tamsulosin hydrochloride 0.4 MG Extended Release Oral Tablet

INDICATIONS AND USAGE Tamsulosin hydrochloride capsules, USP 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 )

DOSAGE AND ADMINISTRATION Tamsulosin hydrochloride capsules 0.4 mg once daily is recommended as the dose for the treatment 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. 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) . 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.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)

WARNINGS AND PRECAUTIONS Advise patients about the possibility of symptoms related to postural hypotension and to avoid situations where injury could result should syncope occur. (5.1) Should not be used in combination with strong inhibitors of CYP3A4. Use with caution in combination with moderate inhibitors of CYP3A4, with strong or moderate inhibitors of CYP2D6, in patients known to be CYP2D6 poor metabolizers, or in combination with other cytochrome P450 inhibitors. (5.2 , 7.1 , 12.3) Should not be used in combination with other alpha adrenergic blocking agents. (5.2 , 7.2 , 12.3) Exercise caution with concomitant administration of warfarin. (5.2 , 7.4 , 12.3) Advise patients about the possibility and seriousness of priapism. (5.3) Intraoperative Floppy Iris Syndrome has been observed during cataract and glaucoma surgery in some patients. Advise patients considering cataract or glaucoma surgery to tell their ophthalmologist that they have taken tamsulosin hydrochloride capsules. (5.5) Advise patients to be screened for the presence of prostate cancer prior to treatment and at regular intervals afterwards. (5.4) 5.1 Orthostasis The signs and symptoms of orthostasis (postural hypotension, dizziness, and vertigo) were detected more frequently in tamsulosin hydrochloride capsule-treated patients than in placebo recipients. As with other alpha adrenergic blocking agents there is a potential risk of syncope [see Adverse Reactions (6.1) ] . Patients beginning treatment with tamsulosin hydrochloride capsules should be cautioned to avoid situations in which injury could result should syncope occur. 5.2 Drug Interactions Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6. Tamsulosin hydrochloride capsules 0.4 mg should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . 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, in patients known to be CYP2D6 poor metabolizers particularly at a dose higher than 0.4 mg (e.g., 0.8 mg) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . Tamsulosin hydrochloride capsules should be used with caution in combination with cimetidine, particularly at a dose higher than 0.4 mg (e.g., 0.8 mg) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . Tamsulosin hydrochloride capsules should not be used in combination with other alpha adrenergic blocking agents [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ] . 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 Drug Interactions (7.3) and Clinical Pharmacology (12.3) ] . Caution should be exercised with concomitant administration of warfarin and tamsulosin hydrochloride capsules [see Drug Interactions (7.4) and Clinical Pharmacology (12.3) ]. 5.3 Priapism Rarely (probably less than 1 in 50,000 patients), tamsulosin, like other alpha 1 antagonists, has been associated with priapism (persistent painful penile erection unrelated to sexual activity). Because this condition can lead to permanent impotence if not properly treated, patients must be advised about the seriousness of the condition. 5.4 Screening for Prostate Cancer Prostate cancer and BPH frequently co-exist; therefore, patients should be screened for the presence of prostate cancer prior to treatment with tamsulosin hydrochloride capsules and at regular intervals afterwards. 5.5 Intraoperative Floppy Iris Syndrome Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract glaucoma surgery in some patients on or previously treated with alpha blockers, including tamsulosin hydrochloride capsules . Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract and glaucoma surgery in some patients on or previously treated with alpha 1 blockers, including tamsulosin hydrochloride capsules [see Adverse Reactions (6.2) ] . Most reports were in patients taking the alpha blocker when IFIS occurred, but in some cases, the alpha blocker had been stopped prior to surgery. In most of these cases, the alpha blocker had been stopped recently prior to surgery (2 to 14 days), but in a few cases, IFIS was reported after the patient had been off the alpha blocker for a longer period (5 weeks to 9 months). IFIS is a variant of small pupil syndrome and is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. Most reports were in patients taking the alpha 1 blocker when IFIS occurred, but in some cases, the alpha 1 blocker had been stopped prior to surgery. In most of these cases, the alpha 1 blocker had been stopped recently prior to surgery (2 to 14 days), but in a few cases, IFIS was reported after the patient had been off the alpha 1 blocker for a longer period (5 weeks to 9 months). IFIS is a variant of small pupil syndrome and is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. IFIS may increase the risk of eye complications during and after the operation. The benefit stopping alpha blocker therapy prior to cataract or glaucoma surgery has not been established. The initiation of therapy with tamsulosin in patients for whom cataract or glaucoma surgery is scheduled is not recommended. IFIS may increase the risk of eye complications during and after the operation. The benefit of stopping alpha 1 blocker therapy prior to cataract or glaucoma surgery has not been established. The initiation of therapy with tamsulosin in patients for whom cataract or glaucoma surgery is scheduled is not recommended. 5.6 Sulfa Allergy In patients with sulfa allergy, allergic reaction to tamsulosin hydrochloride capsules has been rarely reported. If a patient reports a serious or life-threatening sulfa allergy, caution is warranted when administering tamsulosin hydrochloride capsules.

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 )

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 alpha1adrenoceptors, 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 alpha1 adrenoceptor blocking agent, exhibits selectivity for alpha1 receptors in the human prostate. At least three discrete alpha1 adrenoceptor subtypes have been identified: alpha1A, alpha1B, and alpha1D; their distribution differs between human organs and tissue. Approximately 70% of the alpha1 receptors in the human prostate are of the alpha1A 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 (Tmax) 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 (Cmax) compared to fed conditions (Figure 1). [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)] 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 Cmin = observed minimum concentration Cmax = observed maximum tamsulosin hydrochloride plasma concentration Tmax = median time-to-maximum concentration T1/2 = observed half-life AUCτ= area under the tamsulosin hydrochloride plasma time curve over the dosing interval Cmin (ng/mL) 4 ± 2.6 3.8 ± 2.5 12.3 ± 6.7 13.5 ± 7.6 13.3 ± 13.3 Cmax (ng/mL) 10.1 ± 4.8 17.1 ± 17.1 29.8 ± 10.3 29.1 ± 11 41.6 ± 15.6 Cmax/Cmin Ratio 3.1 ± 1 5.3 ± 2.2 2.7 ± 0.7 2.5 ± 0.8 3.6 ± 1.1 Tmax (hours) 6 4 7 6.6 5 T1/2 (hours) - - - - 14.9 ± 3.9 AUCτ (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 alpha1 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≤CLcr <70 mL/min/1.73 m2) or moderate-severe (10 ≤CLcr <30 mL/min/1.73 m2) renal impairment and 6 normal subjects (CLcr >90 mL/min/1.73 m2). While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsul