Flomax (Tamsulosin HCl)


Boehringer Ingelheim

Tamsulosin HCl

Selective Antagonist of Alpha1A-adrenoceptor Subtype in the Prostate

Action And Clinical Pharmacology: Tamsulosin, an alpha1-adrenoceptor blocking agent, exhibits selectivity for alpha1 receptors in the human prostate. At least 3 discrete alpha1-adrenoreceptor subtypes have been identified: alpha1A, alpha1B and alpha1D; their distribution differs between human organs and tissue. Approximately 70% of the alpha1-receptor in human prostate is of the alpha1A subtype.

The symptoms associated with benign prostatic hyperplasia (BPH) are related to bladder outlet obstruction, which is 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. 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 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.

Tamsulosin is not intended for use as an antihypertensive drug.

The pharmacokinetics of tamsulosin have been evaluated in adult healthy volunteers and patients with BPH with doses ranging from 0.1 to 1 mg.

Absorption: Absorption of tamsulosin from the Flomax sustained-release formulation is essentially complete (>90%) following oral administration under fasted conditions. Time to maximum concentration (Tmax) is reached by 4 to 5 hours under fasted conditions and by 6 to 7 hours when tamsulosin is administered with food. The delay in Tmax when tamsulosin is administered with food has the desirable effect of smoothing the tamsulosin plasma concentration profile, thereby reducing fluctuation of the plasma peak and trough concentrations with multiple dosing. Taking tamsulosin under fasted conditions results in a 30% increase in bioavailability (AUC) and 40 to 70% increase in peak concentration (Cmax) compared to fed conditions. The effects of food on the pharmacokinetics of tamsulosin are consistent regardless of whether tamsulosin is taken with a light breakfast or a high-fat breakfast.

Distribution: The mean steady-state apparent volume of distribution of tamsulosin after i.v. administration to 10 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, gallbladder, 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 2-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.

Metabolism/Excretion: 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 radiolabeled dose of tamsulosin 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. Less than 10% of the dose was recovered as unchanged (parent) compound in the urine.

Metabolites of tamsulosin do not contribute significantly to tamsulosin adrenoceptor 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 resulting in a proportional increase in Cmax and AUC at therapeutic 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 i.v. or oral administration of an immediate-release formulation, the elimination half-life of tamsulosin in plasma ranged from 5 to 7 hours. Because of absorption rate-controlled pharmacokinetics with the tamsulosin sustained-release formulation, the apparent half-life of tamsulosin increases to approximately 9 to 13 hours in healthy volunteers and to 14 to 15 hours in the target population.

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.

Indications And Clinical Uses: For the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). Tamsulosin is not indicated for the treatment of hypertension.

Contra-Indications: Patients known to be hypersensitive to tamsulosin or any component of the sustained-release formulation.

Manufacturers’ Warnings In Clinical States: The signs and symptoms of orthostasis (postural hypotension, dizziness and vertigo) were detected more frequently in tamsulosin-treated patients than in placebo recipients. As with other alpha-adrenergic blocking agents, there is a potential risk of syncope (see Adverse Effects).

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

Precautions: 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 tamsulosin therapy to rule out the presence of carcinoma of the prostate.

Orthostatic Hypotension: While syncope is the most severe orthostatic symptom of tamsulosin, other symptoms can occur (dizziness and postural hypotension). In the two U.S. double-blind, placebo-controlled studies (studies 1 and 2), orthostatic testing was conducted at each visit. Postural hypotension was reported in three patients (0.6%) receiving tamsulosin.

In 2 102 patients included in U.S., European, and Japanese placebo-controlled clinical studies, 0.3% of patients receiving tamsulosin experienced postural hypotension, 10.2% experienced dizziness, and 0.7% experienced vertigo; patients receiving placebo experienced postural hypotension, dizziness, and vertigo at rates of 0.1%, 7.2%, and 0.4%, respectively.

Occupational Hazards: Patients in occupations in which orthostatic hypotension could be dangerous should be treated with particular caution.

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

Special Populations: Geriatrics: Cross-study comparisons of tamsulosin overall exposure (AUC) and half-life indicate that the pharmacokinetic disposition of tamsulosin may be slightly prolonged in geriatric males compared to young healthy male volunteers. However, tamsulosin has been found to be a safe and effective alpha1-adrenoceptor antagonist when administered at therapeutic doses (0.4 and 0.8 mg once daily) to patients over the age of 65 years.

Children: Tamsulosin is not indicated for use in children.

Gender Effects: Tamsulosin is not indicated for use in women. Safety, effectiveness, and pharmacokinetics have not been evaluated in women.

Drug Interactions: No clinically significant drug-drug interactions were observed in the 8 controlled clinical studies conducted to determine if a clinically significant interaction would occur when tamsulosin 0.4 or 0.8 mg was administered with one of the following therapeutic agents: nifedipine, atenolol, enalapril, warfarin, digoxin, furosemide, cimetidine, or theophylline.

Nifedipine, Atenolol, Enalapril: No dosage adjustments are necessary when tamsulosin is administered concomitantly with Procardia XL (nifedipine), atenolol, or enalapril. In 3 studies in hypertensive subjects (age range 47 to 79 years) whose blood pressure was controlled with stable doses of Procardia XL (nifedipine), atenolol or enalapril for at least 3 months, tamsulosin 0.4 mg for 7 days followed by tamsulosin 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).

