Dutasteride for Enlarged Prostate (BPH)

INDICATIONS AND USAGE Dutasteride capsules is a 5 alpha-reductase inhibitor indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: ( 1.1 ) improve symptoms, reduce the risk of acute urinary retention, and reduce the risk of the need for BPH-related surgery. Dutasteride capsules in combination with the alpha-adrenergic antagonist, tamsulosin, is indicated for the treatment of symptomatic BPH in men with an enlarged prostate. (1.2) Limitations of Use: Dutasteride capsules is not approved for the prevention of prostate cancer. (1.3) 1.1 Monotherapy Dutasteride capsules are indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: improve symptoms, reduce the risk of acute urinary retention (AUR), and reduce the risk of the need for BPH-related surgery. 1.2 Combination with Alpha-adrenergic Antagonist Dutasteride capsules in combination with the alpha-adrenergic antagonist, tamsulosin, is indicated for the treatment of symptomatic BPH in men with an enlarged prostate. 1.3 Limitations of Use Dutasteride capsules are not approved for the prevention of prostate cancer.

DOSAGE AND ADMINISTRATION The capsules should be swallowed whole and not chewed or opened, as contact with the capsule contents may result in irritation of the oropharyngeal mucosa. Dutasteride capsules may be administered with or without food. Monotherapy: 0.5 mg once daily. ( 2.1 ) Combination with tamsulosin: 0.5 mg once daily and tamsulosin 0.4 mg once daily. ( 2.2 ) Dosing considerations: Swallow whole. May take with or without food. ( 2 ) 2.1 Monotherapy The recommended dose of dutasteride is 1 capsule (0.5 mg) taken once daily. 2.2 Combination with Alpha-adrenergic Antagonist The recommended dose of dutasteride is 1 capsule (0.5 mg) taken once daily and tamsulosin 0.4 mg taken once daily.

WARNINGS AND PRECAUTIONS Orthostatic 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 ) Do not use dutasteride and tamsulosin hydrochloride capsules with other alpha-adrenergic antagonists, as this may increase the risk of hypotension. ( 5.2 ) Dutasteride and tamsulosin hydrochloride capsules reduce serum prostate-specific antigen (PSA) concentration by approximately 50%. However, any confirmed increase in PSA while on dutasteride and tamsulosin hydrochloride capsules 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 ) Do not use dutasteride and tamsulosin hydrochloride capsules 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, a combination of both CYP3A4 and CYP2D6 inhibitors, or known poor metabolizers of CYP2D6. Concomitant use with known inhibitors can cause a marked increase in drug exposure. ( 5.2 , 7.1 , 12.3 ) Exercise caution with concomitant use of phosphodiesterase-5 (PDE-5) inhibitors, as this may increase the risk of hypotension. ( 5.2 ) Drugs that contain dutasteride, including dutasteride and tamsulosin hydrochloride capsules, may increase the risk of high-grade prostate cancer. ( 5.4 , 6.1 ) Prior to initiating treatment with dutasteride and tamsulosin hydrochloride capsules, consideration should be given to other urological conditions that may cause similar symptoms. ( 5.5 ) Females who are pregnant or may be pregnant should not handle dutasteride and tamsulosin hydrochloride capsules due to potential risk to a male fetus. ( 5.6 , 8.1 ) Advise patients about the possibility and seriousness of priapism. ( 5.7 ) Patients should not donate blood until 6 months after their last dose of dutasteride and tamsulosin hydrochloride capsules. ( 5.8 ) Intraoperative 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 dutasteride and tamsulosin hydrochloride capsules. ( 5.9 ) Exercise 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 dutasteride and tamsulosin hydrochloride capsules, and can result in syncope. Patients starting treatment with dutasteride and tamsulosin hydrochloride capsules 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) 3A4 Tamsulosin-containing products, including dutasteride and tamsulosin hydrochloride capsules, 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 a Combination of Both CYP3A4 and CYP2D6 Inhibitors Tamsulosin-containing products, including dutasteride and tamsulosin hydrochloride capsules, 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, a combination of both CYP3A4 and CYP2D6 inhibitors, or in patients known to be poor metabolizers of CYP2D6, as there is a potential for significant increase in tamsulosin exposure [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 ) ] . Cimetidine Caution is advised when tamsulosin-containing products, including dutasteride and tamsulosin hydrochloride capsules, are coadministered with cimetidine [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 ) ] . Other Alpha-adrenergic Antagonists Tamsulosin-containing products, including dutasteride and tamsulosin hydrochloride capsules, should not be coadministered with other alpha-adrenergic antagonists because of the increased risk of symptomatic hypotension. Phosphodiesterase-5 (PDE-5) Inhibitors Caution is advised when alpha-adrenergic-antagonist-containing products, including dutasteride and tamsulosin hydrochloride capsules, 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 2 drug classes can potentially cause symptomatic hypotension. Warfarin Caution should be exercised with concomitant administration of warfarin and tamsulosin-containing products, including dutasteride and tamsulosin hydrochloride capsules [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 3 to 6 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 dutasteride and tamsulosin hydrochloride capsules, may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men treated with a dutasteride-containing product, including dutasteride and tamsulosin hydrochloride capsules, a new baseline PSA should be established at least 3 months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on a dutasteride-containing treatment, including dutasteride and tamsulosin hydrochloride capsules, 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 a 5-alpha-reductase inhibitor. Noncompliance with dutasteride and tamsulosin hydrochloride capsules may also affect PSA test results. To interpret an isolated PSA value in a man treated with dutasteride and tamsulosin hydrochloride capsules, for 3 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 dutasteride and tamsulosin hydrochloride capsules, no adjustment to its value appears necessary. 5.4 Increased Risk of High-Grade Prostate Cancer In men aged 50 to 75 years with a prior negative biopsy for prostate cancer and a 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 8 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 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%). 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

