Dutasteride And Tamsulosin Hydrochloride

1 INDICATIONS AND USAGE Dutasteride and tamsulosin hydrochloride capsules are a combination of dutasteride, a 5-alpha-reductase inhibitor, and tamsulosin, an alpha-adrenergic antagonist, indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate. ( 1.1 ) Limitations of Use: Dutasteride-containing products, including dutasteride and tamsulosin hydrochloride capsules, are not approved for the prevention of prostate cancer. ( 1.2 ) 1.1 Benign Prostatic Hyperplasia (BPH) Treatment Dutasteride and tamsulosin hydrochloride capsules are indicated for the treatment of symptomatic BPH in men with an enlarged prostate. 1.2 Limitations of Use Dutasteride-containing products, including dutasteride and tamsulosin hydrochloride capsules, are not approved for the prevention of prostate cancer.

2 DOSAGE AND ADMINISTRATION The recommended dosage of dutasteride and tamsulosin hydrochloride capsules is 1 capsule (0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride) taken once daily approximately 30 minutes after the same meal each day. The capsules should be swallowed whole and not chewed or opened. Contact with the contents of the dutasteride and tamsulosin hydrochloride capsule may result in irritation of the oropharyngeal mucosa. Take one capsule daily approximately 30 minutes after the same meal each day. ( 2 ) Swallow capsule whole. ( 2 )

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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 dutasteride and tamsulosin hydrochloride, have been evaluated in a 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 a drug cannot be directly compared with rates in the clinical trial of another drug and may not reflect the rates observed in practice. The 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. Trial 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 a 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 1 summarizes adverse reactions reported in at least 1% of subjects receiving coadministration therapy and at a higher incidence than subjects receiving either dutasteride or tamsulosin as monotherapy. Table 1. Adverse Reactions Reported over a 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 Onset Adverse Reaction Adverse Reaction Time of Onset Year 1 Year 2 Year 3 Year 4 Months 0 to 6 Months 7 to 12 Coadministration a Dutasteride Tamsulosin (n = 1,610) (n = 1,623) (n = 1,611) (n = 1,527) (n = 1,548) (n = 1,545) (n = 1,428) (n = 1,464) (n = 1,468) (n = 1,283) (n = 1,325) (n = 1,281) (n = 1,200) (n = 1,200) (n = 1,112) Ejaculation disorders b,c Coadministration Dutasteride Tamsulosin 7.8% 1.0% 2.2% 1.6% 0.5% 0.5% 1.0% 0.5% 0.5% 0.5% 0.2% 0.2% <0.1% 0.3% 0.3% Impotence c,d Coadministration Dutasteride Tamsulosin 5.4% 4.0% 2.6% 1.1% 1.1% 0.8% 1.8% 1.6% 1.0% 0.9% 0.6% 0.6% 0.4% 0.3% 1.1% Decreased libido c,e Coadministration Dutasteride Tamsulosin 4.5% 3.1% 2.0% 0.9% 0.7% 0.6% 0.8% 1.0% 0.7% 0.2% 0.2% 0.2% 0.0% 0.0% <0.1% Breast disorders f Coadministration Dutasteride Tamsulosin 1.1% 0.9% 0.4% 1.1% 0.9% 0.4% 0.8% 1.2% 0.4% 0.9% 0.5% 0.2% 0.6% 0.7% 0.0% Dizziness Coadministration Dutasteride Tamsulosin 1.1% 0.5% 0.9% 0.4% 0.3% 0.5% 0.1% 0.1% 0.4% <0.1% <0.1% <0.1% 0.2% <0.1% 0.0% a Coadministration = AVODART 0.5 mg once daily plus tamsulosin 0.4 mg once daily. b Includes anorgasmia, retrograde ejaculation, semen volume decreased, orgasmic sensation decreased, orgasm abnormal, ejaculation delayed, ejaculation disorder, ejaculation failure, and premature ejaculation. c 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. d Includes erectile dysfunction and disturbance in sexual arousal. e Includes libido decreased, libido disorder, loss of libido, sexual dysfunction, and male sexual dysfunction. f Includes breast enlargement, gynecomastia, breast swelling, breast pain, breast tenderness, nipple pain, and nipple swelling. Cardiac Failure In CombAT, after 4 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 a 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. A 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. Dutasteride Long-term Treatment (Up to 4 Years): High-Grade Prostate Cancer: The REDUCE trial was a randomized, double-blind, placebo-controlled trial that enrolled 8,231 men aged 50 to 75 years with a serum PSA of 2.5 ng/mL to 10 ng/mL and a negative prostate biopsy within the previous 6 months. Subjects were randomized to receive placebo (n = 4,126) or 0.5 mg daily doses of dutasteride (n = 4,105) for up to 4 years. The mean age was 63 years and 91% were white. Subjects underwent protocol-mandated scheduled prostate biopsies at 2 and 4 years of treatment or had “for-cause biopsies” at non-scheduled times if clinically indicated. There was a higher incidence of Gleason score 8 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 a 7-year placebo-controlled clinical trial with another 5-alpha-reductase inhibitor (finasteride 5 mg, PROSCAR), similar results for Gleason score 8 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 Disorders In the 3 pivotal placebo-controlled BPH trials with dutasteride, each 4 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 3 trials, there was 1 case of breast cancer in the dutasteride group and 1 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. Tamsulosin According 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, a 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 a potential risk of syncope [see Warnings and Precautions (5.1) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of the individual components of dutasteride and tamsulosin hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to drug exposure. Dutasteride Immune 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. Tamsulosin Immune 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, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) associated with alpha–adrenergic–antagonist therapy [see Warnings and Precautions (5.9) ].

12.3 Pharmacokinetics The pharmacokinetics of dutasteride and tamsulosin from dutasteride and tamsulosin hydrochloride 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 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-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) 3.00 (1.00 to 10.00) Tamsulosin 92 187.2 (95.7) 11.3 (4.44) 6.00 (2.00 to 24.00) 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. However, a mean 30% decrease in tamsulosin C max was observed when dutasteride and tamsulosin hydrochloride 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 (99.0%) 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 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. 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≤ CL cr <70 mL/min/1.73 m 2 ) or moderate-severe (10≤ CL cr <30 mL/min/1.73 m 2 ) renal impairment and 6 normal subjects (CL cr >90 mL/min/1.73 m 2 ). 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 (CL cr <10 mL/min/1.73 m 2 ) 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. 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. 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 C max 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 C max 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 C max 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.