FLOMAX CR (tamsulosin hydrochloride) is an alpha₁ adrenoreceptor (AR) blocking agent used for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). It exhibits selectivity for both alpha_1A and alpha_1D receptors over the alpha_1B AR subtype. These three AR subtypes have a distinct distribution pattern in human tissue. Whereas approximately 70% of the alpha₁-receptors in human prostate are of the alpha_1A subtype, the human bladder contains predominantly the alpha_1D subtype while blood vessels express predominantly alpha_1B subtype.

Stimulation/antagonism of each of the receptor subtypes gives rise to a distinct pharmacological effect.

Lower Urinary Tract Symptoms (LUTS) suggestive of benign prostatic obstruction (BPO) formerly referred to as symptomatic benign prostatic hyperplasia (BPH) are very common in men >50 years old; the prevalence increases with age. The symptoms associated with LUTS/BPH are comprised of two underlying components: the 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. he 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 adrenoreceptors, which are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoreceptors 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.

It is further believed that blockade of alpha_1D subtypes in the human obstructed bladder may be responsible for reducing detrusor overactivity and subsequent relief of storage symptoms.

FLOMAX CR (tamsulosin hydrochloride) is not intended for use as an antihypertensive drug.

The FLOMAX CR (tamsulosin hydrochloride) tablet is a novel formulation based on the Oral-Controlled Absorption System (OCAS), a patented gel matrix controlled-release technology designed to provide a consistent slow release of tamsulosin which is maintained throughout the gastro-intestinal tract, resulting in an adequate exposure, with little fluctuation, over 24 hours.

The pharmacokinetics of tamsulosin from the OCAS have been evaluated in adult healthy volunteers with doses ranging from 0.4 mg to 1.6 mg.

After a single oral dose of 0.4 mg FLOMAX CR in the fasted state, the plasma concentration of tamsulosin gradually increased reaching C_max at a median time of 6 hours. At steady state, which is reached by day 4 of multiple dosing, plasma concentrations of tamsulosin peak at 4-6 hours in the fasted and fed state. Peak plasma concentrations increase from approximately 6 ng/mL after the first dose to 11 ng/mL in steady state. After C_max is reached, the plasma concentration decreases, but at approximately 16-24 hours post-dose, a small increase or second plateau is observed. The absolute bioavailability of tamsulosin from FLOMAX CR was estimated to be 55-59%.

A study conducted at steady state with 0.4 mg FLOMAX CR demonstrated that the plasma concentration-time profile in the fed state was bioequivalent to the fasted state, indicating the absence of a food effect ( Table 1).

 

Table 1: FLOMAX CR

Mean Pharmacokinetic Parameters of Tamsulosin at Steady Stage Following Administration of Once Daily Doses of 0.4 mg FLOMAX CR in Both the Fed and Fasted State

Parameter	FLOMAX CR 0.4 mg (Fed) (n=24)	FLOMAX CR 0.4 mg (Fasted) (n=24)
AUC0-inf (ng.h/mL)	291.1	278.7
Cmax (ng/mL)	11.1	10.7
C24 (ng/ml)	4.8	4.6
Tmax (h)	4.16	4.75
T1/2 (h)	14.6	15.6

The 0.4 mg FLOMAX CR Controlled-Release tablet is not bioequivalent to the 0.4 mg FLOMAX capsule, as the test/reference ratio for C_max and AUC did not fall within the predefined limits of 80-125%. The plasma concentration-time profile presented in Figure 1 shows the lack of a pronounced spike in C_max with FLOMAX CR tablets compared with capsules which may be consistent with a more favourable safety profile.

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Figure 1-FLOMAX CR

Mean Tamsulosin Plasma vs. Time Profiles of FLOMAX CR 0.4 mg and Tamsulosin Capsules, 0.4 mg (N=12)

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The mean steady-state apparent volume of distribution of tamsulosin after intravenous administration to ten healthy male adults was 16 L, which is suggestive of distribution into extracellular fluids in the body. Additionally, whole body autoradiographic studies in mice, rats and dogs indicate that tamsulosin 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 is extensively bound to human plasma proteins (94% to 99%), primarily alpha-1-acid glycoprotein (AAG) in humans, 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 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 had no effect on the extent of binding of these drugs.

Tamsulosin is extensively metabolized by cytochrome P450 enzymes (CYP3A) in the liver, followed by extensive glucuronide or sulfate conjugation of metabolites. On administration of a dose of radiolabelled tamsulosin 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. Less than 10% of the dose was recovered as unchanged (parent) compound in the urine.

Metabolites of tamsulosin do not contribute significantly to tamsulosin adrenoreceptor antagonist activity. Furthermore, there is no enantiomeric bioconversion from tamsulosin [R(-) isomer] to the S(+) isomer in studies with mice, rats, dogs, and humans.

Tamsulosin undergoes restrictive clearance in humans, with a relatively low systemic clearance (2.88 L/h). Tamsulosin exhibits linear pharmacokinetics following single or multiple dosing of FLOMAX CR resulting in a proportional increase in C_max and AUC with increasing doses. Intrinsic clearance is independent of tamsulosin 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.

Following intravenous or oral administration of an immediate-release formulation, the elimination half-life of tamsulosin in plasma ranged from five to seven hours. Because of absorption rate-controlled pharmacokinetics with the FLOMAX CR formulation, the apparent half-life of tamsulosin increases to approximately 12 to 15 hours in healthy volunteers.

Incubations with human liver microsomes showed no evidence of clinically significant interactions between tamsulosin and drugs which are known to interact or be metabolized by hepatic enzymes, such as amitriptyline, diclofenac, albuterol (beta agonist), glyburide (glibenclamide), finasteride (5 alpha-reductase inhibitor for treatment of BPH), and warfarin. No dose adjustment is warranted in hepatic insufficiency.

