Tamsulosin Hydrochloride

6 ADVERSE REACTIONS The most common adverse events (≥2% of patients and at a higher incidence than placebo) with the 0.4 mg dose or 0.8 mg dose were headache, dizziness, rhinitis, infection, abnormal ejaculation, asthenia, back pain, diarrhea, pharyngitis, chest pain, cough increased, somnolence, nausea, sinusitis, insomnia, libido decreased, tooth disorder, and blurred vision (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Rising Health, LLC at 1-833-395-6928 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The incidence of treatment-emergent adverse events has been ascertained from six short-term U.S. and European placebo-controlled clinical trials in which daily doses of 0.1 to 0.8 mg tamsulosin hydrochloride capsules were used. These studies evaluated safety in 1783 patients treated with tamsulosin hydrochloride capsules and 798 patients administered placebo. Table 1 summarizes the treatment-emergent adverse events that occurred in ≥2% of patients receiving either tamsulosin hydrochloride capsules 0.4 mg or 0.8 mg and at an incidence numerically higher than that in the placebo group during two 13-week U.S. trials (US92-03A and US93-01) conducted in 1487 men. Table 1 Treatment-Emergent 1 Adverse Events Occurring in ≥2% of Tamsulosin Hydrochloride Capsules or Placebo Patients in Two U.S. Short-Term Placebo-Controlled Clinical Studies BODY SYSTEM/ADVERSE EVENT TAMSULOSIN HYDROCHLORIDE CAPSULES GROUPS PLACEBO 0.4 mg n=502 0.8 mg n=492 n=493 BODY AS WHOLE Headache 97 (19.3%) 104 (21.1%) 99 (20.1%) Infection 2 45 (9%) 53 (10.8%) 37 (7.5%) Asthenia 39 (7.8%) 42 (8.5%) 27 (5.5%) Back pain 35 (7%) 41 (8.3%) 27 (5.5%) Chest pain 20 (4%) 20 (4.1%) 18 (3.7%) NERVOUS SYSTEM Dizziness 75 (14.9%) 84 (17.1%) 50 (10.1%) Somnolence 15 (3%) 21 (4.3%) 8 (1.6%) Insomnia 12 (2.4%) 7 (1.4%) 3 (0.6%) Libido decreased 5 (1%) 10 (2%) 6 (1.2%) RESPIRATORY SYSTEM Rhinitis 3 66 (13.1%) 88 (17.9%) 41 (8.3%) Pharyngitis 29 (5.8%) 25 (5.1%) 23 (4.7%) Cough increased 17 (3.4%) 22 (4.5%) 12 (2.4%) Sinusitis 11 (2.2%) 18 (3.7%) 8 (1.6%) DIGESTIVE SYSTEM Diarrhea 31 (6.2%) 21 (4.3%) 22 (4.5%) Nausea 13 (2.6%) 19 (3.9%) 16 (3.2%) Tooth disorder 6 (1.2%) 10 (2%) 7 (1.4%) UROGENITAL SYSTEM Abnormal ejaculation 42 (8.4%) 89 (18.1%) 1 (0.2%) SPECIAL SENSES Blurred vision 1 (0.2%) 10 (2%) 2 (0.4%) 1 A treatment-emergent adverse event was defined as any event satisfying one of the following criteria: The adverse event occurred for the first time after initial dosing with double-blind study medication; The adverse event was present prior to or at the time of initial dosing with double-blind study medication and subsequently increased in severity during double-blind treatment; or The adverse event was present prior to or at the time of initial dosing with double-blind study medication, disappeared completely, and then reappeared during double-blind treatment. 2 Coding preferred terms also include cold, common cold, head cold, flu, and flu-like symptoms. 3 Coding preferred terms also include nasal congestion, stuffy nose, runny nose, sinus congestion, and hay fever. Signs and Symptoms of Orthostasis In the two U.S. studies, symptomatic postural hypotension was reported by 0.2% of patients (1 of 502) in the 0.4 mg group, 0.4% of patients (2 of 492) in the 0.8 mg group, and by no patients in the placebo group. Syncope was reported by 0.2% of patients (1 of 502) in the 0.4 mg group, 0.4% of patients (2 of 492) in the 0.8 mg group, and 0.6% of patients (3 of 493) in the placebo group. Dizziness was reported by 15% of patients (75 of 502) in the 0.4 mg group, 17% of patients (84 of 492) in the 0.8 mg group, and 10% of patients (50 of 493) in the placebo group. Vertigo was reported by 0.6% of patients (3 of 502) in the 0.4 mg group, 1% of patients (5 of 492) in the 0.8 mg group, and by 0.6% of patients (3 of 493) in the placebo group. Multiple testing for orthostatic hypotension was conducted in a number of studies. Such a test was considered positive if it met one or more of the following criteria: (1) a decrease in systolic blood pressure of ≥20 mmHg upon standing from the supine position during the orthostatic tests; (2) a decrease in diastolic blood pressure ≥10 mmHg upon standing, with the standing diastolic blood pressure <65 mmHg during the orthostatic test; (3) an increase in pulse rate of ≥20 bpm upon standing with a standing pulse rate ≥100 bpm during the orthostatic test; and (4) the presence of clinical symptoms (faintness, lightheadedness/lightheaded, dizziness, spinning sensation, vertigo, or postural hypotension) upon standing during the orthostatic test. Following the first dose of double-blind medication in Study 1, a positive orthostatic test result at 4 hours post-dose was observed in 7% of patients (37 of 498) who received tamsulosin hydrochloride capsules 0.4 mg once daily and in 3% of the patients (8 of 253) who received placebo. At 8 hours post-dose, a positive orthostatic test result was observed for 6% of the patients (31 of 498) who received tamsulosin hydrochloride capsules 0.4 mg once daily and 4% (9 of 250) who received placebo (Note: patients in the 0.8 mg group received 0.4 mg once daily for the first week of Study 1). In Studies 1 and 2, at least one positive orthostatic test result was observed during the course of these studies for 81 of the 502 patients (16%) in the tamsulosin hydrochloride capsules 0.4 mg once-daily group, 92 of the 491 patients (19%) in the tamsulosin hydrochloride capsules 0.8 mg once-daily group, and 54 of the 493 patients (11%) in the placebo group. Because orthostasis was detected more frequently in tamsulosin hydrochloride capsules-treated patients than in placebo recipients, there is a potential risk of syncope [see Warnings and Precautions (5.1) ] . Abnormal Ejaculation Abnormal ejaculation includes ejaculation failure, ejaculation disorder, retrograde ejaculation, and ejaculation decrease. As shown in Table 1, abnormal ejaculation was associated with tamsulosin hydrochloride capsules administration and was dose-related in the U.S. studies. Withdrawal from these clinical studies of tamsulosin hydrochloride capsules because of abnormal ejaculation was also dose-dependent, with 8 of 492 patients (1.6%) in the 0.8 mg group and no patients in the 0.4 mg or placebo groups discontinuing treatment due to abnormal ejaculation. Laboratory Tests No laboratory test interactions with tamsulosin hydrochloride capsules are known. Treatment with tamsulosin hydrochloride capsules for up to 12 months had no significant effect on prostate-specific antigen (PSA). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of tamsulosin hydrochloride capsules. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to tamsulosin hydrochloride capsules. Allergic-type reactions such as skin rash, urticaria, pruritus, angioedema, and respiratory symptoms have been reported with positive rechallenge in some cases. Priapism has been reported rarely. Infrequent reports of dyspnea, palpitations, hypotension, atrial fibrillation, arrhythmia, tachycardia, skin desquamation including reports of Stevens-Johnson syndrome, erythema multiforme, dermatitis exfoliative, constipation, vomiting, dry mouth, visual impairment, and epistaxis have been received during the postmarketing period. During cataract and glaucoma surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported in association with alpha 1 blocker therapy [see Warnings and Precautions (5.5) ] .

