URIMAX Capsules (Tamsulosin hydrochloride)

Table of Content

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

Qualitative and Quantitative Composition

URIMAX 0.4

Each capsule contains:

Tamsulosin Hydrochloride .... 400 mcg

(as modified-release pellets)

URIMAX 0.2

Each capsule contains:

Tamsulosin Hydrochloride .... 200 mcg

(as modified-release pellets)

Dosage Form and Strength

0.2 mg & 0.4 mg Capsule

Clinical Particulars

Therapeutic Indications

Urimax 0.2 mg

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

URIMAX 0.4 mg

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

Posology and Method of Administration

0.4 mg once daily with or without food, at the same time every day. The capsule must be swallowed whole and must not be crunched or chewed, as this interferes with the modified release of the active ingredient.

If the patient is unable to tolerate 0.4 mg, then the patient should receive 0.2 mg once daily.

For patients who fail to respond to 0.4 mg after 2-4 weeks of dosing, the dose can be increased to 0.8 mg once daily.

If the drug administration is interrupted or discontinued for a few days due to any reason at either the 0.4 mg or 0.2 mg dose, therapy should be started again with the same dose.

If the patient is receiving 0.8 mg once daily and the drug administration is interrupted or discontinued for few days due to any reason, therapy should be started again at 0.4 mg once daily.

Special Populations

Renal and hepatic Impairment

Patients with renal impairment do not require any dosage adjustment in tamsulosin hydrochloride dosage. However, patients with end-stage renal disease (CLcr2) have not been studied.

Patients with moderate hepatic impairment do not require any dosage adjustment in tamsulosin hydrochloride dosage. Tamsulosin hydrochloride has not been studied in patients with severe hepatic impairment.

Geriatric Patients

No dose adjustment is necessary for the elderly.

Paediatric population

Tamsulosin is not indicated for use in pediatric populations.

Contraindications

Urimax capsules are contraindicated in patients known to be hypersensitive to tamsulosin hydrochloride or any component of Urimax capsules. Reactions have included skin rash, urticaria, pruritus, angioedema, and respiratory symptoms.

Special Warnings and Precautions for Use

Orthostasis

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. Patients beginning treatment with Urimax capsules should be cautioned to avoid situations in which injury could result should syncope occur. At the first signs of orthostatic hypotension, the patient should sit or lie down until the symptoms have disappeared.

Screening for Prostate Cancer

Before therapy with tamsulosin is initiated, the patient should be examined in order to exclude the presence of other conditions such as Prostate cancer, which can cause the same symptoms as benign prostatic hyperplasia. Digital rectal examination and, when necessary, determination of prostate specific antigen (PSA) should be performed before treatment and at regular intervals afterwards.

Priapism

Rarely (probably less than 1 in 50,000 patients), 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.

Intraoperative Floppy Iris Syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract and glaucoma surgery in some patients on or previously treated with alpha1 blockers, including tamsulosin.

Most reports were in patients taking the alpha1 blocker when IFIS occurred, but in some cases, the alpha1 blocker had been stopped prior to surgery. In most of these cases, the alpha1 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 alpha1 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.

IFIS may increase the risk of eye complications during and after the operation. The benefit of stopping alpha1 blocker therapy prior to cataract or glaucoma surgery has not been established. The initiation of therapy with tamsulosin in patients for whom cataract or glaucoma surgery is scheduled is not recommended.

Sulfa Allergy

In patients with sulfa allergy, allergic reaction to tamsulosin has been rarely reported. If a patient reports a serious or life-threatening sulfa allergy, caution is warranted when administering Urimax capsules.

Drug Interactions

Cytochrome P450 Inhibition

Strong and Moderate Inhibitors of CYP3A4 or CYP2D6

Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6.

Concomitant treatment with ketoconazole (a strong inhibitor of CYP3A4) resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. The effects of concomitant administration of a moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of tamsulosin have not been evaluated.

Concomitant treatment with paroxetine (a strong inhibitor of CYP2D6) resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively. A similar increase in exposure is expected in CYP2D6 poor metabolizers (PM) as compared to extensive metabolizers (EM). Since CYP2D6 PMs cannot be readily identified and the potential for significant increase in tamsulosin exposure exists when it is co-administered with strong CYP3A4 inhibitors in CYP2D6 PMs, Urimax capsules 0.4 mg should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole).

