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Flomax (Tamsulosin Hydrochloride) - Description and Clinical Pharmacology

 
 



ATTENTION PHARMACIST: Detach “Patient Information” from package insert and dispense with the product.

Prescribing Information

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:

Each FLOMAX capsule for oral administration contains tamsulosin hydrochloride 0.4 mg, and the following inactive ingredients: methacrylic acid copolymer dispersion NF, microcrystalline cellulose, triacetin, calcium stearate, talc, FD&C blue No. 2, titanium dioxide, ferric oxide, gelatin, and trace amounts of black edible ink.

CLINICAL PHARMACOLOGY

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 alpha1 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 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 human prostate are of the alpha1A subtype.

Flomax® (tamsulosin hydrochloride) capsules are not intended for use as an antihypertensive drug.

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 FLOMAX 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 four to five hours under fasting conditions and by six to seven hours when FLOMAX capsules are administered with food. Taking FLOMAX 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 FLOMAX 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 Flomax® (tamsulosin hydrochloride) capsule is taken with a light breakfast or a high-fat breakfast (Table 1).

Table 1 Mean (± S.D.) Pharmacokinetic Parameters Following FLOMAX 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 18-32 years)
0.8 mg QD to healthy volunteers; n=22
(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/Cmin Ratio  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 (nghr/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 ten healthy male adults was 16 L, which is suggestive of distribution into extracellular fluids in the body.

Tamsulosin hydrochloride is extensively bound to human plasma proteins (94% to 99%), primarily alpha-1 acid glycoprotein (AAG), with linear binding over a wide concentration range (20 to 600 ng/mL). The results of two-way in vitro studies indicate that the binding of tamsulosin hydrochloride to human plasma proteins is not affected by amitriptyline, diclofenac, glyburide, simvastatin plus simvastatin-hydroxy acid metabolite, warfarin, diazepam, propranolol, trichlormethiazide, or chlormadinone. Likewise, tamsulosin hydrochloride had no effect on the extent of binding of these drugs.

Metabolism

There is no enantiomeric bioconversion from tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer in humans. Tamsulosin hydrochloride is extensively metabolized by cytochrome P450 enzymes in the liver and less than 10% of the dose is excreted in urine unchanged. However, the pharmacokinetic profile of the metabolites in humans has not been established. In vitro results indicate that CYP3A4 and CYP2D6 are involved in metabolism of tamsulosin as well as some minor participation of other CYP isoenzymes. Inhibition of hepatic drug-metabolizing enzymes may lead to increased exposure to tamsulosin (see Drug-Drug Interactions, Cytochrome P450 Inhibition ). 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 four 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 five to seven hours. Because of absorption rate-controlled pharmacokinetics with Flomax® (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).

Special Populations

Geriatrics (Age)

Cross-study comparison of FLOMAX 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.

Renal Dysfunction

The pharmacokinetics of tamsulosin hydrochloride have been compared in 6 subjects with mild-moderate (30≤CLcr <70 mL/min/1.73m2) or moderate-severe (10≤CLcr <30 mL/min/1.73m2) renal impairment and 6 normal subjects (CLcr <90 mL/min/1.73m2). 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 Flomax® (tamsulosin hydrochloride) capsules dosing. However, patients with endstage renal disease (CLcr <10 mL/min/1.73m2) have not been studied.

Hepatic Dysfunction

The pharmacokinetics of tamsulosin hydrochloride have been compared in 8 subjects with moderate hepatic dysfunction (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 dysfunction do not require an adjustment in FLOMAX capsules dosage. FLOMAX has not been studied in patients with severe hepatic dysfunction.

Drug-Drug Interactions

Nifedipine, Atenolol, Enalapril

In three studies in hypertensive subjects (age range 47-79 years) whose blood pressure was controlled with stable doses of Procardia XL®, atenolol, or enalapril for at least three months, FLOMAX capsules 0.4 mg for seven days followed by FLOMAX capsules 0.8 mg for another seven 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 FLOMAX capsules are administered concomitantly with Procardia XL®, atenolol, or enalapril.

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 FLOMAX capsules.

Digoxin and Theophylline

In two studies in healthy volunteers (n=10 per study; age range 19-39 years) receiving FLOMAX capsules 0.4 mg/day for two days, followed by FLOMAX capsules 0.8 mg/day for five to eight 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 FLOMAX capsule is administered concomitantly with digoxin or theophylline.