4 CONTRAINDICATIONS Tamsulosin hydrochloride capsules are contraindicated in patients known to be hypersensitive to tamsulosin hydrochloride or any component of tamsulosin hydrochloride capsules. Reactions have included skin rash, urticaria, pruritus, angioedema, and respiratory symptoms [see Adverse Reactions (6.2) ]. Contraindicated in patients known to be hypersensitive to tamsulosin hydrochloride or any component of tamsulosin hydrochloride capsules (4 , 6.2)

11 DESCRIPTION Tamsulosin hydrochloride is an antagonist of alpha 1A adrenoceptors in the prostate. Tamsulosin hydrochloride is (-)-( R )-5-[2-[[2-( o -Ethoxyphenoxy) ethyl]amino]propyl]-2-methoxybenzenesulfonamide, monohydrochloride. Tamsulosin hydrochloride USP is a white or almost white crystalline powder that melts with decomposition at approximately 230°C. It is sparingly soluble in water and methanol, slightly soluble in glacial acetic acid and ethanol, and practically insoluble in ether. The molecular formula of tamsulosin hydrochloride is C 20 H 28 N 2 O 5 S • HCl. The molecular weight of tamsulosin hydrochloride is 444.98. Its structural formula is: Each tamsulosin hydrochloride capsule, USP for oral administration contains tamsulosin hydrochloride USP 0.4 mg, and the following inactive ingredients: calcium stearate, FD&C Blue 2, gelatin, iron oxide red, iron oxide yellow, microcrystalline cellulose, methacrylic acid and ethyl acrylate copolymer dispersion, sodium lauryl sulfate, talc, triacetin, and titanium dioxide. The capsules are printed with SW-9008 Black Ink containing black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, shellac, and strong ammonia solution. Meets USP dissolution test 10. Chemical Structure

2 DOSAGE AND ADMINISTRATION Tamsulosin hydrochloride capsules 0.4 mg once daily is recommended as the dose for the treatment of the signs and symptoms of BPH. It should be administered approximately one-half hour following the same meal each day. Tamsulosin hydrochloride capsules should not be crushed, chewed or opened. For those patients who fail to respond to the 0.4 mg dose after 2 to 4 weeks of dosing, the dose of tamsulosin hydrochloride capsules can be increased to 0.8 mg once daily. Tamsulosin hydrochloride capsules 0.4 mg should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole) [see Warnings and Precautions (5.2) ] . If tamsulosin hydrochloride capsules administration is discontinued or interrupted for several days at either the 0.4 mg or 0.8 mg dose, therapy should be started again with the 0.4 mg once-daily dose. 0.4 mg once daily taken approximately one-half hour following the same meal each day. Tamsulosin hydrochloride capsules should not be crushed, chewed or opened. (2) Can be increased to 0.8 mg once daily for patients who fail to respond to the 0.4 mg dose after 2 to 4 weeks of dosing (2) If discontinued or interrupted for several days, therapy should start again with the 0.4 mg once-daily dose (2)

1 INDICATIONS AND USAGE Tamsulosin hydrochloride capsules are indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) [see Clinical Studies (14) ] . Tamsulosin hydrochloride capsules are not indicated for the treatment of hypertension. Tamsulosin hydrochloride capsules are an alpha 1 adrenoceptor antagonist indicated for treatment of the signs and symptoms of benign prostatic hyperplasia (1) Tamsulosin hydrochloride capsules are not indicated for the treatment of hypertension (1)

10 OVERDOSAGE Should overdosage of tamsulosin hydrochloride capsules lead to hypotension [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ], support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position. If this measure is inadequate, then administration of intravenous fluids should be considered. If necessary, vasopressors should then be used and renal function should be monitored and supported as needed. Laboratory data indicate that tamsulosin hydrochloride is 94% to 99% protein bound; therefore, dialysis is unlikely to be of benefit.