The effects of concomitant administration of a moderate CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of tamsulosin have not been evaluated.

The effects of co-administration of both a CYP3A4 and a CYP2D6 inhibitor with Urimax capsules have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when Urimax 0.4 mg is co-administered with a combination of both CYP3A4 and CYP2D6 inhibitors.

Cimetidine

Concomitant cimetidine brings about a rise in plasma levels of tamsulosin, but as levels remain within the normal range posology need not be adjusted.

Other Alpha Adrenergic Blocking Agents

The pharmacokinetic and pharmacodynamic interactions between tamsulosin and other alpha adrenergic blocking agents have not been determined; however, interactions between Urimax capsules and other alpha adrenergic blocking agents may be expected.

PDE5 Inhibitors

Caution is advised when alpha adrenergic blocking agents including Urimax are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension.

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. Caution should be exercised with concomitant administration of warfarin and Urimax capsules.

Nifedipine, Atenolol, Enalapril

Dosage adjustments are not necessary when Urimax capsule is administered concomitantly with nifedipine, atenolol, or enalapril.

Digoxin and Theophylline

Dosage adjustments are not necessary when Urimax capsule is administered concomitantly with digoxin or theophylline.

Furosemide

Urimax 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 Urimax capsules dosage.

Use in Special Population      

Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of Urimax in pregnant women.

In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Animal Data

No adverse developmental effects were observed in animal studies in which tamsulosin hydrochloride was administered to rats or rabbits during the period of organogenesis (GD 7 to 17 in the rat and GD 6 to 18 in the rabbit).

Administration of tamsulosin hydrochloride to pregnant female rats during the period of organogenesis at dose levels up to approximately 50 times the human therapeutic AUC exposure (300 mg/kg/day) revealed no evidence of harm to the fetus. Administration of tamsulosin hydrochloride to pregnant rabbits during the period of organogenesis at dose levels up to 50 mg/kg/day produced no evidence of fetal harm.

Lactation

Risk Summary

There are no data on the presence of tamsulosin hydrochloride in human milk, the effects of tamsulosin hydrochloride on the breastfed infant, or the effects of tamsulosin hydrochloride on milk production.

Animal Data

Oral administration of radiolabeled tamsulosin hydrochloride to rats demonstrated that tamsulosin hydrochloride and/or its metabolites are excreted into the milk of rats.

Pediatric Use

Urimax capsules are not indicated for use in pediatric populations.

Geriatric Use

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.

Renal Impairment

Patients with renal impairment do not require an adjustment in Urimax capsules dosing. However, patients with end-stage renal disease (CLcr <10 mL/min/1.73 m2) have not been studied.

Hepatic Impairment

Patients with moderate hepatic impairment do not require an adjustment in Urimax capsules dosage. Tamsulosin has not been studied in patients with severe hepatic impairment.

Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be aware of the fact that dizziness can occur.

Undesirable Effects

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

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 Tamsulosin were used. These studies evaluated safety in 1783 patients treated with Tamsulosin and 798 patients administered placebo. Table 1 summarizes the treatment-emergent adverse events that occurred in ≥2% of patients receiving either Tamsulosin 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.

Table 1: Treatment-Emergent1 Adverse Events occurring in ≥2% of Tamsulosin Hydrochloride or Placebo Patients in Two U.S. Short-Term Placebo-Controlled Clinical Studies

Body System/

Adverse Event

Tamsulosin Hydrochloride Groups

Placebo

0.4 mg

0.8 mg

n = 502

n = 492

n = 493

Body As Whole

Headache

 

97 (19.3)

 

104 (21.1%)

 

99 (20.1%)

Infection2

45 (9.0%)

53 (10.8%)

37 (7.5%)

Asthenia

39 (7.8%)

42 (8.5%)

27 (5.5%)

Back pain

35 (7.0%)

41 (8.3%)

27 (5.5%)

Chest pain

20 (4.0%)

20 (4.1%)

18 (3.7%)

Nervous System

 

 

 

Dizziness

75 (14.9%)

84 (17.1%)

50 (10.1%)

Somnolence

15 (3.0%)

21 (4.3%)

8 (1.6%)

Insomnia

12 (2.4%)