Warfarin: No dosage adjustments are recommended when tamsulosin is administered concomitantly with warfarin. In healthy volunteers (age range 20 to 43 years) receiving warfarin, treatment with tamsulosin (0.4 or 0.8 mg) had no significant effect on the anticoagulant activity of warfarin compared to placebo. While definitive conclusions cannot be drawn as only 6 subjects completed the study (3 subjects on tamsulosin and three subjects on placebo), the results suggest that coadministration of tamsulosin with warfarin does not alter the pharmacodynamic activity of warfarin.

Digoxin and Theophylline: No dosage adjustments are necessary when tamsulosin is administered concomitantly with digoxin or theophylline. In 2 studies in healthy volunteers (n=10 per study; age range 19 to 39 years), receiving tamsulosin 0.4 mg/day for 2 days, followed by tamsulosin 0.8 mg/day for 5 to 8 days, single i.v. doses of digoxin 0.5 mg or theophylline 5mg/kg resulted in no change in the pharmacokinetics of digoxin or theophylline. Furthermore, the safety profiles for the 2 drugs in combination with tamsulosin were acceptable.

Furosemide: No dosage adjustments are necessary when tamsulosin is administered concomitantly with furosemide. The pharmacokinetic and pharmacodynamic interaction between tamsulosin 0.8 mg/day (steady-state) and furosemide 20 mg i.v. (single dose) was evaluated in 10 healthy volunteers (age range 21 to 40 years). Tamsulosin had no effect on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an 11 to 12% reduction in tamsulosin Cmax and AUC, these changes are expected to be clinically insignificant and do not require adjustment of the tamsulosin dosage.

Cimetidine: No dosage adjustments are necessary when tamsulosin is administered concomitantly with 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 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 which resulted in a moderate increase in tamsulosin AUC (44%). However, the effects by cimetidine are of questionable clinical significance and no adjustment in the tamsulosin dosage is recommended.

Information to be Provided to the Patient (see Patient Package Insert): Patients should be told that dizziness can occur with tamsulosin, requiring caution in people who must drive, operate machinery, or perform hazardous tasks. Patients should be advised not to crush, chew, or open the capsules of tamsulosin sustained-release formulation. These capsules are specially formulated to control the delivery of tamsulosin HCl to the blood stream.

Laboratory Tests: No laboratory test interactions with tamsulosin are known. Treatment with tamsulosin for up to 12 months had no significant effect on prostate specific antigen (PSA).

Pregnancy: Studies in pregnant rats and rabbits at daily doses of 300 and 50 mg/kg, respectively (30 000 and 5 000 times the anticipated human dose), revealed no evidence of harm to the fetus. Tamsulosin is neither indicated nor recommended for use in women.

Lactation: Tamsulosin is not indicated for use in women.

Children: Tamsulosin is not indicated for use in children.

Adverse Reactions: The incidence of treatment emergent adverse events has been ascertained from 6 short-term U.S. and European placebo-controlled clinical trials in which daily doses of 0.1 to 0.8 mg tamsulosin were used. These studies evaluated safety in 1 783 patients treated with tamsulosin and 798 patients administered placebo. The data suggest that tamsulosin is generally well tolerated at daily dose levels ranging from 0.1 to 0.8 mg. Adverse events seen were generally mild, transient, and self-limiting.

No new types of adverse events were apparent after long-term treatment with tamsulosin. Those adverse events reported with the higher incidence by patients receiving tamsulosin compared to those receiving placebo in the short-term studies were reported with a similar pattern in the long-term studies.

Overdose: Symptoms and Treatment: Should overdosage of tamsulosin lead to hypotension (see Precautions), 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 i.v. 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 is 94 to 99% protein bound; therefore, dialysis is unlikely to be of benefit.

One patient reported an overdose of 30 capsules of tamsulosin 0.4 mg. Following the ingestion of the capsules, the patient reported a headache judged to be severe and probably drug-related that resolved the same day. Dosage

Dosage And Administration: 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.

Depending on individual patient symptomatology and/or flow rates, the dose may be adjusted to 0.8 mg once daily. If tamsulosin administration is discontinued or interrupted for several days at either the 0.4 or 0.8 mg dose, therapy should be reinstituted, beginning with the 0.4 mg once daily dose.

Availability And Storage: Each sustained-release capsule contains: tamsulosin HCl 0.4 mg. Nonmedicinal ingredients: calcium stearate, Eudragit L30D-55 (methacrylic acid copolymer, polysorbate 80, and sodium lauryl sulfate), FD&C Blue No. 2, ferric oxide (red and yellow), gelatin, microcrystalline cellulose, talc, titanium dioxide and triacetin; printing ink: black iron oxide, dimethylpolysiloxane, 2-ethoxyethanol, industrial methylated spirit, purified water, shellac and soya lecithin. HDPE bottles of 100. Store at room temperature (15 to 30°C).

FLOMAX® Boehringer Ingelheim Tamsulosin HCl Selective Antagonist of Alpha1A-adrenoceptor Subtype in the Prostate

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