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. 

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 Cmax 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 and 1,2-dihydrodutasteride metabolites are much less potent than dutasteride against both isoforms of human 5α-reductase. The activity of 6β-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. 

Excretion

Dutasteride: Dutasteride and its metabolites were excreted mainly in feces. As a 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 5 weeks at steady state. The average steady-state serum dutasteride concentration was 40 ng/mL following 0.5 mg/day for 1 year. Following daily dosing, dutasteride serum concentrations achieve 65% of steady-state concentration after 1 month and approximately 90% after 3 months. Due to the long half-life of dutasteride, serum concentrations remain detectable (greater than 0.1 ng/mL) for up to 4 to 6 months after discontinuation of treatment. 

Tamsulosin: On administration of the radiolabeled dose of tamsulosin to 4 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 5 to 7 hours. Because of absorption rate-controlled pharmacokinetics with tamsulosin hydrochloride capsules, the apparent half-life of tamsulosin is approximately 9 to 13 hours in healthy volunteers and 14 to 15 hours in the target population. 

Tamsulosin undergoes restrictive clearance in humans, with a relatively low systemic clearance (2.88 L/h). 

Specific Populations

Pediatric 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 dutasteride and tamsulosin hydrochloride capsules 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 a 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 a 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 dutasteride and tamsulosin hydrochloride capsules. 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 a 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 6 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 6 normal subjects (CLcr >90 mL/min/1.73 m2). While a 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 dutasteride and tamsulosin hydrochloride capsules. 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 8 subjects with moderate hepatic impairment (Child-Pugh classification: Grades A and B) and 8 normal subjects. While a 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 a 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 Studies

There have been no drug interaction studies using dutasteride and tamsulosin hydrochloride capsules. 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 a 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 5 days on the pharmacokinetics of a 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 a 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 9 days on the pharmacokinetics of a 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. A similar increase in exposure is expected in poor metabolizers (PM) of CYP2D6 as compared with extensive metabolizers (EM). A 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 a moderate CYP2D6 inhibitor (e.g. terbinafine) on the pharmacokinetics of tamsulosin have not been evaluated. 

The effects of coadministration of both a CYP3A4 and a CYP2D6 inhibitor with tamsulosin capsules have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when tamsulosin 0.4 mg is coadministered with a combination of both CYP3A4 and CYP2D6 inhibitors. 

Cimetidine: The effects of cimetidine at the highest recommended dose (400 mg every 6 hours for 6 days) on the pharmacokinetics of a single tamsulosin capsule 0.4-mg dose was investigated in 10 healthy volunteers (age range: 21 to 38 years). Treatment with cimetidine resulted in a significant decrease (26%) in the clearance of tamsulosin hydrochloride, which resulted in a moderate increase in tamsulosin hydrochloride AUC (44%). 

Alpha adrenergic Antagonists: Dutasteride: In a 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 a trial of 23 healthy volunteers, 3 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: A 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 3 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 3 months, tamsulosin hydrochloride capsules 0.4 mg for 7 days followed by tamsulosin hydrochloride capsules 0.8 mg for another 7 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 a trial of 20 healthy volunteers, dutasteride did not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at a dose of 0.5 mg/day for 3 weeks. 

Tamsulosin: In 2 trials in healthy volunteers (n = 10 per trial; age range: 19 to 39 years) receiving tamsulosin capsules 0.4 mg/day for 2 days, followed by tamsulosin capsules 0.8 mg/day for 5 to 8 days, single intravenous doses of digoxin 0.5 mg or theophylline 5 mg/kg resulted in no change in the pharmacokinetics of digoxin or theophylline. Therefore, dosage adjustments are not necessary when a 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 a population pharmacokinetics analysis, a decrease in clearance of dutasteride was noted when coadministered with the CYP3A4 inhibitors verapamil (-37%, n = 6) and diltiazem (-44%, n = 5). In contrast, no decrease in clearance was seen when amlodipine, another calcium channel antagonist that is not a CYP3A4 inhibitor, was coadministered with dutasteride (+7%, n = 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 a single 5 mg dose of dutasteride followed 1 hour later by 12 g cholestyramine did not affect the relative bioavailability of dutasteride in 12 normal volunteers.