7 (1.4%)

3 (0.6%)

Libido decreased

5 (1.0%)

10 (2.0%)

6 (1.2%)

Respiratory System

 

 

 

Rhinitis3

66 (13.1%)

88 (17.9%)

41 (8.3%)

Pharyngitis

29 (5.8%)

25 (5.1%)

23 (4.7%)

Cough increased

17 (3.4%)

22 (4.5%)

12 (2.4%)

Sinusitis

11 (2.2%)

18 (3.7%)

8 (1.6%)

Digestive System

 

 

 

Diarrhea

31 (6.2%)

21 (4.3%)

22 (4.5%)

Nausea

13 (2.6%)

19 (3.9%)

16 (3.2%)

Tooth disorder

6 (1.2%)

10 (2.0%)

7 (1.4%)

Urogenital System

 

 

 

Abnormal ejaculation

42 (8.4%)

89 (18.1%)

1 (0.2%)

Special Senses

 

 

 

Blurred vision

1 (0.2%)

10 (2.0%)

2 (0.4%)

1 A treatment-emergent adverse event was defined as any event satisfying one of the following criteria:

  • The adverse event occurred for the first time after initial dosing with the double-blind study medication.
  • The adverse event was present prior to or at the time of initial dosing with the double-blind study medication and subsequently increased in severity during double-blind treatment; or,
  • The adverse event was present prior to or at the time of initial dosing with the double-blind study medication, disappeared completely, and then reappeared during double-blind treatment.

2 Coding preferred terms also include cold, common cold, head cold, flu and flu-like symptoms.

3 Coding preferred terms also include nasal congestion, stuffy nose, runny nose, sinus congestion and hay fever.

The most common adverse events (≥2% of patients and at a higher incidence than placebo) with the 0.4 mg dose or 0.8 mg dose were headache, dizziness, rhinitis, infection, abnormal ejaculation, asthenia, back pain, diarrhea, pharyngitis, chest pain, cough increased, somnolence, nausea, sinusitis, insomnia, libido decreased, tooth disorder, and blurred vision.

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 ≥10 mmHg upon standing, with the standing diastolic blood pressure <65 mmHg during the orthostatic test; (3) an increase in pulse rate of ≥20 bpm upon standing with a standing pulse rate ≥100 bpm 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 Tamsulosin 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 Tamsulosin 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 Tamsulosin 0.4 mg once-daily group, 92 of the 491 patients (19%) in the Tamsulosin 0.8 mg once-daily group, and 54 of the 493 patients (11%) in the placebo group.

Because orthostasis was detected more frequently in Tamsulosin treated patients than in placebo recipients, there is a potential risk of syncope.

Abnormal Ejaculation

Abnormal ejaculation includes ejaculation failure, ejaculation disorder, retrograde ejaculation, and ejaculation decrease. As shown in Table 1, abnormal ejaculation was associated with Tamsulosin administration and was dose-related in the U.S. studies. Withdrawal from these clinical studies of Tamsulosin 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.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of tamsulosin hydrochloride capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in the labelling are typically based on one or more of the following factors:

(1) Seriousness of the reaction; (2) frequency of reporting; or (3) strength of causal connection to tamsulosin hydrochloride.

Allergic-type reactions such as skin rash, urticaria, pruritus, angioedema, and respiratory symptoms have been reported, with a positive re-challenge in some cases. Priapism has been reported rarely. Infrequent reports of dyspnoea, palpitations, hypotension, atrial fibrillation, arrhythmia, tachycardia, skin desquamation, including reports of Stevens-Johnson syndrome, erythema multiforme, dermatitis, exfoliative, constipation, vomiting, dry mouth, visual impairment, and epistaxis have been received during the postmarketing period.

During cataract surgery, a variant of small-pupil syndrome known as Intraoperative floppy iris syndrome (IFIS) has been reported in association with alpha1-blocker therapy.

Reporting of suspected adverse reactions

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla ltd. on 18002677779. By reporting side effects, you can help provide more information on the safety of this product.

Overdosage

Overdosage with tamsulosin hydrochloride can potentially result in severe hypotensive effects. Severe hypotensive effects have been observed at different levels of overdosing.

