%0.5%0.4%<0.1%0.0%Cardiac FailureIn CombAT, after years of treatment, the incidence of the composite term cardiac failure in the coadministration group (12/1,610; 0.7%) was higher than in either monotherapy group: dutasteride, 2/1,623 (0.1%) and tamsulosin, 9/1,611 (0.6%). Composite cardiac failure was also examined in separate 4-year placebo-controlled trial evaluating dutasteride in men at risk for development of prostate cancer. The incidence of cardiac failure in subjects taking dutasteride was 0.6% (26/4,105) compared with 0.4% (15/4,126) in subjects on placebo. majority of subjects with cardiac failure in both trials had comorbidities associated with an increased risk of cardiac failure. Therefore, the clinical significance of the numerical imbalances in cardiac failure is unknown. No causal relationship between dutasteride alone or coadministered with tamsulosin and cardiac failure has been established. No imbalance was observed in the incidence of overall cardiovascular adverse events in either trial.Additional information regarding adverse reactions in placebo-controlled trials with dutasteride or tamsulosin monotherapy follows.DutasterideLong-term Treatment (Up to Years): High-Grade Prostate Cancer: The REDUCE trial was randomized, double-blind, placebo-controlled trial that enrolled 8,231 men aged 50 to 75 years with serum PSA of 2.5 ng/mL to 10 ng/mL and negative prostate biopsy within the previous months. Subjects were randomized to receive placebo (n 4,126) or 0.5-mg daily doses of dutasteride (n 4,105) for up to years. The mean age was 63 years and 91% were white. Subjects underwent protocol-mandated scheduled prostate biopsies at and years of treatment or had for-cause biopsies at non-scheduled times if clinically indicated. There was higher incidence of Gleason score to 10 prostate cancer in men receiving dutasteride (1.0%) compared with men on placebo (0.5%) [see Indications and Usage (1.2), Warnings and Precautions (5.4)]. In 7-year placebo-controlled clinical trial with another 5-alpha-reductase inhibitor (finasteride mg, PROSCAR), similar results for Gleason score to 10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%).No clinical benefit has been demonstrated in patients with prostate cancer treated with dutasteride. Reproductive and Breast DisordersIn the pivotal placebo-controlled BPH trials with dutasteride, each years in duration, there was no evidence of increased sexual adverse reactions (impotence, decreased libido, and ejaculation disorder) or breast disorders with increased duration of treatment. Among these trials, there was case of breast cancer in the dutasteride group and case in the placebo group. No cases of breast cancer were reported in any treatment group in the 4-year CombAT trial or the 4-year REDUCE trial.The relationship between long-term use of dutasteride and male breast neoplasia is currently unknown.TamsulosinAccording to the tamsulosin prescribing information, in two 13-week treatment trials with tamsulosin monotherapy, adverse reactions occurring in at least 2% of subjects receiving 0.4 mg tamsulosin hydrochloride and at an incidence higher than in subjects receiving placebo were: infection, asthenia, back pain, chest pain, somnolence, insomnia, rhinitis, pharyngitis, cough increased, sinusitis, and diarrhea.Signs and Symptoms of Orthostasis: According to the tamsulosin prescribing information, in clinical trials with tamsulosin monotherapy, positive orthostatic test result was observed in 16% (81/502) of subjects receiving 0.4 mg tamsulosin hydrochloride versus 11% (54/493) of subjects receiving placebo. Because orthostasis was detected more frequently in the tamsulosin-treated subjects than in placebo recipients, there is potential risk of syncope [see Warnings and Precautions (5.1)].. oThe most common adverse reactions reported in subjects receiving coadministered dutasteride and tamsulosin were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders, and dizziness. Ejaculation disorders occurred significantly more in subjects receiving coadministration therapy (11%) compared with those receiving dutasteride (2%) or tamsulosin (4%) as monotherapy.. oTrial withdrawal due to adverse reactions occurred in 6% of subjects receiving coadministered dutasteride and tamsulosin, and in 4% of subjects receiving dutasteride or tamsulosin as monotherapy. The most common adverse reaction in all treatment arms leading to trial withdrawal was erectile dysfunction (1% to 1.5%).. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of the individual components of JALYN. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. These reactions have been chosen for inclusion due to combination of their seriousness, frequency of reporting, or potential causal connection to drug exposure.DutasterideImmune System Disorders: Hypersensitivity reactions, including rash, pruritus, urticaria, localized edema, serious skin reactions, and angioedema.Neoplasms: Male breast cancer.Psychiatric Disorders: Depressed mood.Reproductive System and Breast Disorders: Testicular pain and testicular swelling.TamsulosinImmune System Disorders: Hypersensitivity reactions, including rash, urticaria, pruritus, angioedema, and respiratory problems have been reported with positive rechallenge in some cases.Cardiac Disorders: Palpitations, dyspnea, atrial fibrillation, arrhythmia, and tachycardia.Skin Disorders: Skin desquamation, including Stevens-Johnson syndrome, erythema multiforme, dermatitis exfoliative.Gastrointestinal Disorders: Constipation, vomiting, dry mouth.Reproductive System and Breast Disorders: Priapism.Respiratory: Epistaxis.Vascular Disorders: Hypotension.Ophthalmologic Disorders: Blurred vision, visual impairment. During cataract and glaucoma surgery, variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) associated with alpha-adrenergic-antagonist therapy [see Warnings and Precautions (5.9)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No non-clinical studies have been conducted with JALYN. The following information is based on studies performed with dutasteride or tamsulosin.CarcinogenesisDutasteride: 2-year carcinogenicity study was conducted in B6C3F1 mice at doses of 3, 35, 250, and 500 mg/kg/day for males and 3, 35, and 250 mg/kg/day for females; an increased incidence of benign hepatocellular adenomas was noted at 250 mg/kg/day (290-fold the MRHD of 0.5-mg daily dose) in female mice only. Two of the major human metabolites have been detected in mice. The exposure to these metabolites in mice is either lower than in humans or is not known.In 2-year carcinogenicity study in Han Wistar rats, at doses of 1.5, 7.5, and 53 mg/kg/day in males and 0.8, 6.3, and 15 mg/kg/day in females, there was an increase in Leydig cell adenomas in the testes at 135-fold the MRHD (53 mg/kg/day and greater). An increased incidence of Leydig cell hyperplasia was present at 52-fold the MRHD (male rat doses of 7.5 mg/kg/day and greater). positive correlation between proliferative changes in the Leydig cells and an increase in circulating luteinizing hormone levels has been demonstrated with 5-alpha-reductase inhibitors and is consistent with an effect on the hypothalamic-pituitary-testicular axis following 5-alpha-reductase inhibition. At tumorigenic doses, luteinizing hormone levels in rats were increased by 167%. In this study, the major human metabolites were tested for carcinogenicity at approximately to times the expected clinical exposure.Tamsulosin: In rat carcinogenicity assay, no increases in tumor incidence was observed in rats administered up to times the MRHD of 0.8 mg/day (based on AUC of animal doses up to 43 mg/kg/day in males and up to 52 mg/kg/day in females), with the exception of modest increase in the frequency of mammary gland fibroadenomas in female rats receiving doses of 5.4 mg/kg or greater.In carcinogenicity assay, mice were administered up to times the MRHD of tamsulosin (oral doses up to 127 mg/kg/day in males and 158 mg/kg/day in females). There were no significant tumor findings in male mice. Female mice treated for years with the highest doses of 45 and 158 mg/kg/day had statistically significant increases in the incidence of mammary gland fibroadenomas (P<0.0001) and adenocarcinomas.The increased incidences of mammary gland neoplasms in female rats and mice were considered secondary to tamsulosin-induced hyperprolactinemia. It is not known if tamsulosin elevates prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known.MutagenesisDutasteride: Dutasteride was tested for genotoxicity in bacterial mutagenesis assay (Ames test), chromosomal aberration assay in Chinese hamster ovary (CHO) cells, and micronucleus assay in rats. The results did not indicate any genotoxic potential of the parent drug. Two major human metabolites were also negative in either the Ames test or an abbreviated Ames test.Tamsulosin: Tamsulosin produced no evidence of mutagenic potential in vitro in the Ames reverse mutation test, mouse lymphoma thymidine kinase assay, unscheduled DNA repair synthesis assay, and chromosomal aberration assays in CHO cells or human lymphocytes. There were no mutagenic effects in the in vivo sister chromatid exchange and mouse micronucleus assay.Impairment of FertilityDutasteride: Treatment of sexually mature male rats with dutasteride at 0.1 times the MRHD (animal doses of 0.05 mg/kg/day or greater for up to 31 weeks) based on mean serum concentration resulted in dose- and time-dependent decreases in fertility at all doses; reduced cauda epididymal (absolute) sperm counts but not sperm concentration (at 50 and 500 mg/kg/day); reduced weights of the epididymis, prostate, and seminal vesicles; and microscopic changes (cytoplasmic vacuolation of tubular epithelium in the epididymides and/or decreased cytoplasmic content of epithelium, consistent with decreased secretory activity in the prostate and seminal vesicles) in the reproductive organs at all doses in the absence of paternal toxicity. The fertility effects were reversed by Recovery Week at all doses, and sperm counts were normal at the end of 14-week recovery period. The microscopic changes were no longer present at Recovery Week 14 at 0.1 times the MRHD and were partly recovered in the remaining treatment groups. Low levels of dutasteride (0.6 to 17 ng/mL) were detected in the serum of untreated female rats mated to treated males (10 to 500 mg/kg/day for 29 to 30 weeks) which are 16 to 110 times the MRHD based on mean serum concentration. No feminization occurred in male offspring of untreated female rats mated to treated male rats even though detectable blood levels of dutasteride were observed in the female rats.In fertility study in female rats with dosing weeks prior to mating through early gestation, oral administration of dutasteride at doses of 0.05, 2.5, 12.5, and 30 mg/kg/day resulted in reduced litter size due to increased resorptions and in feminization of male fetuses (decreased anogenital distance) at to 10 times the MRHD (animal doses of 2.5 mg/kg/day or greater) based on mean serum concentration, in the presence of maternal toxicity (decreased body weight gain). Fetal body weights were also reduced at approximately 0.02 times the MRHD (rat dose of 0.05 mg/kg/day or greater) based on mean serum concentration, with no no-effect level, in the absence of maternal toxicity.Tamsulosin: Studies in rats revealed significantly reduced fertility in males dosed with single or multiple daily doses of 300 mg/kg/day of tamsulosin hydrochloride (AUC exposure in rats about 50 times the human exposure with the maximum therapeutic dose). The mechanism of decreased fertility in male rats is considered to be an effect of the compound on the vaginal plug formation possibly due to changes of semen content or impairment of ejaculation. The effects on fertility were reversible, showing improvement by days after single dose and weeks after multiple daily dosing. Effects on fertility in males were completely reversed within weeks after discontinuation of multiple daily dosing. Multiple doses of 10 and 100 mg/kg/day tamsulosin hydrochloride (1/5 and 16 times the anticipated human AUC exposure) did not significantly alter fertility in male rats. Effects of tamsulosin on sperm counts or sperm function have not been evaluated.Studies in female rats revealed significant reductions in fertility after single or multiple daily doses of 300 mg/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 daily doses of 10 or 100 mg/kg/day of the racemic mixture did not significantly alter fertility in female rats.