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Tamsulosin
Tamsulosin hydrochloride is an antagonist of alpha1A adrenoceptors in the prostate. Tamsulosin HCl is (-)-( R)-5,4,2-[2-(O-ethoxyphenoxy)ethyl]amino-propyl-2-methoxybenzenesulfonamide, monohydrochloride. Tamsulosin HCl occurs as white crystals that melt with decomposition at approximately 230° C. It is sparingly soluble in water and in methanol, slightly soluble in glacial acetic acid and in ethanol, and practically insoluble in ether. The empirical formula of tamsulosin HCl is C20H28N2O5S • HCl. The molecular weight of tamsulosin HCl is 444.98. Each FLOMAX capsule
for oral administration
contains tamsulosin HCl 0.4 mg, and the following inactive ingredients:
methacrylic acid copolymer,
microcrystalline cellulose,
triacetin, polysorbate 80, sodium
lauryl sulfate, calcium stearate, talc, FD&C blue, No. 2, titanium
dioxide, ferric oxide, gelatin, and trace
amounts of shellac, industrial methylated spirit 740P, soya lecithin,
1-ethoxyethanol, dimethylpolysiloxane, and black
iron oxide E 172.
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: alpha1 A, alpha1 B and alpha1 their distribution differs between human organs and tissue. Approximately 70% of the alpha1- receptors in human prostate are of the alpha1A subtype. FLOMAX capsules are not intended for use as an antihypertensive drug. Pharmacokinetics The pharmacokinetics of tamsulosin HCl 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 HCl from FLOMAX capsules 0.4 mg is essentially complete (> 90%) following oral administration under fasting conditions. Tamsulosin HCl 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. The effects of food on the pharmacokinetics of tamsulosin HCl are consistent regardless of whether a FLOMAX capsule is taken with a light breakfast or a high- fat breakfast (Table 1).
Distribution: The mean steady-state apparent volume of distribution of tamsulosin HCl after intravenous administration to ten healthy male adults was 1.6L, which is suggestive of distribution into extracellular fluids in the body. Additionally, whole body autoradiographic studies in mice and rats and tissue distribution in rats and dogs indicate that tamsulosin HCl is widely distributed to most tissues including kidney, prostate, liver, gall bladder, heart, aorta, and brown fat, and minimally distributed to the brain, spinal cord, and testes. Tamsulosin HCl 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 HCl 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 HCl had no effect on the extent of binding of these drugs. Metabolism: There is no enantiometric bioconversion from tamsulosin HCl [R(-) isomer] to the S(+) isomer in humans. Tamsulosin HCl 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. Additionally, the cytochrome P450 enzymes that primarily catalyze the Phase I metabolism of tamsulosin HCl have not been conclusively identified. Therefore, possible interactions with other cytochrome P450 metabolized compounds cannot be discerned with current information. The metabolites of tamsulosin HCl 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 HCl 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 HCl interaction with diclofenac and warfarin were equivocal. Excretion: On administration of the radiolabeled dose of tamsulosin HCl to four healthy volunteers, 97% of the administered radioactivity was recovered, with unne (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 HCl is in plasma range from five to seven hours. Because of absorption rate- controlled pharmacokinetics with FLOMAX capsules, the apparent half- life of tamsulosin HCl is approximately 9 to 13 hours in healthy volunteers and 14 to 15 hours in the target population. Tamsulosin HCl undergoes restrictive clearance in humans, with a relatively low systemic clearance (2.88 L/h). Renal Dysfunction: The pharmacokinetics of tamsulosin HCl 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 HCl was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin HCl, as well as the intrinsic clearance, remained relatively constant. Therefore, patients with renal impairment do not require an adjustment in FLOMAX capsules dosing. However, patients with endstage renal disease (CLcr < 1 0 mL/min/ l .73m2) have not been studied. Hepatic Dysfunction: The pharmacokinetics of tamsulosin HCl 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 HCl was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin HCl does not change significantly with only a modest (32%) change in intrinsic clearance of unbound tamsulosin HCl. Therefore, patients with moderate hepatic dysfunction do not require an adjustment in FLOMAX capsules dosage. 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 [Study1 (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), any 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). The changes from baseline to week 13 in peak urine flow rate were also significantly greater for the FLOMAX 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). 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.
*Statistically significant difference from placebo (p-value 0.050; Bonferroni-Hoim multiple test procedure); 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. In Study 1, 400
patients (53% of the originally randomized group) elected to continue
in their originally assigned treatment
groups in a double- b.i.d.
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 and 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.
FLOMAX® (tamsulosin HCl) capsules are indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). FLOMAX capsules are not indicated for the treatment of hypertension.