Furosemide

The pharmacokinetic and pharmacodynamic interaction between Flomax® (tamsulosin hydrochloride) capsules 0.8 mg/day (steady-state) and furosemide 20 mg intravenously (single dose) was evaluated in ten healthy volunteers (age range 21-40 years). FLOMAX 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 FLOMAX capsules dosage.

Cytochrome P450 Inhibition:

Cimetidine

The effects of cimetidine at the highest recommended dose (400 mg every six hours for six days) on the pharmacokinetics of a single FLOMAX capsule 0.4 mg dose was investigated in ten healthy volunteers (age range 21-38 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%). Therefore, FLOMAX capsules should be used with caution in combination with cimetidine, particularly at doses higher than 0.4 mg.

Strong Inhibitors of CYP3A4 or CYP2D6

The effects of ketoconazole (a strong inhibitor of CYP3A4) at 400 mg every day on the pharmacokinetics of a single FLOMAX capsule 0.4 mg dose was investigated in 24 healthy volunteers (age range from 23 to 47 years). Treatment with ketoconazole resulted in a Cmax and AUC that increased by a factor of 2.2 and 2.8, respectively. Therefore, FLOMAX 0.4 mg capsules should be used with caution in combination with strong inhibitors of CYP3A4. Doses above 0.4 mg should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole).

The effects of paroxetine (a strong inhibitor of CYP2D6) at 20 mg every day on the pharmacokinetics of a single FLOMAX capsule 0.4 mg dose was investigated in 23 healthy volunteers (age range from 23 to 48 years). Treatment with paroxetine resulted in a Cmax and AUC that increased by a factor of 1.3 and 1.6, respectively. Therefore, FLOMAX capsules should be used with caution in combination with strong inhibitors of CYP2D6, particularly at doses higher than 0.4 mg (e.g., 0.8 mg).

CLINICAL STUDIES

Four placebo-controlled clinical studies and one active-controlled clinical study enrolled a total of 2296 patients (1003 received FLOMAX capsules 0.4 mg once daily, 491 received FLOMAX capsules 0.8 mg once daily, and 802 were control patients) in the U.S. and Europe.

In the two U.S. placebo-controlled, double-blind, 13-week, multicenter studies [Study 1 (US92-03A) and Study 2 (US93-01)], 1486 men with the signs and symptoms of BPH were enrolled. In both studies, patients were randomized to either placebo, FLOMAX capsules 0.4 mg once daily, or FLOMAX capsules 0.8 mg once daily. Patients in FLOMAX capsules 0.8 mg once daily treatment groups received a dose of 0.4 mg once daily for one week before increasing to the 0.8 mg once daily dose. The primary efficacy assessments included: 1) total American Urological Association (AUA) Symptom Score questionnaire, which evaluated irritative (frequency, urgency, and nocturia), and obstructive (hesitancy, incomplete emptying, intermittency, and weak stream) symptoms, where a decrease in score is consistent with improvement in symptoms; and 2) peak urine flow rate, where an increased peak urine flow rate value over baseline is consistent with decreased urinary obstruction.

Mean changes from baseline to Week 13 in total AUA Symptom Score were significantly greater for groups treated with FLOMAX capsules 0.4 mg and 0.8 mg once daily compared to placebo in both U.S. studies (Table 2, Figures 2A and 2B). The changes from baseline to Week 13 in peak urine flow rate were also significantly greater for the Flomax® (tamsulosin hydrochloride) capsules 0.4 mg and 0.8 mg once daily groups compared to placebo in Study 1, and for the FLOMAX capsules 0.8 mg once daily group in Study 2 (Table 2, Figures 3A and 3B). Overall there were no significant differences in improvement observed in total AUA Symptom Scores or peak urine flow rates between the 0.4 mg and the 0.8 mg dose groups with the exception that the 0.8 mg dose in Study 1 had a significantly greater improvement in total AUA Symptom Score compared to the 0.4 mg dose.