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. JALYN is combination of drugs with different mechanisms of action to improve symptoms in patients with BPH: dutasteride, 5-alpha-reductase inhibitor, and tamsulosin, an antagonist of alpha1A-adrenoreceptors.DutasterideDutasteride inhibits the conversion of testosterone to DHT. DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme alpha-reductase, which exists as isoforms, type and type 2. The type isoenzyme is primarily active in the reproductive tissues, while the type isoenzyme is also responsible for testosterone conversion in the skin and liver.Dutasteride is competitive and specific inhibitor of both type and type 5-alpha-reductase isoenzymes, with which it forms stable enzyme complex. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride does not bind to the human androgen receptor.TamsulosinSmooth muscle tone is mediated by the sympathetic nervous stimulation of alpha1-adrenoceptors, which are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and reduction in symptoms of BPH.Tamsulosin, an alpha1-adrenoceptor blocking agent, exhibits selectivity for alpha1-receptors in the human prostate. At least discrete alpha1-adrenoceptor subtypes have been identified: alpha1A, alpha1B, and alpha1D; their distribution differs between human organs and tissue. Approximately 70% of the alpha1-receptors in human prostate are of the alpha1A subtype. Tamsulosin is not intended for use as an antihypertensive.. 12.2 Pharmacodynamics. DutasterideEffect on Alpha-Dihydrotestosterone and Testosterone: The maximum effect of daily doses of dutasteride on the reduction of DHT is dose-dependent and is observed within to weeks. After and weeks of daily dosing with dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. In patients with BPH treated with dutasteride 0.5 mg/day for years, the median decrease in serum DHT was 94% at year, 93% at years, and 95% at both and years. The median increase in serum testosterone was 19% at both and years, 26% at years, and 22% at years, but the mean and median levels remained within the physiologic range.In patients with BPH treated with mg/day of dutasteride or placebo for up to 12 weeks prior to transurethral resection of the prostate, mean DHT concentrations in prostatic tissue were significantly lower in the dutasteride group compared with placebo (784 and 5,793 pg/g, respectively, P<0.001). Mean prostatic tissue concentrations of testosterone were significantly higher in the dutasteride group compared with placebo (2,073 and 93 pg/g, respectively, P<0.001).Adult males with genetically inherited type 5-alpha-reductase deficiency also have decreased DHT levels. These 5-alpha-reductase-deficient males have small prostate gland throughout life and do not develop BPH. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to 5-alpha-reductase deficiency have been observed in these individuals.Effects on Other Hormones: In healthy volunteers, 52 weeks of treatment with dutasteride 0.5 mg/day (n 26) resulted in no clinically significant change compared with placebo (n 23) in sex hormone-binding globulin, estradiol, luteinizing hormone, follicle-stimulating hormone, thyroxine (free T4), and dehydroepiandrosterone. Statistically significant, baseline-adjusted mean increases compared with placebo were observed for total testosterone at weeks (97.1 ng/dL, P<0.003) and thyroid-stimulating hormone at 52 weeks (0.4 mcIU/mL, P<0.05). The median percentage changes from baseline within the dutasteride group were 17.9% for testosterone at weeks and 12.4% for thyroid-stimulating hormone at 52 weeks. After stopping dutasteride for 24 weeks, the mean levels of testosterone and thyroid-stimulating hormone had returned to baseline in the group of subjects with available data at the visit. In subjects with BPH treated with dutasteride in large randomized, double-blind, placebo-controlled trial, there was median percent increase in luteinizing hormone of 12% at months and 19% at both 12 and 24 months.Other Effects: Plasma lipid panel and bone mineral density were evaluated following 52 weeks of dutasteride 0.5 mg once daily in healthy volunteers. There was no change in bone mineral density as measured by dual energy x-ray absorptiometry compared with either placebo or baseline. In addition, the plasma lipid profile (i.e., total cholesterol, low density lipoproteins, high density lipoproteins, triglycerides) was unaffected by dutasteride. No clinically significant changes in adrenal hormone responses to adrenocorticotropic hormone (ACTH) stimulation were observed in subset population (n 13) of the 1-year healthy volunteer trial.. 12.3 Pharmacokinetics. The pharmacokinetics of dutasteride and tamsulosin from JALYN are comparable to the pharmacokinetics of dutasteride and tamsulosin when administered separately.AbsorptionThe pharmacokinetic parameters of dutasteride and tamsulosin observed after administration of JALYN in single-dose, randomized, 3-period, partial cross-over trial are summarized in Table below.Table 2. Arithmetic Means (SD) of Serum Dutasteride and Tamsulosin in Single-dose Pharmacokinetic Parameters under Fed Conditionsa Median (range). N 91.ComponentNAUC(0-t) (ng h/mL)Cmax (ng/mL)Tmax (h)a 1/2 (h)Dutasteride9239.6 (23.1)2.14 (0.77)3.00 (1.00-10.00)Tamsulosin92187.2 (95.7)11.3 (4.44)6.00 (2.00-24.00)13.5 (3.92)b Dutasteride: Following administration of single 0.5-mg dose of soft gelatin capsule, time to peak absolute bioavailability in healthy subjects is approximately 60% (range: 40% to 94%).Tamsulosin: Absorption of tamsulosin is essentially complete (>90%) following oral administration of 0.4-mg tamsulosin hydrochloride capsules under fasting conditions. Tamsulosin exhibits linear kinetics following single and multiple dosing, with achievement of steady-state concentrations by the fifth day of once-daily dosing.Effect of FoodFood does not affect the pharmacokinetics of dutasteride following administration of JALYN. However, mean 30% decrease in tamsulosin Cmax was observed when JALYN was administered with food, similar to that seen when tamsulosin monotherapy was administered under fed versus fasting conditions.DistributionDutasteride: Pharmacokinetic data following single and repeat oral doses show that dutasteride has large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma albumin (99.0%) and alpha-1 acid glycoprotein (AAG, 96.6%).In trial of healthy subjects (n 26) receiving dutasteride 0.5 mg/day for 12 months, semen dutasteride concentrations