FLOMAX 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. For those patients who fail to respond to the 0.4-mg dose after two to four weeks of dosing, the dose of FLOMAX capsules can be increased to 0.8 mg once daily. If FLOMAX 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. HOW SUPPLIED FLOMAX capsules 0.4 mg are supplied in high density polyethylene bottles containing 100 or 1000 hard gelatin capsules with olive green opaque cap and orange opaque body. The capsules are imprinted on one side with “Flomax 0.4 mg” and on the other side with “BI 58.”
Rx only. Store at controlled room temperature 20°- 25° C (68°- 77° F). Keep FLOMAX capsules and all medicines out of reach of children
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 FLOMAX capsules were used. These studies evaluated safety in 1783 patients treated with FLOMAX capsules and 798 patients administered placebo. Table 3 summarizes the treatment- emergent adverse events that occurred in ³2% of patients receiving either FLOMAX 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.
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 l0mmHg upon standing, with the standing diastolic blood pressure <65 mmHg during the orthostatic test; (3) an increase in pulse rate of 20bpm upon standing with a standing pulse rate < 100bpm 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 FLOMAX 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 FLOMAX 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 FLOMAX capsules 0.4-mg once daily group, 92 of the 491 patients (19%) in the FLOMAX 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 FLOMAX capsule-treated patients than in placebo recipients, there is a potential risk of syncope (see WARNINGS). Abnormal Ejaculation Abnormal ejaculation includes ejaculation failure, ejaculation disorder, retrograde ejaculation and ejaculation decrease. As shown in Table 3, abnormal ejaculation was associated with FLOMAX capsules administration and was dose-related in the U.S. studies. Withdrawal from these clinical studies of FLOMAX 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. Post-Marketing Experience Allergic-type reactions such as skin rash, pruritus, angioedema of tongue, lips and face and urticaria have been reported with positive rechallenge in some cases.
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®, atenolot, 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 HCl 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 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 HCl Cmax and A.C. these changes are expected to be clinically insignificant and do not require adjustment of the FLOMAX capsules dosage. 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 HCl which resulted in a moderate increase in tamsulosin
HCl AUC (44%). Therefore,
FLOMAX capsules should be used with caution in combination with
cimetidine, particularly at doses higher than 0.4 mg.
The signs and symptoms of orthostasis (postural hypotension, dizziness and vertigo) were detected more frequently in FLOMAX capsule treated patients than in placebo recipients. As with other alpha-1 adrenergic blocking agents there is a potential risk of syncope (see ADVERSE REACTIONS). Patients beginning treatment with FLOMAX capsules should be cautioned to avoid situations where injury could result should syncope occur.
General Carcinoma of the prostate: Carcinoma of the prostate and BPH cause many of the same symptoms. These two diseases frequently coexist. Patients should be evaluated prior to the start of FLOMAX capsules therapy to rule out the presence of carcinoma of the prostate. Drug-Drug Interactions The pharmacokinetic and pharmacodynamic interactions between FLOMAX capsules and other alpha-adrenergic blocking agents have not been determined. However, interactions may be expected and FLOMAX capsules should NOT be used in combination with other alpha-adrenergic blocking agents. The pharmacokinetic interaction between cimetidine and FLOMAX capsules was investigated. The results indicate significant changes in tamsulosin HCl clearance (26% decrease) and AUC (44% increase). Therefore, FLOMAX capsules should be used with caution in combination with cimetidine, particularly at doses higher than 0.4 mg. Results from limited in vitro and in vivo drug- drug interaction studies between tamsulosin HCl and warfarin are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and FLOMAX capsules. (See also DRUG INTERACTIONS) Laboratory Tests No laboratory test interactions with FLOMAX capsules are known. Treatment with FLOMAX capsules for up to 12 months had no significant effect on prostate- specific antigen (PSA). Pregnancy Teratogenic Effects, Pregnancy Category B. Administration of tamsulosin HCl to pregnant female rats at dose levels up to 300 mg/kg/day (approximately 50 times the human therapeutic AUC exposure) revealed no evidence of harm to the fetus. Administration of tamsulosin HCl to pregnant rabbits at dose levels up to 50 mg/kg/day produced no evidence of fetal harm. FLOMAX capsules are not indicated for use in women. Nursing Mothers FLOMAX capsules are not indicated for use in women. Pediatric Use FLOMAX capsules are not indicated for use in pediatric populations. Carcinogenesis, Mutagenesis, and 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 < 0.01 5). The highest doses of tamsulosin HCl 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 HCl 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 HCl-induced hyperprolactinemia. It is not known if FLOMAX capsules elevate prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known. Tamsulosin HCl produced no evidence of mutagenic potential in vitro in 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 vivo sister chromat-d 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 HCl (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 3 days 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 HCl (1.5 and 16 times the anticipated human AUG exposure) did not significantly alter fertility in male rats. Effects of tamsulosin HCl on sperm counts or sperm function have not been evaluated. Studies in females 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 HCl, 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.
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