Dutasteride

12.1 Mechanism 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 alpha 1A -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 alpha 1 -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 alpha 1 -adrenoceptor blocking agent, exhibits selectivity for alpha 1 -receptors in the human prostate. At least 3 discrete alpha 1 -adrenoceptor subtypes have been identified: alpha 1A , alpha 1B , and alpha 1D ; their distribution differs between human organs and tissue. Approximately 70% of the alpha 1 -receptors in human prostate are of the alpha 1A subtype. Tamsulosin is not intended for use as an antihypertensive.

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 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 dutast

7 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 ) ] .