averaged 3.4 ng/mL (range: 0.4 to 14 ng/mL) at 12 months and, similar to serum, achieved steady-state concentrations at months. On average, at 12 months 11.5% of serum dutasteride concentrations partitioned into semen.Tamsulosin: The mean steady-state apparent volume of distribution of tamsulosin after intravenous administration to 10 healthy male adults was 16 L, which is suggestive of distribution into extracellular fluids in the body.Tamsulosin is extensively bound to human plasma proteins (94% to 99%), primarily AAG, with linear binding over wide concentration range (20 to 600 ng/mL). The results of 2-way in vitro studies indicate that the binding of tamsulosin to human plasma proteins is not affected by amitriptyline, diclofenac, glyburide, simvastatin plus simvastatin-hydroxy acid metabolite, warfarin, diazepam, or propranolol. Likewise, tamsulosin had no effect on the extent of binding of these drugs.MetabolismDutasteride: Dutasteride is extensively metabolized in humans. In vitro studies showed that dutasteride is metabolized by the CYP3A4 and CYP3A5 isoenzymes. Both of these isoenzymes produced the 4-hydroxydutasteride, 6-hydroxydutasteride, and the 6,4-dihydroxydutasteride metabolites. In addition, the 15-hydroxydutasteride metabolite was formed by CYP3A4. Dutasteride is not metabolized in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In human serum following dosing to steady state, unchanged dutasteride, major metabolites (4-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride), and minor metabolites (6,4-dihydroxydutasteride and 15-hydroxydutasteride), as assessed by mass spectrometric response, have been detected. The absolute stereochemistry of the hydroxyl additions in the and 15 positions is not known. In vitro, the 4-hydroxydutasteride and 1,2-dihydrodutasteride metabolites are much less potent than dutasteride against both isoforms of human 5-reductase. The activity of 6-hydroxydutasteride is comparable to that of dutasteride.Tamsulosin: There is no enantiomeric bioconversion from tamsulosin [R(-) isomer] to the S(+) isomer in humans. Tamsulosin is extensively metabolized by cytochrome P450 enzymes in the liver and less than 10% of the dose is excreted in urine unchanged. However, the pharmacokinetic profile of the metabolites in humans has not been established. In vitro studies indicate that CYP3A4 and CYP2D6 are involved in metabolism of tamsulosin as well as some minor participation of other CYP isoenzymes. Inhibition of hepatic drug-metabolizing enzymes may lead to increased exposure to tamsulosin [see Drug Interactions (7.1)]. The metabolites of tamsulosin undergo extensive conjugation to glucuronide or sulfate prior to renal excretion.Incubations with human liver microsomes showed no evidence of clinically significant metabolic interactions between tamsulosin and amitriptyline, albuterol, glyburide, and finasteride. However, results of the in vitro testing of the tamsulosin interaction with diclofenac and warfarin were equivocal.ExcretionDutasteride: Dutasteride and its metabolites were excreted mainly in feces. As percent of dose, there was approximately 5% unchanged dutasteride (approximately 1% to approximately 15%) and 40% as dutasteride-related metabolites (approximately 2% to approximately 90%). Only trace amounts of unchanged dutasteride were found in urine (<1%). Therefore, on average, the dose unaccounted for approximated 55% (range: 5% to 97%). The terminal elimination half-life of dutasteride is approximately weeks at steady state. The average steady-state serum dutasteride concentration was 40 ng/mL following 0.5 mg/day for year. Following daily dosing, dutasteride serum concentrations achieve 65% of steady-state concentration after month and approximately 90% after months. Due to the long half-life of dutasteride, serum concentrations remain detectable (greater than 0.1 ng/mL) for up to to months after discontinuation of treatment.Tamsulosin: On administration of the radiolabeled dose of tamsulosin to healthy volunteers, 97% of the administered radioactivity was recovered, with urine (76%) representing the primary route of excretion compared with feces (21%) over 168 hours.Following intravenous or oral administration of an immediate-release formulation, the elimination half-life of tamsulosin in plasma ranges from to hours. Because of absorption rate-controlled pharmacokinetics with tamsulosin hydrochloride capsules, the apparent half-life of tamsulosin is approximately to 13 hours in healthy volunteers and 14 to 15 hours in the target population.Tamsulosin undergoes restrictive clearance in humans, with relatively low systemic clearance (2.88 L/h).Specific PopulationsPediatric Patients: The pharmacokinetics of dutasteride and tamsulosin administered together have not been investigated in subjects younger than 18 years.Geriatric Patients: Dutasteride and tamsulosin pharmacokinetics using JALYN have not been studied in geriatric patients. The following text reflects information for the individual components. Dutasteride: No dosage adjustment is necessary in the elderly. The pharmacokinetics and pharmacodynamics of dutasteride were evaluated in 36 healthy male subjects aged between 24 and 87 years following administration of single 5-mg dose of dutasteride. In this single-dose trial, dutasteride half-life increased with age (approximately 170 hours in men aged 20 to 49 years, approximately 260 hours in men aged 50 to 69 years, and approximately 300 hours in men older than 70 years). Tamsulosin: Cross-study comparison of tamsulosin overall exposure (AUC) and half-life indicate that the pharmacokinetic disposition of tamsulosin may be slightly prolonged in geriatric males compared with young, healthy male volunteers. Intrinsic clearance is independent of tamsulosin binding to AAG, but diminishes with age, resulting in 40% overall higher exposure (AUC) in subjects aged 55 to 75 years compared with subjects aged 20 to 32 years.Male and Female Patients:Dutasteride: Dutasteride is contraindicated in females who are pregnant and is not indicated for use in females [see Contraindications (4), Warnings and Precautions (5.6)]. The pharmacokinetics of dutasteride in females have not been studied. Tamsulosin: Tamsulosin is not indicated for use in females. No information is available on the pharmacokinetics of tamsulosin in females.Racial