7 DRUG INTERACTIONS Tamsulosin hydrochloride capsules 0.4 mg should not be used with strong inhibitors of CYP3A4 (e.g., ketoconazole). Tamsulosin hydrochloride capsules should be used with caution in combination with moderate inhibitors of CYP3A4 (e.g., erythromycin), in combination with strong (e.g., paroxetine) or moderate (e.g., terbinafine) inhibitors of CYP2D6, or in patients known to be CYP2D6 poor metabolizers, particularly at a dose higher than 0.4 mg (e.g., 0.8 mg). (5.2 , 7.1 , 12.3) Concomitant use of PDE5 inhibitors with tamsulosin can potentially cause symptomatic hypotension. (5.2 , 7.3 , 12.3) 7.1 Cytochrome P450 Inhibition Strong and Moderate Inhibitors of CYP3A4 or CYP2D6 Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6. Concomitant treatment with ketoconazole (a strong inhibitor of CYP3A4) resulted in an increase in the C max and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . The effects of concomitant administration of a moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of tamsulosin hydrochloride have not been evaluated [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . Concomitant treatment with paroxetine (a strong inhibitor of CYP2D6) resulted in an increase in the C max and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . A similar increase in exposure is expected in CYP2D6 poor metabolizers (PM) 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 hydrochloride 0.4 mg is co-administered with strong CYP3A4 inhibitors in CYP2D6 PMs, tamsulosin hydrochloride capsules 0.4 mg should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole) [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . The effects of concomitant administration of a moderate CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of tamsulosin hydrochloride have not been evaluated [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . The effects of co-administration of both a CYP3A4 and a CYP2D6 inhibitor with tamsulosin hydrochloride capsules have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when tamsulosin hydrochloride 0.4 mg is co-administered with a combination of both CYP3A4 and CYP2D6 inhibitors [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . Cimetidine 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%) [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . 7.2 Other Alpha Adrenergic Blocking Agents The pharmacokinetic and pharmacodynamic interactions between tamsulosin hydrochloride capsules and other alpha adrenergic blocking agents have not been determined; however, interactions between tamsulosin hydrochloride capsules and other alpha adrenergic blocking agents may be expected [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . 7.3 PDE5 Inhibitors Caution is advised when alpha adrenergic blocking agents including tamsulosin hydrochloride are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . 7.4 Warfarin A definitive drug-drug interaction study 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 hydrochloride capsules [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . 7.5 Nifedipine, Atenolol, Enalapril Dosage adjustments are not necessary when tamsulosin hydrochloride capsules are administered concomitantly with nifedipine, atenolol, or enalapril [see Clinical Pharmacology (12.3) ] . 7.6 Digoxin and Theophylline Dosage adjustments are not necessary when a tamsulosin hydrochloride capsule is administered concomitantly with digoxin or theophylline [see Clinical Pharmacology (12.3) ] . 7.7 Furosemide Tamsulosin hydrochloride capsules 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 tamsulosin hydrochloride capsules dosage [see Clinical Pharmacology (12.3) ] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The symptoms associated with benign prostatic hyperplasia (BPH) are related to bladder outlet obstruction, which is comprised of two underlying components: static and dynamic. The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck leading to constriction of the bladder outlet. 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 three 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 the human prostate are of the alpha 1A subtype. Tamsulosin hydrochloride capsules are not intended for use as an antihypertensive drug. 12.2 Pharmacodynamics Urologic pharmacodynamic effects have been evaluated in neurologically impaired pediatric patients and in adults with BPH [see Use in Specific Populations (8.4) and Clinical Studies (14) ] . 12.3 Pharmacokinetics The pharmacokinetics of tamsulosin hydrochloride have been evaluated in adult healthy volunteers and patients with BPH after single and/or multiple administration with doses ranging from 0.1 mg to 1 mg. Absorption Absorption of tamsulosin hydrochloride from tamsulosin hydrochloride capsules 0.4 mg is essentially complete (>90%) following oral administration under fasting conditions. Tamsulosin hydrochloride exhibits linear kinetics following single and multiple dosing, with achievement of steady-state concentrations by the fifth day of once-a-day dosing. Effect of Food The time to maximum concentration (T max ) is reached by 4 to 5 hours under fasting conditions and by 6 to 7 hours when tamsulosin hydrochloride capsules are administered with food. Taking tamsulosin hydrochloride capsules under fasted conditions results in a 30% increase in bioavailability (AUC) and 40% to 70% increase in peak concentrations (C max ) compared to fed conditions (Figure 1). The effects of food on the pharmacokinetics of tamsulosin hydrochloride are consistent regardless of whether a tamsulosin hydrochloride capsule is taken with a light breakfast or a high-fat breakfast (Table 2). Table 2 Mean (± S.D.) Pharmacokinetic Parameters Following Tamsulosin Hydrochloride Capsules 0.4 mg Once Daily or 0.8 mg Once Daily with a Light Breakfast, High-Fat Breakfast or Fasted Pharmacokinetic Parameter 0.4 mg QD to healthy volunteers; n=23 (age range 18 to 32 years) 0.8 mg QD to healthy volunteers; n=22 (age range 55 to 75 years) Light Breakfast Fasted Light Breakfast High-Fat Breakfast Fasted C min = observed minimum concentration C max = observed maximum tamsulosin hydrochloride plasma concentration T max = median time-to-maximum concentration T 1/2 = observed half-life AUC τ = area under the tamsulosin hydrochloride plasma time curve over the dosing interval C min (ng/mL) 4 ± 2.6 3.8 ± 2.5 12.3 ± 6.7 13.5 ± 7.6 13.3 ± 13.3 C max (ng/mL) 10.1 ± 4.8 17.1 ± 17.1 29.8 ± 10.3 29.1 ± 11 41.6 ± 15.6 C max /C min Ratio 3.1 ± 1 5.3 ± 2.2 2.7 ± 0.7 2.5 ± 0.8 3.6 ± 1.1 T max (hours) 6 4 7 6.6 5 T 1/2 (hours) - - - - 14.9 ± 3.9 AUC τ (ng•hr/mL) 151 ± 81.5 199 ± 94.1 440 ± 195 449 ± 217 557 ± 257 Distribution The mean steady-state apparent volume of distribution of tamsulosin hydrochloride after intravenous administration to 10 healthy male adults was 16 L, which is suggestive of distribution into extracellular fluids in the body. Tamsulosin hydrochloride is extensively bound to human plasma proteins (94% to 99%), primarily alpha 1 acid glycoprotein (AAG), with linear binding over a wide concentration range (20 to 600 ng/mL). The results of two-way in vitro studies indicate that the binding of tamsulosin hydrochloride to human plasma proteins is not affected by amitriptyline, diclofenac, glyburide, simvastatin plus simvastatin-­hydroxy acid metabolite, warfarin, diazepam, propranolol, trichlormethiazide, or chlormadinone. Likewise, tamsulosin hydrochloride had no effect on the extent of binding of these drugs. Metabolism There is no enantiomeric bioconversion from tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer in humans. Tamsulosin hydrochloride 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. Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6 as well as via some minor participation of other CYP isoenzymes. Inhibition of hepatic drug-metabolizing enzymes may lead to increased exposure to tamsulosin [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] . The metabolites of tamsulosin hydrochloride 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 hydrochloride and amitriptyline, albuterol (beta agonist), glyburide (glibenclamide) and finasteride (5alpha-reductase inhibitor for treatment of BPH). However, results of the in vitro testing of the tamsulosin hydrochloride interaction with diclofenac and warfarin were equivocal. Excretion On administration of the radiolabeled dose of tamsulosin hydrochloride to 4 healthy volunteers, 97% of the administered radioactivity was recovered, with urine (76%) representing the primary route of excretion compared to feces (21%) over 168 hours. Following intravenous or oral administration of an immediate-release formulation, the elimination half-life of tamsulosin hydrochloride in plasma ranged from 5 to 7 hours. Because of absorption rate-controlled pharmacokinetics with tamsulosin hydrochloride capsules, the apparent half-life of tamsulosin hydrochloride is approximately 9 to 13 hours in healthy volunteers and 14 to 15 hours in the target population. Tamsulosin hydrochloride undergoes restrictive clearance in humans, with a relatively low systemic clearance (2.88 L/h). Specific Populations Pediatric Use Tamsulosin hydrochloride capsules are not indicated for use in pediatric populations [see Use in Specific Populations (8.4) ] . Geriatric (Age) Use Cross-study comparison of tamsulosin hydrochloride capsules overall exposure (AUC) and half-life indicates that the pharmacokinetic disposition of tamsulosin hydrochloride may be slightly prolonged in geriatric males compared to young, healthy male volunteers. Intrinsic clearance is independent of tamsulosin hydrochloride binding to AAG, but diminishes with age, resulting in a 40% overall higher exposure (AUC) in subjects of age 55 to 75 years compared to subjects of age 20 to 32 years [see Use in Specific Populations (8.5) ] . Renal Impairment The pharmacokinetics of tamsulosin hydrochloride 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 hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride, as well as the intrinsic clearance, remained relatively constant. Therefore, patients with renal impairment do not require an adjustment in tamsulosin hydrochloride capsules dosing. However, patients with end-stage renal disease (CL cr <10 mL/min/1.73 m 2 ) have not been studied [see Use in Specific Populations (8.6) ] . Hepatic Impairment The pharmacokinetics of tamsulosin hydrochloride have been compared in 8 subjects with moderate hepatic impairment (Child-Pugh’s classification: Grades A and B) and 8 normal subjects. While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride does not change significantly, with only a modest (32%) change in intrinsic clearance of unbound tamsulosin hydrochloride. Therefore, patients with moderate hepatic impairment do not require an adjustment in tamsulosin hydrochloride capsules dosage. Tamsulosin hydrochloride has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7) ] . Drug Interactions Cytochrome P450 Inhibition 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 an increase in the C max and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . The effects of concomitant administration of a moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of tamsulosin hydrochloride have not been evaluated [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] . The effects of paroxetine (a strong inhibitor of CYP2D6) at 20 mg once daily for 9 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 paroxetine resulted in an increase in the C max and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] . A similar increase in exposure is expected in CYP2D6 poor metabolizers (PM) as compared to extensive metabolizers (EM). A fraction of the population (about 7% of Caucasians 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 hydrochloride 0.4 mg is co-administered with strong CYP3A4 inhibitors in CYP2D6 PMs, tamsulosin hydrochloride capsules 0.4 mg should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole) [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] . The effects of concomitant administration of a moderate CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of tamsulosin hydrochloride have not been evaluated [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] . The effects of co-administration of both a CYP3A4 and a CYP2D6 inhibitor with tamsulosin hydrochloride capsules have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when tamsulosin hydrochloride 0.4 mg is co-administered with a combination of both CYP3A4 and CYP2D6 inhibitors [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] . 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 hydrochloride 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%) [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ]. Other Alpha Adrenergic Blocking Agents The pharmacokinetic and pharmacodynamic interactions between tamsulosin hydrochloride capsules and other alpha adrenergic blocking agents have not been determined; however, interactions between tamsulosin hydrochloride capsules and other alpha adrenergic blocking agents may be expected [see Warnings and Precautions (5.2) and Drug Interactions (7.2) ] . PDE5 Inhibitors Caution is advised when alpha adrenergic blocking agents, including tamsulosin hydrochloride, are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension [see Warnings and Precautions (5.2) and Drug Interactions (7.3) ] . Warfarin A definitive drug-drug interaction study between tamsulosin hydrochloride 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 hydrochloride capsules [see Warnings and Precautions (5.2) and Drug Interactions (7.4) ] . Nifedipine, Atenolol, Enalapril In three studies in hypertensive subjects (age range 47 to 79 years) whose blood pressure was controlled with stable doses of nifedipine, 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 study) resulted in no clinically significant effects on blood pressure and pulse rate compared to placebo (n=4 per study). Therefore, dosage adjustments are not necessary when tamsulosin hydrochloride capsules are administered concomitantly with nifedipine, atenolol, or enalapril [see Drug Interactions (7.5) ] . Digoxin and Theophylline In two studies in healthy volunteers (n=10 per study; age range 19 to 39 years) receiving tamsulosin hydrochloride capsules 0.4 mg/day for 2 days, followed by tamsulosin hydrochloride 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 hydrochloride capsule is administered concomitantly with digoxin or theophylline [see Drug Interactions (7.6) ] . Furosemide 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 hydrochloride capsules 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 tamsulosin hydrochloride capsules dosage [see Drug Interactions (7.7) ] . Figure 1 Mean Plasma Tamsulosin Hydrochloride Concentrations Following Single-Dose Administration of Tamsulosin Hydrochloride Capsules 0.4 mg Under Fasted and Fed Conditions (n=8)

