5.1 Orthostasis

The signs and symptoms of orthostasis (postural hypotension, dizziness, and vertigo) were detected more frequently in Tamsulosin Hydrochloride Capsules -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 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 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 1antagonists, 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 and glaucoma surgery in some patients on or previously treated with alpha 1blockers, including Tamsulosin Hydrochloride Capsules [ see Adverse Reactions (6.2)].
Most reports were in patients taking the alpha 1blocker when IFIS occurred, but in some cases, the alpha 1blocker had been stopped prior to surgery. In most of these cases, the alpha 1blocker 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 1blocker 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 of stopping alpha 1blocker 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.

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 1Adverse Events Occurring in ≥ 2% of Tamsulosin Hydrochloride Capsules or Placebo Patients in Two U.S. Short-Term Placebo-Controlled Clinical Studies.

1A 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.

2Coding preferred terms also include cold, common cold, head cold, flu, and flu-like symptoms.

3Coding 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).

To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993 or FDA at 1-800-332-1088 or www.fda.gov/medwatch.

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 1blocker therapy [ see Warnings and Precautions (5.5)].

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 Cmax 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 maxand 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. Alphaadrenergic 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 vitroand in vivostudies 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 Capsules 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 maxand 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)].

8.1 Pregnancy

Teratogenic Effects,Pregnancy Category B.
Administration of tamsulosin hydrochloride to pregnant female rats 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 at dose levels up to 50 mg/kg/day produced no evidence of fetal harm. Tamsulosin Hydrochloride Capsules are not indicated for use in women.

8.2 Labor & Delivery

8.3 Nursing Mothers

Tamsulosin Hydrochloride Capsules are not indicated for use in women.

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 2O) 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 2O. 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 Capsules has not been studied in patients with severe hepatic impairment [ see Clinical Pharmacology (12.3)].

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 1adrenoceptors, 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 1adrenoceptor blocking agent, exhibits selectivity for alpha 1receptors in the human prostate. At least three discrete alpha 1adrenoceptor subtypes have been identified: alpha 1A, alpha 1B, and alpha 1D; their distribution differs between human organs and tissue. Approximately 70% of the alpha 1receptors in the human prostate are of the alpha 1Asubtype. 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).

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 Capsules 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

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

AUCt= area under the tamsulosin hydrochloride plasma time curve over the dosing interval.

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 vitrostudies 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 vitrotesting 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 Capsules 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 Capsules 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 Cmax 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 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 Capsules 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 Cmax 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 Capsules 0.4 mg is co-administered with strong CYP3A4 inhibitors in CYP2D6 PMs, Tamsulosin Hydrochloride Capsules 0.4 mg capsules 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 Capsules 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 Capsules 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 Capsules 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 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 Drug Interactions (7.3)].

Warfarin

A definitive drug-drug interaction study between tamsulosin hydrochloride and warfarin was not conducted. Results from limited in vitroand in vivostudies 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 Capsules  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 Cmax 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)].

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 vitroin 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 vivosister 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 3days 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.

13.2 Animal Pharmacology & OR Toxicology