Tamsumax

Each Tamsulosin HCl (Tamsumax) sustained release capsule for oral administration contains tamsulosin hydrochloride 200 mcg or 400 mcg.
Tamsulosin HCl 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 or almost white crystalline powder that melts with decomposition at approximately 230°C. It is slightly soluble in water, freely soluble in formic acid, slightly soluble in anhydrous ethanol, sparingly soluble in methanol, slightly soluble in glacial acetic acid, and practically insoluble in ether.
The molecular formula of Tamsulosin hydrochloride is C₂₀H₂₈N₂O₅S·HCl. The molecular weight of Tamsulosin hydrochloride is 444.98.

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 alpha-1 adrenoceptor blocking agent, exhibits selectivity for alpha-1 receptors in the human prostate. At least three discrete alpha-1 adrenoceptor subtypes have been identified: alpha-1A, alpha-1B and alpha-1D; their distribution differs between human organs and tissue. Approximately 70% of the alpha-1 receptors in human prostate are of the alpha-1A subtype.
Tamsulosin HCl (Tamsumax) 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 Tamsulosin HCl (Tamsumax) 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 (T_max) is reached by four to five hours under fasting conditions and by six to seven hours when Tamsulosin HCl (Tamsumax) capsules are administered with food. Taking Tamsulosin HCl (Tamsumax) capsules under fasted conditions results in a 30% increase in bioavailability (AUC) and 40% to 70% increase in peak concentrations (C_max) compared to fed conditions.
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. 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 (5-alpha-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 TAMSUMAX (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 Tamsulosin HCl (Tamsumax) 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/1.73 m²) or moderate-severe (10≤CLcr <30 mL/min/1.73 m²) renal impairment and 6 normal subjects (CLcr <90 mL/min/1.73 m²). 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 Tamsulosin HCl (Tamsumax) capsules dosing. However, patients with endstage renal disease (CLcr <10 mL/min/1.73 m²) 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 TAMSUMAX capsules dosage. Tamsulosin HCl (Tamsumax) has not been studied in patients with severe hepatic dysfunction.

Tamsulosin HCl (Tamsumax) capsules are indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). TAMSUMAX capsules are not indicated for the treatment of hypertension.

Tamsulosin HCl (Tamsumax) 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 Tamsulosin HCl (Tamsumax) capsules can be increased to 0.8 mg once daily. The 0.8 mg dose should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole).
If Tamsulosin HCl (Tamsumax) 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.

Should overdosage of Tamsulosin HCl (Tamsumax) capsules lead to hypotension, 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 intravenous 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 hydrochloride is 94% to 99% protein bound; therefore, dialysis is unlikely to be of benefit.
One patient reported an overdose of thirty 0.4 mg Tamsulosin HCl (Tamsumax) capsules. Following the ingestion of the capsules, the patient reported a severe headache.

Tamsulosin HCl (Tamsumax) capsules are contraindicated in patients known to be hypersensitive to tamsulosin hydrochloride or any component of Tamsulosin HCl (Tamsumax) capsules.

The signs and symptoms of orthostasis (postural hypotension, dizziness and vertigo) were detected more frequently in Tamsulosin HCl (Tamsumax) capsule-treated patients than in placebo recipients. As with other alpha-adrenergic blocking agents there is a potential risk of syncope.
Patients beginning treatment with Tamsulosin HCl (Tamsumax) capsules should be cautioned to avoid situations where injury could result should syncope occur.
Doses of Tamsulosin HCl (Tamsumax) higher than 0.4 mg (e.g., 0.8 mg) should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole).
Rarely (probably less than 1 in 50,000 patients), tamsulosin, like other alpha-1 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.