and Ethnic Groups: The effect of race on the pharmacokinetics of dutasteride and tamsulosin administered together or separately has not been studied.Patients with Renal Impairment: The effect of renal impairment on dutasteride and tamsulosin pharmacokinetics has not been studied using JALYN. The following text reflects information for the individual components. Dutasteride: The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of steady-state 0.5-mg dose of dutasteride is recovered in human urine, so no adjustment in dosage is anticipated for patients with renal impairment. Tamsulosin: The pharmacokinetics of tamsulosin have been compared in subjects with mild-moderate (30<= CLcr <70 mL/min/1.73 m2) or moderate-severe (10<= CLcr <30 mL/min/1.73 m2) renal impairment and normal subjects (CLcr >90 mL/min/1.73 m2). While change in the overall plasma concentration of tamsulosin was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin, as well as the intrinsic clearance, remained relatively constant. Therefore, patients with renal impairment do not require an adjustment in tamsulosin dosing. However, patients with end-stage renal disease (CLcr <10 mL/min/1.73 m2) have not been studied.Patients with Hepatic Impairment: The effect of hepatic impairment on dutasteride and tamsulosin pharmacokinetics has not been studied using JALYN. The following text reflects information available for the individual components. Dutasteride: The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients. Tamsulosin: The pharmacokinetics of tamsulosin have been compared in subjects with moderate hepatic impairment (Child-Pugh classification: Grades and B) and normal subjects. While change in the overall plasma concentration of tamsulosin was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin does not change significantly with only modest (32%) change in intrinsic clearance of unbound tamsulosin. Therefore, patients with moderate hepatic impairment do not require an adjustment in tamsulosin dosage. Tamsulosin has not been studied in patients with severe hepatic impairment.Drug Interaction StudiesThere have been no drug interaction studies using JALYN. The following text reflects information available for the individual components.Cytochrome P450 Inhibitors:Dutasteride: No clinical drug interaction trials have been performed to evaluate the impact of CYP3A enzyme inhibitors on dutasteride pharmacokinetics. However, based on in vitro data, blood concentrations of dutasteride may increase in the presence of inhibitors of CYP3A4/5 such as ritonavir, ketoconazole, verapamil, diltiazem, cimetidine, troleandomycin, and ciprofloxacin.Dutasteride does not inhibit the in vitro metabolism of model substrates for the major human cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentration of 1,000 ng/mL, 25 times greater than steady-state serum concentrations in humans. Tamsulosin: Strong and Moderate Inhibitors of CYP3A4 or CYP2D6: The effects of ketoconazole (a strong inhibitor of CYP3A4) at 400 mg once daily for days on the pharmacokinetics of single tamsulosin hydrochloride capsule 0.4-mg dose was investigated in 24 healthy volunteers (age range: 23 to 47 years). Concomitant treatment with ketoconazole resulted in increases in the Cmax and AUC of tamsulosin by factors of 2.2 and 2.8, respectively. The effects of concomitant administration of moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of tamsulosin have not been evaluated.The effects of paroxetine (a strong inhibitor of CYP2D6) at 20 mg once daily for days on the pharmacokinetics of single tamsulosin capsule 0.4-mg dose was investigated in 24 healthy volunteers (age range: 23 to 47 years). Concomitant treatment with paroxetine resulted in increases in the Cmax and AUC of tamsulosin by factors of 1.3 and 1.6, respectively. similar increase in exposure is expected in poor metabolizers (PM) of CYP2D6 as compared with extensive metabolizers (EM). fraction of the population (about 7% of whites and 2% of African-Americans) are CYP2D6 PMs. Since CYP2D6 PMs cannot be readily identified and the potential for significant increase in tamsulosin exposure exists when tamsulosin 0.4 mg is coadministered with strong CYP3A4 inhibitors in CYP2D6 PMs, tamsulosin 0.4-mg capsules should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole).The effects of concomitant administration of moderate CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of tamsulosin have not been evaluated.The effects of coadministration of both CYP3A4 and CYP2D6 inhibitor with tamsulosin capsules have not been evaluated. However, there is potential for significant increase in tamsulosin exposure when tamsulosin 0.4 mg is coadministered with combination of both CYP3A4 and CYP2D6 inhibitors.Cimetidine: The effects of cimetidine at the highest recommended dose (400 mg every hours for days) on the pharmacokinetics of single tamsulosin capsule 0.4-mg dose was investigated in 10 healthy volunteers (age range: 21 to 38 years). Treatment with cimetidine resulted in significant decrease (26%) in the clearance of tamsulosin hydrochloride, which resulted in moderate increase in tamsulosin hydrochloride AUC (44%).Alpha-adrenergic Antagonists:Dutasteride: In single-sequence, crossover trial in healthy volunteers, the administration of tamsulosin or terazosin in combination with dutasteride had no effect on the steady-state pharmacokinetics of either alpha-adrenergic antagonist. Although the effect of administration of tamsulosin or terazosin on dutasteride pharmacokinetic parameters was not evaluated, the percent change in DHT concentrations was similar for dutasteride, alone or in combination with tamsulosin or terazosin.Warfarin: Dutasteride: In trial of 23 healthy volunteers, weeks of treatment with dutasteride 0.5 mg/day did not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time when administered with warfarin. Tamsulosin: definitive drug-drug interaction trial between tamsulosin and warfarin was not conducted. Results from limited in vitro and in vivo studies are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and tamsulosin.Nifedipine, Atenolol, Enalapril:Tamsulosin: In trials in hypertensive subjects (age range: 47 to 79 years) whose blood pressure was controlled with stable doses of nifedipine extended-release, atenolol, or enalapril for at least months, tamsulosin