Flomax®

Tamsulosin HCl

Selective Antagonist of Alpha1A-adrenoceptor Subtype in the Prostate

Boehringer Ingelheim

http://www.boehringer-ingelheim.com/corporate/home/home.asp

Flomax Monograph PDF download here.

 

CPS:PIS_m217100

 

 

 

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: alpha_1A, alpha_1B and alpha_1D; their distribution differs between human organs and tissue. Approximately 70% of the alpha₁-receptor in human prostate are of the alpha_1A 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.

 

Pharmacokokinetics

     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 0.4 mg sustained-release formulation is essentially complete (>90%) following oral administration under fasted conditions. Time to maximum concentration (T_max) 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 T_max 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 (C_max) 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 (see  Table 1).

CPS:Flomax_t1Click here for Table 1

Table 1: Flomax

Mean Pharmacokinetic Parameters Following Daily Dosing with Flomax 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 Once Daily to Healthy Volunteers (Age Range 18-32 Years)		0.8 mg Once Daily to Healthy Volunteers (Age Range 55-75 Years)
	Light Breakfast	Fasted	Light Breakfast	High-fat Breakfast	Fasted
AUC (ng·h/mL)	151	199	440	449	557
Tmax (h)a	6.0	4.0	7.0	6.5	5.0
Cmax (ng/mL)	10.1	17.1	29.8	29.1	41.6
Cmin (ng/mL)	3.8	4.0	12.3	13.5	13.3
Cmax/Cmin Ratio	3.1	5.3	2.7	2.5	3.6

 

 ^a Median.

 

 

Legend: AUC: Area under the tamsulosin plasma time curve over the dosing interval.

T_max: Median time-to-maximum concentration.

C_max: Observed maximum tamsulosin plasma concentration.

C_min: Observed minimum concentration. Coefficients of variation (%CV) for C_max and AUC generally ranged from 35 to 53%, collectively.

 

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 C_max 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

For the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).

 

Contraindications

In patients known to be hypersensitive to tamsulosin or any component of the sustained-release formulation.

 

Warnings

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).

     Very rarely tamsulosin, like other alpha₁ antagonists, has been associated with priapism (persistent painful penile erection unrelated to sexual activity). Because this condition can lead to permanent impotence if not properly treated, patients must be advised about the seriousness of the condition (see Precautions, Information to Be Provided to the Patient).

 

Precautions

 

General

Tamsulosin is not indicated for the treatment of hypertension.

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 US double-blind, placebo-controlled studies (studies 1 and 2), orthostatic testing was conducted at each visit. Postural hypotension was reported in 3 patients (0.6%) receiving tamsulosin.

     In 2102 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.

Renally Impaired Patients: The treatment of severely renally impaired patients (creatinine clearance of <10 mL/min) should be approached with caution, as these patients have not been studied.

Hepatic Impairment: The treatment of patients with severe hepatic impairment should be approached with caution as no studies have been conducted in this patient population.

 

Drug Interactions

The pharmacokinetic and pharmacodynamic interactions between tamsulosin and other alpha-adrenergic blocking agents have not been determined. However, interactions may be expected and caution should be exercised with concomittant administration of tamsulosin capsules and alpha-adrenergic blocking agents.

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

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 5 mg/kg resulted in no change in the pharmacokinetics of digoxin or theophylline.

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 C_max and AUC, these changes are expected to be clinically insignificant and do not require adjustment of the tamsulosin dosage.

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 moderate increase in tamsulosin AUC (44%) due to a significant decrease (26%) in the clearance of tamsulosin. Therefore, tamsulosin capsules should be used with caution in combination with cimetidine, particularly at doses higher than 0.4 mg.

Information to be Provided to the Patient (see Information for the Patient): 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.

     Patients should be advised about the possibility of priapism as a result of treatment with tamsulosin capsules and other similar medications. Patients should be informed that this reaction is extremely rare, but if not brought to immediate medical attention, can lead to permanent erectile dysfunction (impotence).

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 5000 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 Effects

The incidence of treatment emergent adverse events has been ascertained from 6 short-term US 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 1783 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.  Table 2 summarizes the treatment emergent adverse events occurring in ≥ 1% of patients receiving either tamsulosin or placebo during these 6 short-term (US and European) placebo-controlled trials.

     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.