General: Carcinoma of the Prostate: Carcinoma of the prostate and BPH cause many of the same symptoms. These two diseases frequently co-exist. Patients should be evaluated prior to the start of Tamsulosin HCl (Tamsumax) capsules therapy to rule out the presence of carcinoma of the prostate.
Intraoperative Floppy Iris Syndrome: Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-1 blockers, including Tamsulosin HCl (Tamsumax) capsules. Most reports were in patients taking the alpha-1 blocker when IFIS occurred, but in some cases, the alpha-1 blocker had been stopped prior to surgery. In most of these cases, the alpha-1-blocker 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 the alpha-1 blocker for a longer period (5 weeks to 9 months). IFIS is a variant of small pupil syndrome and 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 prior to cataract surgery has not been established.
Sulfa Allergy: In patients with sulfa allergy, allergic reaction to Tamsulosin HCl (Tamsumax) capsules has been rarely reported. If a patient reports a serious or life-threatening sulfa allergy, caution is warranted when administering Tamsulosin HCl (Tamsumax) capsules.
Drug-Drug Interactions: The pharmacokinetic and pharmacodynamic interactions between Tamsulosin HCl (Tamsumax) capsules and other alpha-adrenergic blocking agents have not been determined. However, interactions may be expected and Tamsulosin HCl (Tamsumax) capsules should NOT be used in combination with other alpha-adrenergic blocking agents.
The pharmacokinetic interaction between cimetidine, a mild inhibitor of several CYP enzymes, and Tamsulosin HCl (Tamsumax) capsules was investigated in 10 subjects. The results indicate significant changes in both tamsulosin hydrochloride clearance (26% decrease) and exposure (44% increase in AUC). Therefore, Tamsulosin HCl (Tamsumax) capsules should be used with caution in combination with cimetidine, particularly at doses higher than 0.4 mg.
Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6. When co-administered with 0.4 mg Tamsulosin HCl (Tamsumax) capsules, ketoconazole (a strong CYP3A4 inhibitor) caused an increase in the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. Tamsulosin HCl (Tamsumax) capsules 0.4 mg should therefore be used with caution in combination with strong inhibitors of CYP3A4. Daily doses of Tamsulosin HCl (Tamsumax) higher than 0.4 mg (e.g., 0.8 mg) should not be used in combination with strong inhibitors of CYP3A4.When co-administered with 0.4 mg Tamsulosin HCl (Tamsumax) capsules, paroxetine (a strong CYP2D6 inhibitor) caused an increase in the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively. Tamsulosin HCl (Tamsumax) capsules should therefore be used with caution in combination with strong inhibitors of CYP2D6, particularly at doses higher than 0.4 mg (e.g., 0.8 mg).
Results from limited in vitro and in vivo drug-drug interaction studies between tamsulosin hydrochloride and warfarin are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and Tamsulosin HCl (Tamsumax) capsules.
Patients should be told about the possible occurrence of symptoms related to postural hypotension, such as dizziness, when taking Tamsulosin HCl (Tamsumax) capsules, and they should be cautioned about driving, operating machinery or performing hazardous tasks. Patients should be advised not to crush, chew or open the Tamsulosin HCl (Tamsumax) capsules.
Patients should be advised about the possibility of priapism as a result of treatment with Tamsulosin HCl (Tamsumax) 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).
Patients should be advised that if they are considering cataract surgery, to tell their ophthalmologist that they have taken Tamsulosin HCl (Tamsumax) capsules.
Laboratory Tests: No laboratory test interactions with Tamsulosin HCl (Tamsumax) capsules are known. Treatment with Tamsulosin HCl (Tamsumax) capsules for up to 12 months had no significant effect on prostate-specific antigen (PSA).
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 <0.015). The highest doses of tamsulosin hydrochloride 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 hydrochloride 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 hydrochloride-induced hyperprolactinemia. It is not known if Tamsulosin HCl (Tamsumax) capsules elevate prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known.
Tamsulosin hydrochloride 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 chromatid 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 hydrochloride (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 hydrochloride (1/5 and 16 times the anticipated human AUC exposure) did not significantly alter fertility in male rats. Effects of tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated.
Studies in female 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 hydrochloride, 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.
Use in Pregancy: Teratogenic Effects, Pregnancy Category B. Administration of tamsulosin hydrochloride 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 hydrochloride to pregnant rabbits at dose levels up to 50 mg/kg/day produced no evidence of fetal harm. Tamsulosin HCl (Tamsumax) capsules are not indicated for use in women.
Use in Lactation: Tamsulosin HCl (Tamsumax) capsules are not indicated for use in women.
Use in Children: Tamsulosin HCl (Tamsumax) capsules are not indicated for use in pediatric populations.
Use in the Elderly: Of the total number of subjects (1783) in clinical studies of tamsulosin, 36% were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and the other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Nifedipine, Atenolol, Enalapril: In three studies in hypertensive subjects (age range 47-79 years) whose blood pressure was controlled with stable doses of Nifedipine, atenolol, or enalapril for at least three months, Tamsulosin HCl (Tamsumax) capsules 0.4 mg for seven days followed by Tamsulosin HCl (Tamsumax) 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 Tamsulosin HCl (Tamsumax) capsules are administered concomitantly with Nifedipine, 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 Tamsulosin HCl (Tamsumax) capsules.
Digoxin and Theophylline: In two studies in healthy volunteers (n=10 per study; age range 19-39 years) receiving Tamsulosin HCl (Tamsumax) capsules 0.4 mg/day for two days, followed by Tamsulosin HCl (Tamsumax) 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 Tamsulosin HCl (Tamsumax) capsule is administered concomitantly with digoxin or theophylline.
Furosemide: The pharmacokinetic and pharmacodynamic interaction between Tamsulosin HCl (Tamsumax) 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). Tamsulosin HCl (Tamsumax) 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 Tamsulosin HCl (Tamsumax) 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 Tamsulosin HCl (Tamsumax) 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, Tamsulosin HCl (Tamsumax) 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 Tamsulosin HCl (Tamsumax) 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, Tamsulosin HCl (Tamsumax) 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 Tamsulosin HCl (Tamsumax) 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, Tamsulosin HCl (Tamsumax) 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).

Store at temperatures not exceeding 25°C.

Drugs for Bladder & Prostate Disorders

G04CA02 - tamsulosin ; Belongs to the class of alpha-adrenoreceptor antagonists. Used in the treatment of benign prostatic hypertrophy.

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