12.1 Mechanism of Action The symptoms associated with benign prostatic hyperplasia (BPH) are related to bladder outlet obstruction, which is comprised of two underlying components: static and dynamic. The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck leading to constriction of the bladder outlet. 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 three 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 the human prostate are of the alpha 1A subtype. Tamsulosin hydrochloride capsules are not intended for use as an antihypertensive drug.

12.2 Pharmacodynamics Urologic pharmacodynamic effects have been evaluated in neurologically impaired pediatric patients and in adults with BPH [see Use in Specific Populations (8.4) and Clinical Studies (14) ] .

12.3 Pharmacokinetics The pharmacokinetics of tamsulosin hydrochloride have been evaluated in adult healthy volunteers and patients with BPH after single and/or multiple administration with doses ranging from 0.1 mg to 1 mg. Absorption Absorption of tamsulosin hydrochloride from tamsulosin hydrochloride capsules 0.4 mg is essentially complete (>90%) following oral administration under fasting conditions. Tamsulosin hydrochloride exhibits linear kinetics following single and multiple dosing, with achievement of steady-state concentrations by the fifth day of once-a-day dosing. Effect of Food The time to maximum concentration (T max ) is reached by 4 to 5 hours under fasting conditions and by 6 to 7 hours when tamsulosin hydrochloride capsules are administered with food. Taking tamsulosin hydrochloride capsules under fasted conditions results in a 30% increase in bioavailability (AUC) and 40% to 70% increase in peak concentrations (C max ) compared to fed conditions (Figure 1). The effects of food on the pharmacokinetics of tamsulosin hydrochloride are consistent regardless of whether a tamsulosin hydrochloride capsule is taken with a light breakfast or a high-fat breakfast (Table 2). Table 2 Mean (± S.D.) Pharmacokinetic Parameters Following Tamsulosin Hydrochloride Capsules 0.4 mg Once Daily or 0.8 mg Once Daily with a Light Breakfast, High-Fat Breakfast or Fasted Pharmacokinetic Parameter 0.4 mg QD to healthy volunteers; n=23 (age range 18 to 32 years) 0.8 mg QD to healthy volunteers; n=22 (age range 55 to 75 years) Light Breakfast Fasted Light Breakfast High-Fat Breakfast Fasted C min = observed minimum concentration C max = observed maximum tamsulosin hydrochloride plasma concentration T max = median time-to-maximum concentration T 1/2 = observed half-life AUC τ = area under the tamsulosin hydrochloride plasma time curve over the dosing interval C min (ng/mL) 4 ± 2.6 3.8 ± 2.5 12.3 ± 6.7 13.5 ± 7.6 13.3 ± 13.3 C max (ng/mL) 10.1 ± 4.8 17.1 ± 17.1 29.8 ± 10.3 29.1 ± 11 41.6 ± 15.6 C max /C min Ratio 3.1 ± 1 5.3 ± 2.2 2.7 ± 0.7 2.5 ± 0.8 3.6 ± 1.1 T max (hours) 6 4 7 6.6 5 T 1/2 (hours) - - - - 14.9 ± 3.9 AUC τ (ng•hr/mL) 151 ± 81.5 199 ± 94.1 440 ± 195 449 ± 217 557 ± 257 Distribution The mean steady-state apparent volume of distribution of tamsulosin hydrochloride after intravenous administration to 10 healthy male adults was 16 L, which is suggestive of distribution into extracellular fluids in the body. Tamsulosin hydrochloride is extensively bound to human plasma proteins (94% to 99%), primarily alpha 1 acid glycoprotein (AAG), with linear binding over a wide concentration range (20 to 600 ng/mL). The results of two-way in vitro studies indicate that the binding of tamsulosin hydrochloride to human plasma proteins is not affected by amitriptyline, diclofenac, glyburide, simvastatin plus simvastatin-­hydroxy acid metabolite, warfarin, diazepam, propranolol, trichlormethiazide, or chlormadinone. Likewise, tamsulosin hydrochloride had no effect on the extent of binding of these drugs. Metabolism There is no enantiomeric bioconversion from tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer in humans. Tamsulosin hydrochloride 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. Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6 as well as via some minor participation of other CYP isoenzymes. Inhibition of hepatic drug-metabolizing enzymes may lead to increased exposure to tamsulosin [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] . The metabolites of tamsulosin hydrochloride 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 hydrochloride and amitriptyline, albuterol (beta agonist), glyburide (glibenclamide) and finasteride (5alpha-reductase inhibitor for treatment of BPH). However, results of the in vitro testing of the tamsulosin hydrochloride interaction with diclofenac and warfarin were equivocal. Excretion On administration of the radiolabeled dose of tamsulosin hydrochloride to 4 healthy volunteers, 97% of the administered radioactivity was recovered, with urine (76%) representing the primary route of excretion compared to feces (21%) over 168 hours. Following intravenous or oral administration of an immediate-release formulation, the elimination half-life of tamsulosin hydrochloride in plasma ranged from 5 to 7 hours. Because of absorption rate-controlled pharmacokinetics with tamsulosin hydrochloride capsules, the apparent half-life of tamsulosin hydrochloride is approximately 9 to 13 hours in healthy volunteers and 14 to 15 hours in the target population. Tamsulosin hydrochloride undergoes restrictive clearance in humans, with a relatively low systemic clearance (2.88 L/h). Specific Populations Pediatric Use Tamsulosin hydrochloride capsules are not indicated for use in pediatric populations [see Use in Specific Populations (8.4) ] . Geriatric (Age) Use Cross-study comparison of tamsulosin hydrochloride capsules overall exposure (AUC) and half-life indicates that the pharmacokinetic disposition of tamsulosin hydrochloride may be slightly prolonged in geriatric males compared to young, healthy male volunteers. Intrinsic clearance is independent of tamsulosin hydrochloride binding to AAG, but diminishes with age, resulting in a 40% overall higher exposure (AUC) in subjects of age 55 to 75 years compared to subjects of age 20 to 32 years [see Use in Specific Populations (8.5) ] . Renal Impairment The pharmacokinetics of tamsulosin hydrochloride 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 hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride, as well as the intrinsic clearance, remained relatively constant. Therefore, patients with renal impairment do not require an adjustment in tamsulosin hydrochloride capsules dosing. However, patients with end-stage renal disease (CL cr <10 mL/min/1.73 m 2 ) have not been studied [see Use in Specific Populations (8.6) ] . Hepatic Impairment The pharmacokinetics of tamsulosin hydrochloride have been compared in 8 subjects with moderate hepatic impairment (Child-Pugh’s classification: Grades A and B) and 8 normal subjects. While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride does not change significantly, with only a modest (32%) change in intrinsic clearance of unbound tamsulosin hydrochloride. Therefore, patients with moderate hepatic impairment do not require an adjustment in tamsulosin hydrochloride capsules dosage. Tamsulosin hydrochloride has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7) ] . Drug Interactions Cytochrome P450 Inhibition 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 an increase in the C max and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . The effects of concomitant administration of a moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of tamsulosin hydrochloride have not been evaluated [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] . The effects of paroxetine (a strong inhibitor of CYP2D6) at 20 mg once daily for 9 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 paroxetine resulted in an increase in the C max and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] . A similar increase in exposure is expected in CYP2D6 poor metabolizers (PM) as compared to extensive metabolizers (EM). A fraction of the population (about 7% of Caucasians 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 hydrochloride 0.4 mg is co-administered with strong CYP3A4 inhibitors in CYP2D6 PMs, tamsulosin hydrochloride capsules 0.4 mg should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole) [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] . The effects of concomitant administration of a moderate CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of tamsulosin hydrochloride have not been evaluated [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] . The effects of co-administration of both a CYP3A4 and a CYP2D6 inhibitor with tamsulosin hydrochloride capsules have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when tamsulosin hydrochloride 0.4 mg is co-administered with a combination of both CYP3A4 and CYP2D6 inhibitors [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] . 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 hydrochloride 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%) [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ]. Other Alpha Adrenergic Blocking Agents The pharmacokinetic and pharmacodynamic interactions between tamsulosin hydrochloride capsules and other alpha adrenergic blocking agents have not been determined; however, interactions between tamsulosin hydrochloride capsules and other alpha adrenergic blocking agents may be expected [see Warnings and Precautions (5.2) and Drug Interactions (7.2) ] . PDE5 Inhibitors Caution is advised when alpha adrenergic blocking agents, including tamsulosin hydrochloride, are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension [see Warnings and Precautions (5.2) and Drug Interactions (7.3) ] . Warfarin A definitive drug-drug interaction study between tamsulosin hydrochloride 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 hydrochloride capsules [see Warnings and Precautions (5.2) and Drug Interactions (7.4) ] . Nifedipine, Atenolol, Enalapril In three studies in hypertensive subjects (age range 47 to 79 years) whose blood pressure was controlled with stable doses of nifedipine, 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 study) resulted in no clinically significant effects on blood pressure and pulse rate compared to placebo (n=4 per study). Therefore, dosage adjustments are not necessary when tamsulosin hydrochloride capsules are administered concomitantly with nifedipine, atenolol, or enalapril [see Drug Interactions (7.5) ] . Digoxin and Theophylline In two studies in healthy volunteers (n=10 per study; age range 19 to 39 years) receiving tamsulosin hydrochloride capsules 0.4 mg/day for 2 days, followed by tamsulosin hydrochloride 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 hydrochloride capsule is administered concomitantly with digoxin or theophylline [see Drug Interactions (7.6) ] . Furosemide 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 hydrochloride capsules 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 tamsulosin hydrochloride capsules dosage [see Drug Interactions (7.7) ] . Figure 1 Mean Plasma Tamsulosin Hydrochloride Concentrations Following Single-Dose Administration of Tamsulosin Hydrochloride Capsules 0.4 mg Under Fasted and Fed Conditions (n=8)

20230927

16

3 DOSAGE FORMS AND STRENGTHS Capsule: 0.4 mg are olive green opaque/orange opaque size ‘0’ hard gelatin capsules imprinted with ‘D’ on cap and ‘53’ on body with black edible ink filled with white to off-white beadlets. Capsules: 0.4 mg (3)

Tamsulosin Hydrochloride Tamsulosin Hydrochloride CALCIUM STEARATE FD&C BLUE NO. 2 GELATIN, UNSPECIFIED FERRIC OXIDE RED FERRIC OXIDE YELLOW MICROCRYSTALLINE CELLULOSE METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A SODIUM LAURYL SULFATE TALC TRIACETIN TITANIUM DIOXIDE FERROSOFERRIC OXIDE BUTYL ALCOHOL ALCOHOL ISOPROPYL ALCOHOL POTASSIUM HYDROXIDE PROPYLENE GLYCOL SHELLAC AMMONIA TAMSULOSIN HYDROCHLORIDE TAMSULOSIN Olive Green Opaque Orange Opaque D;53

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Rats administered doses up to 43 mg/kg/day in males and 52 mg/kg/day in females had no increases in tumor incidence, with the exception of a modest increase in the frequency of mammary gland fibroadenomas in female rats receiving doses ≥5.4 mg/kg (P<0.015). The highest doses of tamsulosin hydrochloride evaluated in the rat carcinogenicity study produced systemic exposures (AUC) in rats 3 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day. Mice were administered 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 two 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 (P<0.0075). The highest dose levels of tamsulosin hydrochloride evaluated in the mice carcinogenicity study produced systemic exposures (AUC) in mice 8 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day. The increased incidences of mammary gland neoplasms in female rats and mice were considered secondary to tamsulosin hydrochloride-induced hyperprolactinemia. It is not known if tamsulosin hydrochloride capsules elevate prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known. Tamsulosin hydrochloride 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 Chinese hamster ovary cells or human lymphocytes. There were no mutagenic effects in the in vivo sister chromatid exchange and mouse micronucleus assay. Studies in rats revealed significantly reduced fertility in males dosed with single or multiple daily doses of 300 mg/kg/day of tamsulosin hydrochloride (AUC exposure in rats about 50 times the human exposure with the maximum therapeutic dose). The mechanism of decreased fertility in male rats is considered to be an effect of the compound on the vaginal plug formation possibly due to changes of semen content or impairment of ejaculation. The effects on fertility were reversible, showing improvement by 3 days after a single dose and 4 weeks after multiple dosing. Effects on fertility in males were completely reversed within nine weeks of discontinuation of multiple dosing. Multiple doses of 10 and 100 mg/kg/day tamsulosin hydrochloride (1/5 and 16 times the anticipated human AUC exposure) did not significantly alter fertility in male rats. Effects of tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated. Studies in female rats revealed significant reductions in fertility after single or multiple dosing with 300 mg/kg/day of the R-isomer or racemic mixture of tamsulosin hydrochloride, respectively. In female rats, the reductions in fertility after single doses were considered to be associated with impairments in fertilization. Multiple dosing with 10 or 100 mg/kg/day of the racemic mixture did not significantly alter fertility in female rats.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Rats administered doses up to 43 mg/kg/day in males and 52 mg/kg/day in females had no increases in tumor incidence, with the exception of a modest increase in the frequency of mammary gland fibroadenomas in female rats receiving doses ≥5.4 mg/kg (P<0.015). The highest doses of tamsulosin hydrochloride evaluated in the rat carcinogenicity study produced systemic exposures (AUC) in rats 3 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day. Mice were administered 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 two 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 (P<0.0075). The highest dose levels of tamsulosin hydrochloride evaluated in the mice carcinogenicity study produced systemic exposures (AUC) in mice 8 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day. The increased incidences of mammary gland neoplasms in female rats and mice were considered secondary to tamsulosin hydrochloride-induced hyperprolactinemia. It is not known if tamsulosin hydrochloride capsules elevate prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known. Tamsulosin hydrochloride 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 Chinese hamster ovary cells or human lymphocytes. There were no mutagenic effects in the in vivo sister chromatid exchange and mouse micronucleus assay. Studies in rats revealed significantly reduced fertility in males dosed with single or multiple daily doses of 300 mg/kg/day of tamsulosin hydrochloride (AUC exposure in rats about 50 times the human exposure with the maximum therapeutic dose). The mechanism of decreased fertility in male rats is considered to be an effect of the compound on the vaginal plug formation possibly due to changes of semen content or impairment of ejaculation. The effects on fertility were reversible, showing improvement by 3 days after a single dose and 4 weeks after multiple dosing. Effects on fertility in males were completely reversed within nine weeks of discontinuation of multiple dosing. Multiple doses of 10 and 100 mg/kg/day tamsulosin hydrochloride (1/5 and 16 times the anticipated human AUC exposure) did not significantly alter fertility in male rats. Effects of tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated. Studies in female rats revealed significant reductions in fertility after single or multiple dosing with 300 mg/kg/day of the R-isomer or racemic mixture of tamsulosin hydrochloride, respectively. In female rats, the reductions in fertility after single doses were considered to be associated with impairments in fertilization. Multiple dosing with 10 or 100 mg/kg/day of the racemic mixture did not significantly alter fertility in female rats.

ANDA202433

Tamsulosin Hydrochloride

Tamsulosin Hydrochloride

43063-725

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 0.4 mg Tamsulosin Hydrochloride Capsules, USP 0.4 mg Rx only image

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information) ● Hypotension Advise the patient about the possible occurrence of symptoms related to postural hypotension, such as dizziness, when taking tamsulosin hydrochloride capsules, and they should be cautioned about driving, operating machinery, or performing hazardous tasks [see Warnings and Precautions (5.1) ] . ● Drug Interactions Advise the patient that tamsulosin hydrochloride should not be used in combination with strong inhibitors of CYP3A4 [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] . ● Priapism Advise the patient about the possibility of priapism as a result of treatment with tamsulosin hydrochloride capsules and other similar medications. Patients should be informed that this reaction is extremely rare, but if not brought to immediate medical attention, can lead to permanent erectile dysfunction (impotence) [see Warnings and Precautions (5.3) ] . ● Screening for Prostate Cancer Prostate cancer and BPH frequently co-exist; therefore, screen patients for the presence of prostate cancer prior to treatment with tamsulosin hydrochloride capsules and at regular intervals afterwards [see Warnings and Precautions (5.4) ]. ● Intraoperative Floppy Iris Syndrome Advise the patient when considering cataract or glaucoma surgery to tell their ophthalmologist that they have taken tamsulosin hydrochloride capsules [see Warnings and Precautions (5.5) ] . ● Administration Advise the patient that tamsulosin hydrochloride capsules should not be crushed, chewed or opened [see Dosage and Administration (2) ]. FDA-approved Patient Labeling Patient labeling is provided at the end of this prescribing information. Distributed by: Rising Health, LLC Saddle Brook, NJ 07663 Made in India Code: TS/DRUGS/22/2009 Revised: 08/2020