CPS:Flomax_t2Click here for Table 2

Table 2: Flomax

Treatment Emergent Adverse Events Occurring in ≥ 1% of Tamsulosin or Placebo Patients During Short-term (US and European) Placebo-controlled Trials^a

 

Body System/Adverse Event	Tamsulosin (N=1783) (%)	Placebo (N=798) (%)
Body as a Whole
Headache	14.7	15.5
Infection	7.9	6.8
Pain	7.6	7.3
Asthenia	6.1	5.0
Back Pain	6.2	4.5
Abdominal Pain	3.4	4.3
Chest Pain	3.3	3.1
Accidental Injury	2.1	3.0
Flu Syndrome	2.1	2.9
Neck Pain	1.0	1.1
Fever	1.0	1.0
Chills	0.7	1.0
Malaise	0.4	1.1
Cardiovascular
Hypertension	0.9	1.1
Digestive
Diarrhea	4.4	4.4
Dyspepsia	3.8	5.4
Nausea	2.6	2.9
Constipation	1.3	1.4
Tooth Disorder	1.1	0.9
Metabolic and Nutritional Disorders
Peripheral Edema	0.8	1.0
Musculoskeletal
Arthralgia	3.0	3.3
Myalgia	1.7	2.1
Arthritis	1.1	1.0
Nervous
Dizziness	11.8	8.9
Somnolence	2.5	1.5
Insomnia	1.7	0.6
Hypertonia	1.1	1.5
Libido Decreased	1.2	0.9
Paresthesia	0.4	1.1
Respiratory
Rhinitis	11.6	6.9
Pharyngitis	4.3	3.9
Cough Increased	3.1	2.4
Sinusitis	2.1	1.3
Dyspnea	1.1	1.1
Lung Disorder	1.1	0.9
Skin and Appendages
Rash	1.8	1.8
Pruritus	1.0	1.0
Sweating	1.1	0.8
Urogenital
Abnormal Ejaculation	8.7	0.5
Urinary Tract Infection	1.5	0.4
Dysuria	1.2	1.3
Impotence	1.2	1.5

 

 ^a Adverse events from patients given 0.1 to 0.8 mg tamsulosin daily were pooled.

 

 

     Adverse reactions occurring in <1% of the tamsulosin and placebo patient population include amblyopia, with a frequency of 0.6% and 0.2%, respectively.

     Tamsulosin has not been associated with any clinically significant changes in the urinalysis or the routine biochemical and hematologic tests.

      Table 3 shows the treatment emergent adverse events from which ≥ 0.5% of the patients administered tamsulosin (N=1783) placebo (N=798) discontinued US and European short-term, placebo-controlled clinical studies. The most frequent adverse events resulting in discontinuation of tamsulosin treatment were dizziness, asthenia, abnormal ejaculation, and chest pain.

CPS:Flomax_t3Click here for Table 3

Table 3: Flomax

Description of Discontinuations Occurring in ≥ 0.5% of Tamsulosin or Placebo Patients in US and European Short-term Placebo-controlled Clinical Studies^a

 

Body System/Adverse Event	Tamsulosin (N=1783) (%)	Placebo (N=798) (%)
Body as a Whole
Asthenia	0.7	0.6
Headache	0.4	0.6
Chest Pain	0.5	0.3
Nervous System
Dizziness	1.4	0.9
Urogenital
Abnormal Ejaculationb	0.6	0

 

 ^a Adverse events from patients given 0.1 to 0.8 mg tamsulosin daily were pooled.

 ^b Abnormal ejaculation includes ejaculation failure, ejaculation disorder, retrograde ejaculation and ejaculation decrease. Abnormal ejaculation was dose related in US studies: 8.4% in 0.4 mg group, 18.1% in 0.8 mg group. Withdrawal from these clinical studies of Flomax because of abnormal ejaculation was also dose dependent: 1.6% in the 0.8 mg group, and no patients in the 0.4 mg or placebo groups.

 

 

Postmarketing Experience: The following adverse reactions have been reported during the use of tamsulosin: dizziness, abnormal ejaculation and, less frequently, headache, asthenia, postural hypotension, palpitations and rhinitis.

     Gastrointestinal reactions such as nausea, vomiting, diarrhea and constipation can occasionally occur.

     Hypersensitivity reactions such as rash, pruritus, and urticaria can occur occasionally; angioedema has been rarely reported.

     Syncope has been reported rarely. Priapism has been reported very rarely.

 

Overdose

 

 

 

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.

     Measures, such as emesis, can be taken to impede absorption. When large quantities are involved, gastric lavage can be applied and activated charcoal and an osmotic laxative, such as sodium sulfate, can be administered.

     One patient reported an overdose of thirty 0.4 mg capsules of tamsulosin. 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

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.

 

Supplied

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; imprinting ink: black iron oxide, dimethylpolysiloxane, industrial methylated spirit, isopropyl alcohol, n-butyl alcohol, propylene glycol, shellac. HDPE bottles of 100. Store at room temperature (15 to 30°C).