Table 2 Mean (±S.D.) Changes from Baseline to Week 13 in Total AUA Symptom Score ** and Peak Urine Flow Rate (mL/sec)
Total AUA Symptom Score Peak Urine Flow Rate
Mean Baseline
Value
Mean
Change
Mean Baseline
Value
Mean
Change
 *   Statistically significant difference from placebo (p-value ≤0.050; Bonferroni-Holm multiple test procedure).
**  Total AUA Symptom Scores ranged from 0 to 35.
†    Peak urine flow rate measured 4 to 8 hours post dose at Week 13.
‡   Peak urine flow rate measured 24 to 27 hours post dose at Week 13.
Week 13: For patients not completing the 13-week study, the last observation was carried forward.
Study 1
 FLOMAX capsules
0.8 mg once daily
 19.9 ± 4.9
n=247
 -9.6* ± 6.7
n=237
 9.57 ± 2.51
n=247
 1.78* ± 3.35
n=247
 FLOMAX capsules
0.4 mg once daily
 19.8 ± 5.0
n=254
 -8.3* ± 6.5
n=246
 9.46 ± 2.49
n=254
 1.75* ± 3.57
n=254
 Placebo  19.6 ± 4.9
n=254
 -5.5 ± 6.6
n=246
 9.75 ± 2.54
n=254
 0.52 ± 3.39
n=253
Study 2
 FLOMAX capsules
0.8 mg once daily
 18.2 ± 5.6
n=244
 -5.8* ± 6.4
n=238
 9.96 ± 3.16
n=244
 1.79* ± 3.36
n=237
 FLOMAX capsules
0.4 mg once daily
 17.9 ± 5.8
n=248
 -5.1* ± 6.4
n=244
 9.94 ± 3.14
n=248
 1.52 ± 3.64
n=244
 Placebo  19.2 ± 6.0
n=239
 -3.6 ± 5.7
n=235
 9.95 ± 3.12
n=239
 0.93 ± 3.28
n=235

Mean total AUA Symptom Scores for both FLOMAX capsules 0.4 mg and 0.8 mg once daily groups showed a rapid decrease starting at one week after dosing and remained decreased through 13 weeks in both studies (Figures 2A and 2B).

In Study 1, 400 patients (53% of the originally randomized group) elected to continue in their originally assigned treatment groups in a double-blind, placebo controlled, 40 week extension trial (138 patients on 0.4 mg, 135 patients on 0.8 mg and 127 patients on placebo). Three hundred twenty-three patients (43% of the originally randomized group) completed one year. Of these, 81% (97 patients) on 0.4 mg, 74% (75 patients) on 0.8 mg and 56% (57 patients) on placebo had a response ≥25% above baseline in total AUA Symptom Score at one year.

Figure 2A Mean Change from Baseline in Total AUA Symptom Score (0-35) Study 1

* indicates significant difference from placebo (p-value ≤0.050).
B = Baseline determined approximately one week prior to the initial dose of double-blind medication at Week 0. Subsequent values are observed cases.
LOCF = Last observation carried forward for patients not completing the 13-week study.
Note: Patients in the 0.8 mg treatment group received 0.4 mg for the first week.
Note: Total AUA Symptom Scores range from 0 to 35.
 

Figure 2B Mean Change from Baseline in Total AUA Symptom Score (0-35) Study 2

* indicates significant difference from placebo (p-value ≤0.050).
Baseline measurement was taken Week 0. Subsequent values are observed cases.
LOCF = Last observation carried forward for patients not completing the 13-week study.
Note: Patients in the 0.8 mg treatment group received 0.4 mg for the first week.
Note: Total AUA Symptom Scores range from 0 to 35.
 

Figure 3A Mean Increase in Peak Urine Flow Rate (mL/Sec) Study 1

* indicates significant difference from placebo (p-value ≤0.050).
B = Baseline determined approximately one week prior to the initial dose of double-blind medication at Week 0.
Subsequent values are observed cases.
LOCF = Last observation carried forward for patients not completing the 13-week study.
Note: The uroflowmetry assessments at Week 0 were recorded 4-8 hours after patients received the first dose of double-blind medication.
Measurements at each visit were scheduled 4-8 hours after dosing (approximate peak plasma tamsulosin concentration).
Note: Patients in the 0.8 mg treatment groups received 0.4 for the first week.
 

Figure 3B Mean Increase in Peak Urine Flow Rate (mL/Sec) Study 2

* indicates significant difference from placebo (p-value ≤0.050).
Baseline measurement was taken Week 0. Subsequent values are observed cases.
LOCF = Last observation carried forward for patients not completing the 13-week study.
Note: Patients in the 0.8 mg treatment group received 0.4 mg for the first week.
Note: Week 1 and Week 2 measurements were scheduled 4-8 hours after dosing (approximate peak plasma tamsulosin concentration).
All other visits were scheduled 24-27 hours after dosing (approximate trough tamsulosin concentration).

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