DRUG INTERACTIONS There have been no drug interaction trials using dutasteride and tamsulosin hydrochloride capsules. The following sections reflect information available for the individual components. 7.1 Cytochrome P450 Inhibition Dutasteride Dutasteride is extensively metabolized in humans by the CYP3A4 and CYP3A5 isoenzymes. The effect of potent CYP3A4 inhibitors on dutasteride has not been studied. Because of the potential for drug-drug interactions, use caution when prescribing a dutasteride-containing product, including dutasteride and tamsulosin hydrochloride capsules, to patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir) [see Clinical Pharmacology ( 12.3 ) ] . Tamsulosin Strong and Moderate Inhibitors of CYP3A4 or CYP2D6: Tamsulosin is extensively metabolized, mainly by CYP3A4 or CYP2D6. Concomitant treatment with ketoconazole (a strong inhibitor of CYP3A4) resulted in increases in the C max and AUC of tamsulosin by factors of 2.2 and 2.8, respectively. Concomitant treatment with paroxetine (a strong inhibitor of CYP2D6) resulted in increases in the C max and area under the concentration-time curve (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 to extensive metabolizers (EM). 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 coadministration of both a CYP3A4 and a CYP2D6 inhibitor with tamsulosin 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 [see Warnings and Precautions ( 5.2 ), Clinical Pharmacology ( 12.3 ) ] . Cimetidine : Treatment with cimetidine resulted in a moderate increase in tamsulosin hydrochloride AUC (44%) [see Warnings and Precautions ( 5.2 ), Clinical Pharmacology ( 12.3 ) ] . 7.2 Warfarin Dutasteride Concomitant administration of dutasteride 0.5 mg/day for 3 weeks with warfarin does not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time [see Clinical Pharmacology ( 12.3 ) ] . Tamsulosin A definitive drug-drug interaction trial between tamsulosin hydrochloride and warfarin was not conducted. Results from limited in vitro and in vivo studies are inconclusive. Caution should be exercised with concomitant administration of warfarin and tamsulosin-containing products, including dutasteride and tamsulosin hydrochloride capsules [see Warnings and Precautions ( 5.2 ), Clinical Pharmacology ( 12.3 ) ] . 7.3 Nifedipine, Atenolol, Enalapril Tamsulosin Dosage adjustments are not necessary when tamsulosin is administered concomitantly with nifedipine, atenolol, or enalapril [see Clinical Pharmacology ( 12.3 ) ] . 7.4 Digoxin and Theophylline Dutasteride Dutasteride does not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at a dose of 0.5 mg/day for 3 weeks [see Clinical Pharmacology ( 12.3 )] . Tamsulosin Dosage adjustments are not necessary when tamsulosin is administered concomitantly with digoxin or theophylline [see Clinical Pharmacology ( 12.3 ) ] . 7.5 Furosemide Tamsulosin Tamsulosin had no effect on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an 11% to 12% reduction in tamsulosin hydrochloride C max and AUC, these changes are expected to be clinically insignificant and do not require adjustment of the dose of tamsulosin [see Clinical Pharmacology ( 12.3 ) ] . 7.6 Calcium Channel Antagonists Dutasteride Coadministration of verapamil or diltiazem decreases dutasteride clearance and leads to increased exposure to dutasteride. The change in dutasteride exposure is not considered to be clinically significant. No dosage adjustment of dutasteride is recommended [see Clinical Pharmacology ( 12.3 ) ] . 7.7 Cholestyramine Dutasteride Administration of a single 5 mg dose of dutasteride followed 1 hour later by a 12 g dose of cholestyramine does not affect the relative bioavailability of dutasteride [see Clinical Pharmacology ( 12.3 ) ] .

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 AvKARE at 1-855-361-3993 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 capsules, 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 0-6 Months 7-12 Coadministration a (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 disorders b,c Coadministration 7.8% 1.6% 1.0% 0.5% <0.1% Dutasteride 1.0% 0.5% 0.5% 0.2% 0.3% Tamsulosin 2.2% 0.5% 0.5% 0.2% 0.3% Impotence c,d Coadministration 5.4% 1.1% 1.8% 0.9% 0.4% Dutasteride 4.0% 1.1% 1.6% 0.6% 0.3% Tamsulosin 2.6% 0.8% 1.0% 0.6% 1.1% Decreased libido c,e Coadministration 4.5% 0.9% 0.8% 0.2% 0.0% Dutasteride 3.1% 0.7% 1.0% 0.2% 0.0% Tamsulosin 2.0% 0.6% 0.7% 0.2% <0.1% Breast disorders ,f Coadministration 1.1% 1.1% 0.8% 0.9% 0.6% Dutasteride 0.9% 0.9% 1.2% 0.5% 0.7% Tamsulosin 0.4% 0.4% 0.4% 0.2% 0.0% Dizziness Coadministration 1.1% 0.4% 0.1% <0.1% 0.2% Dutasteride 0.5% 0.3% 0.1% <0.1% <0.1% Tamsulosin 0.9% 0.5% 0.4% <0.1% 0.0% a Coadministration = dutasteride 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 monotheraphy 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 clinica