In case of acute hypotension occurring after overdosage cardiovascular support should be given. Blood pressure can be restored and heart rate brought back to normal by lying the patient down. If this does not help then volume expanders and, when necessary, vasopressors could be employed. Renal function should be monitored and general supportive measures applied. Dialysis is unlikely to be of help as tamsulosin is very highly bound to plasma proteins.

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 sulphate, can be administered.

Pharmacological Properties

Mechanism of Action

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: alpha1A, alpha1B, and alpha1D; their distribution differs between human organs and tissue. Approximately 70% of the alpha1 receptors in the human prostate are of the alpha1A subtype.

Pharmacodynamic Properties

Tamsulosin increases the maximum urinary flow rate. It relieves obstruction by relaxing smooth muscle in prostate and urethra thereby improving voiding symptoms.

It also improves the storage symptoms in which bladder instability plays an important role. These effects on storage and voiding symptoms are maintained during long - term therapy. The need for surgery or catheterization is significantly delayed.

α-1 adrenoceptors antagonists can reduce blood pressure by lowering peripheral resistance. No reduction in blood pressure of any clinical significance was observed during studies with tamsulosin.

Pharmacokinetic Properties

Absorption

Absorption of tamsulosin hydrochloride 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 (Tmax) is reached by 4 to 5 hours under fasting conditions and by 6 to 7 hours when tamsulosin is administered with food. Taking tamsulosin under fasted conditions results in a 30% increase in bioavailability (AUC) and 40% to 70% increase in peak concentrations (Cmax) compared to fed conditions.

Distribution

The mean steady-state apparent volume of distribution of tamsulosin hydrochloride after intravenous administration to 10 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 alpha1 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.

Biotransformation

There is no enantiomeric bioconversion from tamsulosin hydrochloride 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. Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6 as well as via 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.

Excretion

On administration of the radiolabeled dose of tamsulosin hydrochloride 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.

Following intravenous or oral administration of an immediate-release formulation, the elimination half-life of tamsulosin hydrochloride in plasma ranged from 5 to 7 hours. Because of absorption rate-controlled pharmacokinetics with Tamsulosin, 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).

Pharmacokinetics in Special Populations

Geriatric Patients

Cross-study comparison of tamsulosin 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.

Paediatric

Urimax capsules are not indicated for use in pediatric populations.

Renal Impairment

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 Urimax capsules dosing. However, patients with end-stage renal disease (CLcr <10 mL/min/1.73 m2) have not been studied.

Hepatic Impairment

The pharmacokinetics of tamsulosin hydrochloride have been compared in 8 subjects with moderate hepatic impairment (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 impairment do not require an adjustment in Urimax capsules dosage. Tamsulosin has not been studied in patients with severe hepatic impairment.

Nonclinical Properties

Carcinogenicity

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 elevate prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known.

Mutagenesis

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.

Impairment of Fertility

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.

Description

Tamsulosin hydrochloride is an antagonist of alpha1A adrenoceptors in the prostate.

Tamsulosin hydrochloride is (-)-(R)-5-amino]propyl]-2methoxybenzenesulfonamide, monohydrochloride. Tamsulosin hydrochloride is a white crystalline powder that melts with decomposition at approximately 230°C. It is sparingly soluble in water and methanol, slightly soluble in glacial acetic acid and ethanol, and practically insoluble in ether.

The empirical formula of tamsulosin hydrochloride is C20H28N2O5S • HCl. The molecular weight of tamsulosin hydrochloride is 444.98. Its structural formula is:
 

 

Each Urimax capsule for oral administration contains tamsulosin hydrochloride, USP 0.4 mg, and the following inactive ingredients: microcrystalline cellulose; methacrylic acid copolymer dispersion; triacetin; calcium stearate; talc; gelatin; iron oxide; FD&C blue No. 2; titanium dioxide; propylene glycol; and shellac.

Pharmaceutical Particulars

Incompatibilities

NA

Shelf-Life

NA

Packaging Information

Urimax 0.4: Blister pack of 15 capsules

Urimax 0.2: Blister pack of 15 capsules

Storage and Handling Instructions 

NA

Details of Manufacturer

Mfg By Cipla Ltd

Registered Office: Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg Lower Parel, Mumbai – 400 013, India

Details of Permission or Licence Number with Date

NA

Date of Revision

30/06/2021