Tamsulosin Hydrochloride: Package Insert and Label Information (Page 2 of 4)

8 USE IN SPECIFIC POPULATIONS

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 USP are not indicated for use in women.

8.3 Nursing Mothers

Tamsulosin hydrochloride capsules USP are not indicated for use in women.

8.4 Pediatric Use

Tamsulosin hydrochloride capsules USP 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 H2O) 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 H2O. 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 USP dosing. However, patients with end-stage renal disease (CLcr<10 mL/min/1.73 m2) 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 USP dosage. Tamsulosin hydrochloride capsules USP have not been studied in patients with severe hepatic impairment [see CLINICAL PHARMACOLOGY (12.3)].

10 OVERDOSAGE

Should overdosage of tamsulosin hydrochloride capsules USP 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.

11 DESCRIPTION

Tamsulosin hydrochloride is an antagonist of alpha1A adrenoceptors in the prostate.

Tamsulosin hydrochloride is (-)-(R)-5-[2-[[2-(o-Ethoxyphenoxy) ethyl]amino]propyl]-2-methoxybenzenesulfonamide, monohydrochloride. Tamsulosin hydrochloride is a 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 empirical formula of tamsulosin hydrochloride is C20H28N2O5S • HCl. The molecular weight of tamsulosin hydrochloride is 444.98. Its structural formula is:

[ab8b786d-figure-01]

Each tamsulosin hydrochloride capsule USP for oral administration contains tamsulosin hydrochloride 0.4 mg, and the following inactive ingredients: methacrylic acid copolymer, microcrystalline cellulose, purified water, talc, triethyl citrate, black iron oxide, FD&C Blue No. 2, gelatin, red iron oxide, titanium dioxide, yellow iron oxide and trace amounts of antifoam DC 1510, industrial methylated spirit, lecithin, n-butyl alcohol, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, ammonium, potassium hydroxide and shellac.

Complies with USP Dissolution Test 4.

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 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 USP 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 USP 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 USP are administered with food. Taking tamsulosin hydrochloride capsules USP 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 USP 0.4 mg Under Fasted and Fed Conditions (n=8)

[1]

The effects of food on the pharmacokinetics of tamsulosin hydrochloride are consistent regardless of whether tamsulosin hydrochloride capsules USP are taken with a light breakfast or a high-fat breakfast (Table 2).

Table 2 Mean (± S.D.) Pharmacokinetic Parameters Following Tamsulosin Hydrochloride Capsules USP 0.4 mg Once Daily or 0.8 mg Once Daily with a Light Breakfast, High-Fat Breakfast or Fasted
Pharmacokinetic 0.4 mg QD to healthy volunteers; n=23 0.8 mg QD to healthy volunteers; n=22
Parameter (age range 18-32 years) (age range 55-75 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) 4.0 ± 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 ± 11.0 41.6 ± 15.6
Cmax/CminRatio 3.1 ± 1.0 5.3 ± 2.2 2.7 ± 0.7 2.5 ± 0.8 3.6 ± 1.1
Tmax (hours) 6.0 4.0 7.0 6.6 5.0
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 USP, 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 USP 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 USP 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 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 USP dosing. However, patients with end-stage renal disease (CLcr<10 mL/min/1.73 m2) 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 USP dosage. Tamsulosin hydrochloride capsules USP have 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 USP 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 USP 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 USP 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 USP 0.4 mg are co-administered with strong CYP3A4 inhibitors in CYP2D6 PMs, tamsulosin hydrochloride capsules USP 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 capsules USP 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 USP have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when tamsulosin hydrochloride capsules USP 0.4 mg are 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 USP 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 USP and other alpha adrenergic blocking agents have not been determined; however, interactions between tamsulosin hydrochloride capsules USP 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 USP, 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 USP [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 USP 0.4 mg for 7 days followed by tamsulosin hydrochloride capsules USP 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 USP 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 USP 0.4 mg/day for 2 days, followed by tamsulosin hydrochloride capsules USP 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 tamsulosin hydrochloride capsules USP are administered concomitantly with digoxin or theophylline [see DRUG INTERACTIONS (7.6)].

Furosemide

The pharmacokinetic and pharmacodynamic interaction between tamsulosin hydrochloride capsules USP 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 USP 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 USP dosage [see DRUG INTERACTIONS (7.7)].

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