14 CLINICAL STUDIES Four placebo-controlled clinical studies and one active-controlled clinical study enrolled a total of 2296 patients (1003 received tamsulosin hydrochloride capsules 0.4 mg once daily, 491 received tamsulosin hydrochloride capsules 0.8 mg once daily, and 802 were control patients) in the U.S. and Europe. In the two U.S. placebo-controlled, double-blind, 13-week, multicenter studies [Study 1 (US92-03A) and Study 2 (US93-01)], 1486 men with the signs and symptoms of BPH were enrolled. In both studies, patients were randomized to either placebo, tamsulosin hydrochloride capsules 0.4 mg once daily, or tamsulosin hydrochloride capsules 0.8 mg once daily. Patients in tamsulosin hydrochloride capsules 0.8 mg once-daily treatment groups received a dose of 0.4 mg once daily for one week before increasing to the 0.8 mg once-daily dose. The primary efficacy assessments included: 1) total American Urological Association (AUA) Symptom Score questionnaire, which evaluated irritative (frequency, urgency, and nocturia), and obstructive (hesitancy, incomplete emptying, intermittency, and weak stream) symptoms, where a decrease in score is consistent with improvement in symptoms; and 2) peak urine flow rate, where an increased peak urine flow rate value over baseline is consistent with decreased urinary obstruction. Mean changes from baseline to Week 13 in total AUA Symptom Score were significantly greater for groups treated with tamsulosin hydrochloride capsules 0.4 mg and 0.8 mg once daily compared to placebo in both U.S. studies (Table 3, Figures 2A and 2B). The changes from baseline to Week 13 in peak urine flow rate were also significantly greater for the tamsulosin hydrochloride capsules 0.4 mg and 0.8 mg once-daily groups compared to placebo in Study 1, and for the tamsulosin hydrochloride capsules 0.8 mg once-daily group in Study 2 (Table 3, Figures 3A and 3B). Overall there were no significant differences in improvement observed in total AUA Symptom Scores or peak urine flow rates between the 0.4 mg and the 0.8 mg dose groups with the exception that the 0.8 mg dose in Study 1 had a significantly greater improvement in total AUA Symptom Score compared to the 0.4 mg dose. Table 3 Mean (±S.D.) Changes from Baseline to Week 13 in Total AUA Symptom Score** and Peak Urine Flow Rate (mL/sec) Total AUA Symptom Score Peak Urine Flow Rate Mean Baseline Value Mean Change Mean Baseline Value Mean Change * Statistically significant difference from placebo (p-value ≤0.050; Bonferroni-Holm multiple test procedure). ** Total AUA Symptom Scores ranged from 0 to 35. † Peak urine flow rate measured 4 to 8 hours post dose at Week 13. ‡ Peak urine flow rate measured 24 to 27 hours post dose at Week 13. Week 13: For patients not completing the 13-week study, the last observation was carried forward. Study 1 † Tamsulosin hydrochloride capsules 0.8 mg once daily 19.9 ± 4.9 n=247 -9.6* ± 6.7 n=237 9.57 ± 2.51 n=247 1.78* ± 3.35 n=247 Tamsulosin hydrochloride capsules 0.4 mg once daily 19.8 ± 5 n=254 -8.3* ± 6.5 n=246 9.46 ± 2.49 n=254 1.75* ± 3.57 n=254 Placebo 19.6 ± 4.9 n=254 -5.5 ± 6.6 n=246 9.75 ± 2.54 n=254 0.52 ± 3.39 n=253 Study 2 ‡ Tamsulosin hydrochloride capsules 0.8 mg once daily 18.2 ± 5.6 n=244 -5.8* ± 6.4 n=238 9.96 ± 3.16 n=244 1.79* ± 3.36 n=237 Tamsulosin hydrochloride capsules 0.4 mg once daily 17.9 ± 5.8 n=248 -5.1* ± 6.4 n=244 9.94 ± 3.14 n=248 1.52 ± 3.64 n=244 Placebo 19.2 ± 6 n=239 -3.6 ± 5.7 n=235 9.95 ± 3.12 n=239 0.93 ± 3.28 n=235 Mean total AUA Symptom Scores for both tamsulosin hydrochloride capsules 0.4 mg and 0.8 mg once-daily groups showed a rapid decrease starting at 1 week after dosing and remained decreased through 13 weeks in both studies (Figures 2A and 2B). In Study 1, 400 patients (53% of the originally randomized group) elected to continue in their originally assigned treatment groups in a double-blind, placebo-controlled, 40-week extension trial (138 patients on 0.4 mg, 135 patients on 0.8 mg, and 127 patients on placebo). Three hundred twenty-three patients (43% of the originally randomized group) completed one year. Of these, 81% (97 patients) on 0.4 mg, 74% (75 patients) on 0.8 mg, and 56% (57 patients) on placebo had a response ≥25% above baseline in total AUA Symptom Score at one year. * indicates significant difference from placebo (p-value ≤0.050). B = Baseline determined approximately one week prior to the initial dose of double-blind medication at Week 0. Subsequent values are observed cases. LOCF = Last observation carried forward for patients not completing the 13-week study. Note: Patients in the 0.8 mg treatment group received 0.4 mg for the first week. Note: Total AUA Symptom Scores range from 0 to 35. * indicates significant difference from placebo (p-value ≤0.050). Baseline measurement was taken Week 0. Subsequent values are observed cases. LOCF = Last observation carried forward for patients not completing the 13-week study. Note: Patients in the 0.8 mg treatment group received 0.4 mg for the first week. Note: Total AUA Symptom Scores range from 0 to 35. * indicates significant difference from placebo (p-value ≤0.050). B = Baseline determined approximately one week prior to the initial dose of double-blind medication at Week 0. Subsequent values are observed cases. LOCF = Last observation carried forward for patients not completing the 13-week study. Note: The uroflowmetry assessments at Week 0 were recorded 4 to 8 hours after patients received the first dose of double-blind medication. Measurements at each visit were scheduled 4 to 8 hours after dosing (approximate peak plasma tamsulosin concentration). Note: Patients in the 0.8 mg treatment groups received 0.4 mg for the first week. * indicates significant difference from placebo (p-value ≤0.050). Baseline measurement was taken Week 0. Subsequent values are observed cases. LOCF = Last observation carried forward for patients not completing the 13-week study. Note: Patients in the 0.8 mg treatment group received 0.4 mg for the first week. Note: Week 1 and Week 2 measurements were scheduled 4 to 8 hours after dosing (approximate peak plasma tamsulosin concentration). All other visits were scheduled 24 to 27 hours after dosing (approximate trough tamsulosin concentration). Figure 2A Mean Change from Baseline in Total AUA Symptom Score (0 to 35) Study 1 Figure 2B Mean Change from Baseline in Total AUA Symptom Score (0 to 35) Study 2 Figure 3A Mean Increase in Peak Urine Flow Rate (mL/Sec) Study 1 Figure 3B Mean Increase in Peak Urine Flow Rate (mL/Sec) Study 2

8.5 Geriatric Use Of the total number of subjects (1783) in clinical studies of tamsulosin, 36% were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and the other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) ] .

8.2 Lactation Tamsulosin hydrochloride is not indicated for use in women. There are no data on the presence of tamsulosin hydrochloride in human milk, the effects of tamsulosin hydrochloride on the breastfed infant, or the effects of tamsulosin hydrochloride on milk production. Tamsulosin hydrochloride is present in the milk of lactating rats [ see Data ] . Data Oral administration of radiolabeled tamsulosin hydrochloride to rats demonstrated that tamsulosin hydrochloride and/or its metabolites are excreted into the milk of rats.