hydrochloride capsules 0.4 mg for days followed by tamsulosin hydrochloride capsules 0.8 mg for another days (n 8 per trial) resulted in no clinically significant effects on blood pressure and pulse rate compared with placebo (n 4 per trial). Therefore, dosage adjustments are not necessary when tamsulosin is administered concomitantly with nifedipine extended-release, atenolol, or enalapril.Digoxin and Theophylline:Dutasteride: In trial of 20 healthy volunteers, dutasteride did not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at dose of 0.5 mg/day for weeks. Tamsulosin: In trials in healthy volunteers (n 10 per trial; age range: 19 to 39 years) receiving tamsulosin capsules 0.4 mg/day for days, followed by tamsulosin capsules 0.8 mg/day for to days, single intravenous doses of digoxin 0.5 mg or theophylline mg/kg resulted in no change in the pharmacokinetics of digoxin or theophylline. Therefore, dosage adjustments are not necessary when tamsulosin capsule is administered concomitantly with digoxin or theophylline.Furosemide:Tamsulosin: The pharmacokinetic and pharmacodynamic interaction between tamsulosin hydrochloride capsules 0.8 mg/day (steady-state) and furosemide 20 mg intravenously (single dose) was evaluated in 10 healthy volunteers (age range: 21 to 40 years). Tamsulosin had no effect on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an 11% to 12% reduction in tamsulosin Cmax and AUC, these changes are expected to be clinically insignificant and do not require dose adjustment for tamsulosin.Calcium Channel Antagonists:Dutasteride: In population pharmacokinetics analysis, decrease in clearance of dutasteride was noted when coadministered with the CYP3A4 inhibitors verapamil (-37%, = 6) and diltiazem (-44%, = 5). In contrast, no decrease in clearance was seen when amlodipine, another calcium channel antagonist that is not CYP3A4 inhibitor, was coadministered with dutasteride (+7%, = 4). The decrease in clearance and subsequent increase in exposure to dutasteride in the presence of verapamil and diltiazem is not considered to be clinically significant. No dosage adjustment is recommended.Cholestyramine:Dutasteride: Administration of single 5-mg dose of dutasteride followed hour later by 12 cholestyramine did not affect the relative bioavailability of dutasteride in 12 normal volunteers.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The trial supporting the efficacy of JALYN was 4-year multicenter, randomized, double-blind, parallel-group trial (CombAT trial) investigating the efficacy of the coadministration of dutasteride 0.5 mg/day and tamsulosin hydrochloride 0.4 mg/day (n 1,610) compared with dutasteride alone (n 1,623) or tamsulosin alone (n 1,611). Subjects were aged at least 50 years with serum PSA >=1.5 ng/mL and <10 ng/mL and BPH diagnosed by medical history and physical examination, including enlarged prostate (>=30 cc) and BPH symptoms that were moderate to severe according to the International Prostate Symptom Score (IPSS). Eighty-eight percent (88%) of the enrolled trial population was white. Approximately 52% of subjects had previous exposure to 5-alpha-reductase inhibitor or alpha-adrenergic antagonist treatment. Of the 4,844 subjects randomly assigned to receive treatment, 69% of subjects in the coadministration group, 67% in the dutasteride group, and 61% in the tamsulosin group completed years of double-blind treatment.Effect on Symptom ScoreSymptoms were quantified using the first questions of the International Prostate Symptom Score (IPSS). The baseline score was approximately 16.4 units for each treatment group. Coadministration therapy was statistically superior to each of the monotherapy treatments in decreasing symptom score at Month 24, the primary time point for this endpoint. At Month 24, 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 mean difference between coadministration and dutasteride of -1.3 units (P<0.001; [95% CI: -1.69, -0.86]), and between coadministration and tamsulosin of -1.8 units (P<0.001; [95% CI: -2.23, -1.40]). significant difference was seen by Month and continued through Month 48. 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 mean difference between coadministration and dutasteride of -0.96 units (P<0.001; [95% CI: -1.40, -0.52]), and between coadministration and tamsulosin of -2.5 units (P<0.001; [95% CI: -2.96, -2.07]). See Figure 1.Figure 1. International Prostate Symptom Score Change from Baseline over 48-Month Period (Randomized, Double-blind, Parallel-group Trial [CombAT Trial]) Effect on Acute Urinary Retention (AUR) or the Need for BPH-related SurgeryAfter years of treatment, coadministration therapy with dutasteride and tamsulosin did not provide benefit over dutasteride monotherapy in reducing the incidence of AUR or BPH-related surgery. In separate 2-year randomized, double-blind trials, compared with placebo, dutasteride monotherapy was associated with statistically significantly lower incidence of AUR (1.8% for dutasteride versus 4.2% for placebo; 57% reduction in risk) and with statistically significantly lower incidence of BPH-related surgery (2.2% for dutasteride versus. 4.1% for placebo; 48% reduction in risk).Effect on Maximum Urine Flow RateThe baseline Qmax was approximately 10.7 mL/sec for each treatment group. Coadministration therapy was statistically superior to each of the monotherapy treatments in increasing Qmax at Month 24, the primary time point for this endpoint. At Month 24, the mean increases from baseline (+-SD) in Qmax were 2.4 (+-5.26) mL/sec for coadministration group, 1.9 (+-5.10) mL/sec for dutasteride, and 0.9 (+-4.57) mL/sec for tamsulosin, with mean difference between coadministration and dutasteride of 0.5 mL/sec (P 0.003; [95% CI: 0.17, 0.84]), and between coadministration and tamsulosin of 1.5 mL/sec (P<0.001; [95% CI: 1.19, 1.86]). This difference was seen by Month and continued through Month 24. See Figure 2.The additional improvement in Qmax of coadministration therapy over dutasteride monotherapy was no longer statistically significant at Month 48.Figure 2. Qmax Change from Baseline over 24-Month Period (Randomized, Double-blind, Parallel-group Trial [CombAT Trial])Effect on Prostate VolumeThe mean prostate volume at trial entry was approximately 55 cc. At Month 24, the primary time point for this endpoint, the mean percent changes from baseline (+-SD) in prostate volume were -26.9% (+-22.57) for coadministration therapy, -28.0% (+-24.88) for dutasteride, and 0% (+-31.14) for tamsulosin, with mean difference between coadministration and dutasteride of 1.1% (P NS; [95% CI: -0.6, 2.8]), and between coadministration and tamsulosin of -26.9% (P<0.001; [95% CI: -28.9, -24.9]). Similar changes were seen at Month 48: -27.3% (+-24.91) for coadministration therapy, -28.0% (+-25.74) for dutasteride, and +4.6% (+-35.45) for tamsulosin.. Figure 1. Figure 2.