Tamsulosin Hydrochloride

Dosage and Administration ( 2 ) 10/2014 Warnings and Precautions Intraoperative Floppy Iris Syndrome ( 5.5 ) 07/2014

1 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, USP are not indicated for the treatment of hypertension. • Tamsulosin hydrochloride capsule, USP is an alpha 1 adrenoceptor antagonist indicated for treatment of the signs and symptoms of benign prostatic hyperplasia ( 1 ) • Tamsulosin hydrochloride capsules, USP are not indicated for the treatment of hypertension ( 1 )

2 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)

3 DOSAGE FORMS AND STRENGTHS Capsule: 0.4 mg, white to off-white free flowing pellets filled in size '2' empty hard gelatin capsules with green colored cap printed with "ZA-18" in black ink and peach colored body printed with "0.4 mg" in black ink. • Capsules: 0.4 mg ( 3 )

4 CONTRAINDICATIONS Tamsulosin hydrochloride capsules, USP are contraindicated in patients known to be hypersensitive to tamsulosin hydrochloride or any component of tamsulosin hydrochloride capsules, USP. 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, USP ( 4 , 6.2 )

6 ADVERSE REACTIONS The most common adverse events (32% 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 AvKARE at 1-855-361-3993 or FDA at 1-800-332-1088 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 CAPSULE GROUPS PLACEBO n=493 0.4 mg n=502 0.8 n=492 BODY AS A WHOLE Headache 97 (19.3%) 104 (21.1%) 99 (20.1%) Infection 2 45 (9.0%) 53 (10.8%) 37 (7.5%) Asthenia 39 (7.8%) 42 (8.5%) 27 (5.5%) Back pain 35 (7.0%) 41 (8.3%) 27 (5.5%) Chest pain 20 (4.0%) 20 (4.1%) 18 (3.7%) NERVOUS SYSTEM Dizziness 75 (14.9%) 84(17.1%) 50(10.1%) Somnolence 15 (3.0%) 21 (4.3%) 8 (1.6%) Insomnia 12 (2.4%) 7 (1.4%) 3 (0.6%) Libido decreased 5 (1.0%) 10 (2.0%) 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 (2.0%) 7 (1.4%) UROGENITAL SYSTEM Abnormal ejaculation 42 (8.4%) 89 (18.1%) 1 (0.2%) SPECIAL SENSES Blurred vision 1 (0.2%) 10 (2.0%) 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 …

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 capsules 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 capsules 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 capsules 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 capsules 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 capsules 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 inconclus …

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 capsule is not indicated for use in women. There are no adequate data on the developmental risk associated with the use of tamsulosin hydrochloride capsules 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 2-4% and 15-20%, 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 capsule 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 capsule [ 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 capsule 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 cli …

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.

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 is a white or almost white crystalline powder that melts with decomposition at approximately 230°C. It is slightly soluble in water, freely soluble in formic acid, slightly soluble in anhydrous ethanol, sparingly soluble in methanol, slightly soluble in glacial acetic acid, 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: microcrystalline cellulose, methacrylic acid copolymer dispersion, hypromellose acetate succinate, triethyl citrate, talc, and sodium lauryl sulfate. The capsule shell contains gelatin, sodium lauryl sulfate, FD&C blue No. 2, ferric oxide red, ferric oxide yellow, and titanium dioxide. Imprinting black ink contains shellac, dehydrated alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, and potassium hydroxide. It meets USP Dissolution Test 9. chemical-structure

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Tamsulosin Hydrochloride Capsules, USP 0.4 mg are supplied in high density polyethylene bottles. Tamsulosin Hydrochloride Capsules, 0.4 mg - Hard gelatin capsules with olive green opaque cap and orange opaque body. The capsules are imprinted on one side with “TAM” on cap & “0.4 mg” on body in black ink. NDC: 71335-1538-1 30 CAPSULE in a BOTTLE NDC: 71335-1538-2 100 CAPSULE in a BOTTLE NDC: 71335-1538-3 60 CAPSULE in a BOTTLE NDC: 71335-1538-4 10 CAPSULE in a BOTTLE NDC: 71335-1538-5 90 CAPSULE in a BOTTLE NDC: 71335-1538-6 180 CAPSULE in a BOTTLE NDC: 71335-1538-7 7 CAPSULE in a BOTTLE NDC: 71335-1538-8 15 CAPSULE in a BOTTLE NDC: 71335-1538-9 120 CAPSULE in a BOTTLE NDC: 71335-1538-0 3 CAPSULE in a BOTTLE Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep tamsulosin hydrochloride capsules and all medicines out of reach of children. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504