8.3 Females and Males of Reproductive Potential Infertility Males Abnormal ejaculation including ejaculation failure, ejaculation disorder, retrograde ejaculation, and ejaculation decrease has been associated with tamsulosin hydrochloride [ see Clinical Trials Experience (6.1) ] . Studies in rats revealed significantly reduced fertility in males considered to be due to impairment of ejaculation, which was reversible [ see Nonclinical Toxicology (13.1) ] . Females Tamsulosin hydrochloride is not indicated for use in women. Female fertility in rats was significantly reduced, considered to be due to impairment of fertilization [ see Nonclinical Toxicology (13.1) ] .

8.4 Pediatric Use Tamsulosin hydrochloride capsules are not indicated for use in pediatric populations. Efficacy and positive benefit/risk of tamsulosin hydrochloride was not demonstrated in two studies conducted in patients 2 years to 16 years of age with elevated detrusor leak point pressure (>40 cm H 2 O) associated with known neurological disorder (e.g., spina bifida). Patients in both studies were treated on a weight-based mg/kg schema (0.025 mg, 0.05 mg, 0.1 mg, 0.2 mg, or 0.4 mg tamsulosin hydrochloride) for the reduction in detrusor leak point pressure below 40 cm H 2 O. In a randomized, double-blind, placebo-controlled, 14-week, pharmacokinetic, safety and efficacy study in 161 patients, no statistically significant difference in the proportion of responders was observed between groups receiving tamsulosin hydrochloride and placebo. In an open-label, 12-month safety study, 87 patients were treated with tamsulosin hydrochloride. The most frequently reported adverse events (≥5%) from the pooled data of both studies were urinary tract infection, vomiting, pyrexia, headache, nasopharyngitis, cough, pharyngitis, influenza, diarrhea, abdominal pain, and constipation.

8.1 Pregnancy Risk Summary Tamsulosin hydrochloride is not indicated for use in women. There are no adequate data on the developmental risk associated with the use of tamsulosin hydrochloride in pregnant women. No adverse developmental effects were observed in animal studies in which tamsulosin hydrochloride was administered to rats or rabbits during the period of organogenesis (GD 7 to 17 in the rat and GD 6 to 18 in the rabbit) [ see Data ] . In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Administration of tamsulosin hydrochloride to pregnant female rats during the period of organogenesis at dose levels up to approximately 50 times the human therapeutic AUC exposure (300 mg/kg/day) revealed no evidence of harm to the fetus. Administration of tamsulosin hydrochloride to pregnant rabbits during the period of organogenesis at dose levels up to 50 mg/kg/day produced no evidence of fetal harm.

8 USE IN SPECIFIC POPULATIONS Pediatric Use: Not indicated for use in pediatric populations. (8.4 , 12.3) Geriatric Use: No overall differences in efficacy or safety vs. younger patients, but greater sensitivity of some older adults cannot be ruled out (8.5 , 12.3) Renal Impairment: Has not been studied in patients with end-stage renal disease (8.6 , 12.3) Hepatic Impairment: Has not been studied in patients with severe hepatic impairment (8.7 , 12.3) 8.1 Pregnancy Risk Summary Tamsulosin hydrochloride is not indicated for use in women. There are no adequate data on the developmental risk associated with the use of tamsulosin hydrochloride in pregnant women. No adverse developmental effects were observed in animal studies in which tamsulosin hydrochloride was administered to rats or rabbits during the period of organogenesis (GD 7 to 17 in the rat and GD 6 to 18 in the rabbit) [ see Data ] . In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Administration of tamsulosin hydrochloride to pregnant female rats during the period of organogenesis at dose levels up to approximately 50 times the human therapeutic AUC exposure (300 mg/kg/day) revealed no evidence of harm to the fetus. Administration of tamsulosin hydrochloride to pregnant rabbits during the period of organogenesis at dose levels up to 50 mg/kg/day produced no evidence of fetal harm. 8.2 Lactation Tamsulosin hydrochloride is not indicated for use in women. There are no data on the presence of tamsulosin hydrochloride in human milk, the effects of tamsulosin hydrochloride on the breastfed infant, or the effects of tamsulosin hydrochloride on milk production. Tamsulosin hydrochloride is present in the milk of lactating rats [ see Data ] . Data Oral administration of radiolabeled tamsulosin hydrochloride to rats demonstrated that tamsulosin hydrochloride and/or its metabolites are excreted into the milk of rats. 8.3 Females and Males of Reproductive Potential Infertility Males Abnormal ejaculation including ejaculation failure, ejaculation disorder, retrograde ejaculation, and ejaculation decrease has been associated with tamsulosin hydrochloride [ see Clinical Trials Experience (6.1) ] . Studies in rats revealed significantly reduced fertility in males considered to be due to impairment of ejaculation, which was reversible [ see Nonclinical Toxicology (13.1) ] . Females Tamsulosin hydrochloride is not indicated for use in women. Female fertility in rats was significantly reduced, considered to be due to impairment of fertilization [ see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use Tamsulosin hydrochloride capsules are not indicated for use in pediatric populations. Efficacy and positive benefit/risk of tamsulosin hydrochloride was not demonstrated in two studies conducted in patients 2 years to 16 years of age with elevated detrusor leak point pressure (>40 cm H 2 O) associated with known neurological disorder (e.g., spina bifida). Patients in both studies were treated on a weight-based mg/kg schema (0.025 mg, 0.05 mg, 0.1 mg, 0.2 mg, or 0.4 mg tamsulosin hydrochloride) for the reduction in detrusor leak point pressure below 40 cm H 2 O. In a randomized, double-blind, placebo-controlled, 14-week, pharmacokinetic, safety and efficacy study in 161 patients, no statistically significant difference in the proportion of responders was observed between groups receiving tamsulosin hydrochloride and placebo. In an open-label, 12-month safety study, 87 patients were treated with tamsulosin hydrochloride. The most frequently reported adverse events (≥5%) from the pooled data of both studies were urinary tract infection, vomiting, pyrexia, headache, nasopharyngitis, cough, pharyngitis, influenza, diarrhea, abdominal pain, and constipation. 8.5 Geriatric Use Of the total number of subjects (1783) in clinical studies of tamsulosin, 36% were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and the other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) ] . 8.6 Renal Impairment Patients with renal impairment do not require an adjustment in tamsulosin hydrochloride capsules dosing. However, patients with end-stage renal disease (CL cr <10 mL/min/1.73 m 2 ) have not been studied [see Clinical Pharmacology (12.3) ] . 8.7 Hepatic Impairment Patients with moderate hepatic impairment do not require an adjustment in tamsulosin hydrochloride capsules dosage. Tamsulosin hydrochloride has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Tamsulosin Hydrochloride Capsules USP, 0.4 mg are olive green opaque/orange opaque size '0' hard gelatin capsules imprinted with 'D' on cap and '53' on body with black edible ink filled with white to off-white beadlets. Bottles of 30 NDC 43063-725-30 Bottles of 90 NDC 43063-725-90 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Preserve in tight container. Avoid excessive moisture. Keep tamsulosin hydrochloride capsules and all medicines out of reach of children.