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oOrthostatic hypotension and/or syncope can occur. Advise patients of symptoms related to postural hypotension and to avoid situations where injury could result if syncope occurs. (5.1)oDo not use JALYN with other alpha-adrenergic antagonists, as this may increase the risk of hypotension. (5.2)oJALYN reduces serum prostate-specific antigen (PSA) concentration by approximately 50%. However, any confirmed increase in PSA while on JALYN may signal the presence of prostate cancer and should be evaluated, even if those values are still within the normal range for untreated men. (5.3) oDo not use JALYN with strong inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole). Use caution in combination with moderate CYP3A4 inhibitors (e.g., erythromycin) or strong (e.g., paroxetine) or moderate CYP2D6 inhibitors, combination of both CYP3A4 and CYP2D6 inhibitors, or known poor metabolizers of CYP2D6. Concomitant use with known inhibitors can cause marked increase in drug exposure. (5.2, 7.1, 12.3)oExercise caution with concomitant use phosphodiesterase-5 (PDE-5) inhibitors, as this may increase the risk of hypotension. (5.2)oDrugs that contain dutasteride, including JALYN, may increase the risk of high-grade prostate cancer. (5.4, 6.1)oPrior to initiating treatment with JALYN, consideration should be given to other urological conditions that may cause similar symptoms. (5.5)oFemales who are pregnant or may be pregnant should not handle JALYN capsules due to potential risk to male fetus. (5.6, 8.1)oAdvise patients about the possibility and seriousness of priapism. (5.7)oPatients should not donate blood until months after their last dose of JALYN. (5.8)oIntraoperative Floppy Iris Syndrome has been observed during cataract and glaucoma surgery after alpha-adrenergic antagonist exposure. Advise patients considering cataract or glaucoma surgery to tell their ophthalmologist that they take or have taken JALYN capsules. (5.9)oExercise caution with concomitant use of warfarin. (5.2, 7.2, 12.3). oOrthostatic hypotension and/or syncope can occur. Advise patients of symptoms related to postural hypotension and to avoid situations where injury could result if syncope occurs. (5.1). oDo not use JALYN with other alpha-adrenergic antagonists, as this may increase the risk of hypotension. (5.2). oJALYN reduces serum prostate-specific antigen (PSA) concentration by approximately 50%. However, any confirmed increase in PSA while on JALYN may signal the presence of prostate cancer and should be evaluated, even if those values are still within the normal range for untreated men. (5.3) oDo not use JALYN with strong inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole). Use caution in combination with moderate CYP3A4 inhibitors (e.g., erythromycin) or strong (e.g., paroxetine) or moderate CYP2D6 inhibitors, combination of both CYP3A4 and CYP2D6 inhibitors, or known poor metabolizers of CYP2D6. Concomitant use with known inhibitors can cause marked increase in drug exposure. (5.2, 7.1, 12.3). oExercise caution with concomitant use phosphodiesterase-5 (PDE-5) inhibitors, as this may increase the risk of hypotension. (5.2). oDrugs that contain dutasteride, including JALYN, may increase the risk of high-grade prostate cancer. (5.4, 6.1). oPrior to initiating treatment with JALYN, consideration should be given to other urological conditions that may cause similar symptoms. (5.5). oFemales who are pregnant or may be pregnant should not handle JALYN capsules due to potential risk to male fetus. (5.6, 8.1). oAdvise patients about the possibility and seriousness of priapism. (5.7). oPatients should not donate blood until months after their last dose of JALYN. (5.8). oIntraoperative Floppy Iris Syndrome has been observed during cataract and glaucoma surgery after alpha-adrenergic antagonist exposure. Advise patients considering cataract or glaucoma surgery to tell their ophthalmologist that they take or have taken JALYN capsules. (5.9). oExercise caution with concomitant use of warfarin. (5.2, 7.2, 12.3). 5.1 Orthostatic Hypotension. As with other alpha-adrenergic antagonists, orthostatic hypotension (postural hypotension, dizziness, and vertigo) may occur in patients treated with tamsulosin-containing products, including JALYN, and can result in syncope. Patients starting treatment with JALYN should be cautioned to avoid situations where syncope could result in an injury [see Adverse Reactions (6.1)].. 5.2 Drug-Drug Interactions. Strong Inhibitors of Cytochrome P450 (CYP) 3A4Tamsulosin-containing products, including JALYN, should not be coadministered with strong CYP3A4 inhibitors (e.g., ketoconazole) as this can significantly increase tamsulosin exposure [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. Moderate Inhibitors of CYP3A4, Inhibitors of CYP2D6, or Combination of Both CYP3A4 and CYP2D6 InhibitorsTamsulosin-containing products, including JALYN, should be used with caution when coadministered with moderate inhibitors of CYP3A4 (e.g., erythromycin), strong (e.g., paroxetine) or moderate (e.g., terbinafine) inhibitors of CYP2D6, combination of both CYP3A4 and CYP2D6 inhibitors, or in patients known to be poor metabolizers of CYP2D6, as there is potential for significant increase in tamsulosin exposure [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].CimetidineCaution is advised when tamsulosin-containing products, including JALYN, are coadministered with cimetidine [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].Other Alpha-adrenergic AntagonistsTamsulosin-containing products, including JALYN, should not be coadministered with other alpha-adrenergic antagonists because of the increased risk of symptomatic hypotension.Phosphodiesterase-5 (PDE-5) InhibitorsCaution is advised when alpha-adrenergic-antagonist-containing products, including JALYN, are coadministered with PDE-5 inhibitors. Alpha-adrenergic antagonists and PDE-5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these drug classes can potentially cause symptomatic hypotension.WarfarinCaution should be exercised with concomitant administration of warfarin and tamsulosin-containing products, including JALYN [see Drug Interactions (7.2), Clinical Pharmacology (12.3)].. 