FLOMAX CR (tamsulosin hydrochloride) is indicated for the treatment of Lower Urinary Tract Symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).

FLOMAX CR (tamsulosin hydrochloride) is contraindicated in patients known to be hypersensitive to tamsulosin or any component of the FLOMAX CR controlled release formulation.

As with all α₁-adrenoceptor antagonists, a reduction in blood pressure can occur in individual cases during treatment with FLOMAX CR, as a result of which, rarely, syncope can occur. At the first signs of orthostatic hypotension (dizziness, weakness), the patient should sit or lie down until the symptoms have disappeared.

Patients beginning treatment with FLOMAX CR should be cautioned to avoid situations where injury could result should syncope occur (see Adverse Effects).

FLOMAX CR (tamsulosin hydrochloride) is not indicated for the treatment of hypertension.

Carcinoma of the prostate and BPH cause many of the same symptoms. These two diseases frequently co-exist. Patients should be evaluated to rule out the presence of carcinoma of the prostate.

While syncope is the most severe orthostatic symptom of α₁-adrenoceptor antagonists, other symptoms can occur (dizziness and postural hypotension). In a phase III, randomized, double-blind, placebo-controlled trial involving male patients treated once daily with either 0.4 mg FLOMAX CR (n=350) or placebo (n=356), both supine and standing blood pressure were monitored over the course of the 12 week treatment period. There was a small, clinically insignificant decrease from baseline in mean supine and standing systolic/diastolic BP in both treatment groups; the decrease in BP from baseline in the FLOMAX CR group (<2 mmHg) was comparable to the placebo group (<1.5 mmHg). There were no cases of orthostatic hypotension or syncope reported in either treatment group.

Patients in occupations in which orthostatic hypotension could be dangerous should be treated with caution.

If hypotension occurs, the patient should be placed in the supine position and if this measure is inadequate, volume expansion with intravenous fluids or vasopressor therapy may be used. A transient hypotensive response is not a contraindication to further therapy with FLOMAX CR.

During cataract surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported during post-marketing surveillance in association with alpha-1 blocker therapy, including Flomax. Most reports to date were in patients taking Flomax when IFIS occurred, but in some cases, Flomax had been stopped prior to surgery. In most of these cases, the Flomax 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 Flomax for a longer period. This variant of small pupil syndrome 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. The benefit of stopping alpha-1 blocker therapy, including Flomax prior to cataract surgery has not been established.

There were no pharmacokinetic studies conducted in geriatric patients with FLOMAX CR. Cross-study comparisons of overall exposure (AUC) and half-life of FLOMAX capsules indicate that the pharmacokinetic disposition of tamsulosin may be slightly prolonged in geriatric males compared to young healthy male volunteers. However, FLOMAX capsules have been found to be a safe and effective alpha₁ adrenoreceptor antagonist when administered at therapeutic doses to patients over the age of 65 years.

FLOMAX CR is not indicated for use in children.

FLOMAX CR is not indicated for use in women. Safety, effectiveness, and pharmacokinetics have not been evaluated in women.

FLOMAX CR is not indicated for use in women. Studies in pregnant rats and rabbits at daily doses of 300 and 50 mg/kg, respectively (30,000 and 5000 times the anticipated human dose), revealed no evidence of harm to the fetus. There are no adequate data on the use of tamsulosin in pregnant women; therefore the potential risk from the use of tamsulosin during pregnancy in humans is unknown.

The treatment of patients with severe renal impairment (creatinine clearance of <10mL/min) should be approached with caution, as these patients have not been studied.

The treatment of patients with severe hepatic impairment should be approached with caution as no studies have been conducted in this patient population. No dose adjustment is warranted in hepatic insufficiency.

There were no drug interaction studies conducted specifically with FLOMAX CR tablets and it is expected that the interaction profile would not be any different than that of FLOMAX capsules. As with FLOMAX capsules, caution should be exercised with concomitant administration of FLOMAX CR and other alpha-adrenergic blocking agents.

No clinically significant drug-drug interactions were observed when FLOMAX capsules 0.4 mg or 0.8 mg were administered with one of the following therapeutic agents: nifedipine, atenolol, enalapril, digoxin, furosemide or theophylline.

No dosage adjustments are necessary when FLOMAX CR is administered concomitantly with Procardia XL (nifedipine), atenolol, or enalapril. In three studies in hypertensive subjects (age range 47-79 years) whose blood pressure was controlled with stable doses of Procardia XL (nifedipine), atenolol or enalapril for at least three months, FLOMAX 0.4 mg capsules for seven days followed by FLOMAX 0.8 mg capsules 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).

A definitive drug-drug interaction study between tamsulosin 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 CR.

No dosage adjustments are necessary when FLOMAX CR is administered concomitantly with digoxin or 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.

No dosage adjustments are necessary when FLOMAX CR is administered concomitantly with 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 a 11% to 12% reduction in tamsulosin C_max and AUC, these changes are expected to be clinically insignificant and do not require adjustment of the FLOMAX CR dosage.

The effects of cimetidine at the highest recommended dose (400 mg every six hours for six days) on the pharmacokinetics of a single FLOMAX 0.4 mg capsules dose was investigated in ten healthy volunteers (age range 21-38 years). Treatment with cimetidine resulted in a moderate increase in tamsulosin AUC (44%) due to a significant decrease (26%) in the clearance of tamsulosin. Therefore, FLOMAX CR should be used with caution in combination with cimetidine.