Dutasteride and tamsulosin hydrochloride .5 mg; .4 mg Capsule, 30-count — NDC 68382-640-06 (Billing 68382-0640-06)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Dutasteride and tamsulosin hydrochloride capsules are a combination of 2 drugs with different mechanisms of action to improve symptoms in patients with BPH: dutasteride, a 5-alpha-reductase inhibitor, and tamsulosin, an antagonist of alpha1A-adrenoreceptors. Dutasteride: Dutasteride 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 5 alpha-reductase, which exists as 2 isoforms, type 1 and type 2. The type 2 isoenzyme is primarily active in the reproductive tissues, while the type 1 isoenzyme is also responsible for testosterone conversion in the skin and liver. Dutasteride is a competitive and specific inhibitor of both type 1 and type 2 5-alpha-reductase isoenzymes, with which it forms a 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. Tamsulosin: Smooth 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 a reduction in symptoms of BPH. Tamsulosin, an alpha1-adrenoceptor blocking agent, exhibits selectivity for alpha1-receptors in the human prostate. At least 3 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.

12.2Pharmacodynamics Dutasteride Effect on 5 Alpha-Dihydrotestosterone and Testosterone The maximum effect of daily doses of dutasteride on the reduction of DHT is dose-dependent and is observed within 1 to 2 weeks. After 1 and 2 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 4 years, the median decrease in serum DHT was 94% at 1 year, 93% at 2 years, and 95% at both 3 and 4 years.

The median increase in serum testosterone was 19% at both 1 and 2 years, 26% at 3 years, and 22% at 4 years, but the mean and median levels remained within the physiologic range. In patients with BPH treated with 5 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 2 5-alpha-reductase deficiency also have decreased DHT levels. These 5-alpha-reductase-deficient males have a 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 8 weeks (97.1 ng/dL, P <0.003) and thyroid-stimulating hormone at 52 weeks… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Dutasteride and tamsulosin hydrochloride capsules are a combination of 2 drugs with different mechanisms of action to improve symptoms in patients with BPH: dutasteride, a 5-alpha-reductase inhibitor, and tamsulosin, an antagonist of alpha1A-adrenoreceptors. Dutasteride: Dutasteride 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 5 alpha-reductase, which exists as 2 isoforms, type 1 and type 2. The type 2 isoenzyme is primarily active in the reproductive tissues, while the type 1 isoenzyme is also responsible for testosterone conversion in the skin and liver. Dutasteride is a competitive and specific inhibitor of both type 1 and type 2 5-alpha-reductase isoenzymes, with which it forms a 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. Tamsulosin: Smooth 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 a reduction in symptoms of BPH. Tamsulosin, an alpha1-adrenoceptor blocking agent, exhibits selectivity for alpha1-receptors in the human prostate. At least 3 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.

12.3Pharmacokinetics The pharmacokinetics of dutasteride and tamsulosin from dutasteride and tamsulosin hydrochloride capsules are comparable to the pharmacokinetics of dutasteride and tamsulosin when administered separately. Absorption The pharmacokinetic parameters of dutasteride and tamsulosin observed after administration of dutasteride and tamsulosin hydrochloride capsules in a single-dose, randomized, 3-period, partial cross-over trial are summarized in Table 2 below. Table 2 Arithmetic Means (SD) of Serum Dutasteride and Tamsulosin in Single-dose Pharmacokinetic Parameters under Fed Conditions a Median (range). b N = 91.

Component N AUC (0 to t) (ng h/mL) C max (ng/mL) T max (h) a t ½ (h) Dutasteride 92 39.6 (23.1) 2.14 (0.77) 3 (1 to 10) Tamsulosin 92 187.2 (95.7) 11.3 (4.44) 6 (2 to 24) 13.5 (3.92) b Dutasteride: Following administration of a single 0.5 mg dose of a soft gelatin capsule, time to peak absolute bioavailability in 5 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 Food Food does not affect the pharmacokinetics of dutasteride following administration of dutasteride and tamsulosin hydrochloride capsules. However, a mean 30% decrease in tamsulosin C max was observed when dutasteride and tamsulosin hydrochloride capsules was administered with food, similar to that seen when tamsulosin monotherapy was administered under fed versus fasting conditions.

Distribution Dutasteride: Pharmacokinetic data following single and repeat oral doses show that dutasteride has a large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma albumin (99%) and alpha-1 acid glycoprotein (AAG, 96.6%). In a 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 6 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 a 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. Metabolism Dutasteride: 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, 3 major metabolites (4′-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride), and 2 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 6 and 15 positions is not known.

In vitro , the 4′-hydroxydutasteride… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Dutasteride Effect on 5 Alpha-Dihydrotestosterone and Testosterone The maximum effect of daily doses of dutasteride on the reduction of DHT is dose-dependent and is observed within 1 to 2 weeks. After 1 and 2 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 4 years, the median decrease in serum DHT was 94% at 1 year, 93% at 2 years, and 95% at both 3 and 4 years.

The median increase in serum testosterone was 19% at both 1 and 2 years, 26% at 3 years, and 22% at 4 years, but the mean and median levels remained within the physiologic range. In patients with BPH treated with 5 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 2 5-alpha-reductase deficiency also have decreased DHT levels. These 5-alpha-reductase-deficient males have a 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 8 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 8 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 a large randomized, double-blind, placebo-controlled trial, there was a median percent increase in luteinizing hormone of 12% at 6 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 a subset population (n = 13) of the 1-year healthy volunteer trial.

14 CLINICAL STUDIES The trial supporting the efficacy of dutasteride and tamsulosin hydrochloride capsules was a 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 a 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 4 years of double-blind treatment.

Effect on Symptom Score Symptoms were quantified using the first 7 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 a 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]). A significant difference was seen by Month 9 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 a 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 a 48-Month Period (Randomized, Double-blind, Parallel-group Trial [CombAT Trial]) Effect on Acute Urinary Retention(AUR) or the Need for BPH-related Surgery After 4 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 a statistically significantly lower incidence of AUR (1.8% for dutasteride versus 4.2% for placebo; 57% reduction in risk) and with a 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 Rate The 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 a 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 6 and continued through Month 24. See Figure 2.

The additional improvement in Qmax of coadministration therapy over dutast… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility No non-clinical studies have been conducted with dutasteride and tamsulosin hydrochloride capsules. The following information is based on studies performed with dutasteride or tamsulosin. Carcinogenesis Dutasteride: A 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 a 0.5 mg daily dose) in female mice only.

Two of the 3 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 a 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). A 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 1 to 3 times the expected clinical exposure. Tamsulosin: In a rat carcinogenicity assay, no increases in tumor incidence was observed in rats administered up to 3 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 a modest increase in the frequency of mammary gland fibroadenomas in female rats receiving doses of 5.4 mg/kg or greater.

In a carcinogenicity assay, mice were administered up to 8 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 2 years with the 2 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.

Mutagenesis Dutasteride: Dutasteride was tested for genotoxicity in a bacterial mutagenesis assay (Ames test), a chromosomal aberration assay in Chinese hamster ovary (CHO) cells, and a 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 Fertility Dutasteride: 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 microscop… [Excerpted — this section continues on DailyMed.]