5.3 Effects on Prostate-Specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection. Coadministration of dutasteride with tamsulosin resulted in similar changes to serum PSA as with dutasteride monotherapy.In clinical trials, dutasteride reduced serum PSA concentration by approximately 50% within to months of treatment. This decrease was predictable over the entire range of PSA values in patients with symptomatic BPH, although it may vary in individuals. Dutasteride-containing treatment, including JALYN, may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men treated with dutasteride-containing product, including JALYN, new baseline PSA should be established at least months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on dutasteride-containing treatment, including JALYN, may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking 5-alpha-reductase inhibitor. Noncompliance with JALYN may also affect PSA test results.To interpret an isolated PSA value in man treated with JALYN, for months or more, the PSA value should be doubled for comparison with normal values in untreated men.The free-to-total PSA ratio (percent free PSA) remains constant, even under the influence of dutasteride. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving JALYN, no adjustment to its value appears necessary.. 5.4 Increased Risk of High-Grade Prostate Cancer. In men aged 50 to 75 years with prior negative biopsy for prostate cancer and baseline PSA between 2.5 ng/mL and 10.0 ng/mL taking dutasteride in the 4-year Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, there was an increased incidence of Gleason score to 10 prostate cancer compared with men taking placebo (dutasteride 1.0% versus placebo 0.5%) [see Indications and Usage (1.2), Adverse Reactions (6.1)]. In 7-year placebo-controlled clinical trial with another 5-alpha-reductase inhibitor (finasteride mg, PROSCAR), similar results for Gleason score to 10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%).5-alpha-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5-alpha-reductase inhibitors to reduce prostate volume or trial-related factors impacted the results of these trials has not been established.. 5.5 Evaluation for Other Urological Diseases. Prior to initiating treatment with JALYN, consideration should be given to other urological conditions that may cause similar symptoms. In addition, BPH and prostate cancer may coexist.. 5.6 Transdermal Exposure of JALYN in Pregnant Females--Risk to Male Fetus. JALYN capsules should not be handled by females who are pregnant or may be pregnant. Dutasteride can be absorbed through the skin and could result in unintended fetal exposure and potential risk to male fetus. If female who is or may be pregnant comes in contact with leaking capsule, the contact area should be washed immediately with soap and water [see Use in Specific Populations (8.1)]. Dutasteride can be absorbed through the skin based on animal studies [see Nonclinical Toxicology (13.2)].. 5.7 Priapism. Priapism (persistent painful penile erection unrelated to sexual activity) has been associated (probably less than in 50,000) with the use of alpha-adrenergic antagonists, including tamsulosin, which is component of JALYN. Because this condition can lead to permanent impotence if not properly treated, patients should be advised about the seriousness of the condition.. 5.8 Blood Donation. Men being treated with dutasteride-containing product, including JALYN, should not donate blood until at least months have passed following their last dose. The purpose of this deferred period is to prevent administration of dutasteride to pregnant female transfusion recipient.. 5.9 Intraoperative Floppy Iris Syndrome. Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract and glaucoma surgery in some patients on or previously treated with alpha-adrenergic antagonists, including tamsulosin, which is component of JALYN. Most reports were in patients taking the alpha-adrenergic antagonist when IFIS occurred, but in some cases, the alpha-adrenergic antagonist had been stopped prior to surgery. In most of these cases, the alpha-adrenergic antagonist had been stopped recently prior to surgery (2 to 14 days), but in few cases, IFIS was reported after the patients had been off the alpha-adrenergic antagonist for longer period (5 weeks to months). IFIS is variant of small pupil syndrome and is characterized by the combination of flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patients ophthalmologist should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. IFIS may increase the risk of eye complications during and after the operation. The benefit of stopping alpha-adrenergic antagonist therapy prior to cataract or glaucoma surgery has not been established. The initiation of therapy with tamsulosin in patients for whom cataract or glaucoma surgery is scheduled is not recommended.. 5.10 Sulfa Allergy. In patients with sulfa allergy, allergic reaction to tamsulosin has been rarely reported. If patient reports serious or life-threatening sulfa allergy, caution is warranted when administering tamsulosin-containing products, including JALYN.. 5.11 Effect on Semen Characteristics. DutasterideThe effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in healthy men throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, compared with placebo, dutasteride treatment resulted in mean reduction in total sperm count, semen volume, and sperm motility; the effects on total sperm count were not reversible after 24 weeks of follow-up. Sperm concentration and sperm morphology were unaffected and mean values for all semen parameters remained within the normal range at all timepoints. The clinical significance of the effect of dutasteride on semen characteristics for an individual patients fertility is not known [see Use in Specific Populations (8.3)].TamsulosinThe effects of tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated.