Harnal D

Tamsulosin HCl.

Active Ingredient (in each tablet): Tamsulosin Hydrochloride 0.2mg.
Physicochemical Properties: Tamsulosin hydrochloride occurs as white crystals. It is freely soluble in formic acid, sparingly soluble in water, slightly soluble in acetic acid (100), and very slightly soluble in ethanol (99.5).
Nonproprietary name: Tamsulosin Hydrochloride.
Chemical name: 5-{(2R)-2-[2-(2-Ethoxyphenoxy)ethylamino]propy}-2-methoxybenzenesulfonamide monohydrochloride.
Molecular formula: C₂₀H₂₈N₂O₅S·HCl.
Molecular weight: 444.97.
Melting point: Approx. 230 °C (decomposition).
Excipients/Inactive Ingredients: Microcrystalline cellulose spheres, Hypromellose, Ethylcellulose, Methacrylic acid copolymer LD, Sodium lauryl sulfate, Polysorbate 80, Cetanol, Ethyl acrylate-methyl methacrylate copolymer, Polyoxyethylene nonylphenyl ether, D-mannitol, Lactose hydrate, Maltose syrup powder, Calcium stearate.

Pharmacology: Mechanism of Action: This product decreases urethral pressure in the prostatic zone of the intraurethral pressure curve by inhibiting α₁-receptors in the urethra and prostate, thus improving bladder outlet obstruction associated with benign prostatic hyperplasia.
Effects on Humans: In a receptor binding assay using human prostate specimen, this product was 2.2 times and 40 times stronger than prazosin hydrochloride and phentolamine mesylate in α₁-receptor blocking activity, respectively (in vitro study).
Effects on Animals: Blockade of α-adrenergic receptors: In a receptor binding assay using rat cerebral membrane specimen and an extraction experiment using rabbit aorta specimen, this product inhibited α₁-receptors selectively and competitively. Its action was 1/2.2 to 22 times more potent than prazosin hydrochloride and 45 to 140 times more potent than phentolamine mesylate. In extraction experiments using isolated rabbit aorta, isolated rat vas deferens and isolated guinea pig intestine specimen, tamsulosin hydrochloride proved to be 5,400 to 24,000 times more selective for α₁-receptors than for α₂-receptors (in vitro study).
Effect on the lower urinary tract (urethra and urinary bladder) and prostate: In an extraction experiment using smooth muscle from rabbit urethra, prostate and urinary bladder base specimen, tamsulosin hydrochloride was 23 to 98 times more potent than prazosin hydrochloride in α₁-receptor blocking activity, and 87 to 320 times more potent than phentolamine mesylate (in vitro study).
In anesthetized dogs, the drug inhibited the α₁-agonist (phenylephrine)-induced increase in intrauretheral pressure with 13 times greater potency than the increase in diastolic blood pressure.
Improvement of bladder outlet obstruction: In anesthetized male dogs, this product decreased urethral pressure in the prostatic zone of the intraurethral pressure curve. In anesthetized rats, however, the drug did not affect rhythmic bladder contraction or threshold intravesical pressure.
Clinical Studies: Clinical Studies for Efficacy and Safety: Phase II/III study in Japan: This product significantly decreased intraurethral pressure in the prostatic urethra, and improved urinary flow rate and residual urine volume in a dose-dependent manner. The evaluation results of overall improvement in 276 cases are presented in the following table. Results of a double-blind comparative study showed that HARNAL Capsules administered in a 0.2 mg once daily dose was clinically useful. (See Table 1.)

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Pharmacokinetics: Blood Level: Single dose: The plasma concentration of unchanged drug reached its peak 7 to 8h after an oral administration of 0.1 to 0.6mg^Note) HARNAL Capsules to healthy adults. The half-life was 9.0 to 11.6h. The C_max and AUC increased in a nearly dose-dependent manner. In a 7-day repeated oral administration study, the half-life was slightly prolonged and plasma concentrations reached a steady state on day 4. (See Table 2.)

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Bioequivalence study: When a single dose of HARNAL D Tablets 0.2mg or HARNAL 0.2mg Capsules is orally administered to healthy adults using a cross-over method, the plasma concentration of unchanged tamsulosin hydrochloride is shown as follows. HARNAL D Tablets and HARNAL Capsules were demonstrated to be bioequivalent. (See figure and Table 3.)

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Metabolism: In vitro experiments show Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6.
Drug Interaction: PK studies in healthy volunteers revealed that concomitant administration with strong inhibitors of CYP3A4 or CYP2D6 may lead to increased exposure to tamsulosin. Concomitant administration with ketoconazole (a known CYP3A4 inhibitor) resulted in a C_max and AUC of tamsulosin that had increased by a factor of 2.2 and 2.8, respectively. Concomitant administration with paroxetine (a known CYP2D6 inhibitor) resulted in a C_max and AUC of tamsulosin that had increased by a factor of 1.3 and 1.6, respectively.
Excretion: HARNAL Capsules of 0.1 to 0.6mg^Note) were orally administered to healthy adults. The excretion rate of the unchanged drug in the urine up to 30h after administration remained almost constant at 12% to 14%. No significant changes in the excretion rate after repeated administrations were observed.
Patients with Specific Backgrounds: Patients with renal impairment: HARNAL 0.2mg Capsules were orally administered to 11 patients with renal dysfunction. Their blood pressure did not decrease, but an increase in the plasma concentration of tamsulosin hydrochloride was observed in 2 patients with serious renal impairment. The plasma concentrations of the drug were intimately correlated with an increase in the plasma concentration of α₁-AGP (α₁-acid glycoprotein).
This increase in the plasma concentration of the drug may be caused by the binding of the tamsulosin hydrochloride to plasma α₁-AGP. [See Precautions Concerning Patients with Specific Backgrounds: Patients with Renal Impairment: Patients with severe renal impairment and Use in the Elderly under Precautions.]
In addition, the plasma concentration of the unbound drug, which is presumed to be directly related to the appearance of the effects and adverse reactions of tamsulosin hydrochloride, was almost the same for these patients as for persons with normal renal function, regardless of the plasma concentration of α₁-AGP.
^Note) The approved daily dose for this product is 0.2mg. The dosage may be adjusted depending on the patient's age and symptoms.

Bladder outlet obstruction associated with benign prostatic hyperplasia.

For adults, the usual dosage is 0.2 mg as tamsulosin hydrochloride orally administered once daily after meals.
The dosage may be adjusted according to the patient's age and symptoms.

Patients with known hypersensitivity to this drug or any of the components of this product.

Precautions Concerning Indications: Caution should be paid to the point that the treatment with this product is a symptomatic treatment, not causal therapy. If the expected effect is not noted, surgical therapy or other alternative procedures should be considered.
The diagnosis and treatment of benign prostatic hyperplasia should be carried out in reference to the latest information such as academic societies' guidelines, etc.
Precautions Concerning Dosage and Administration: Elderly patients are more likely to experience renal dysfunction. Such patients should be carefully monitored. If expected effect is not noted at dosage of 0.2mg, the dose should not be increased further, and other appropriate measures should be taken. [See Precautions Concerning Patients with Specific Backgrounds: Use in the Elderly as follows.]
Important Precautions: Overdosage may cause a decrease in blood pressure. Use with caution concerning dosage.
Blood pressure in the orthostatic position may decrease. Patients must be watched for any changes in blood pressure occurring with postural change. [See Precautions Concerning Patients with Specific Backgrounds: Patients with Complication or History of Diseases, etc.: Patients with orthostatic hypotension as follows.]
Since this product may induce symptoms such as dizziness, patients should be instructed to exercise caution against engaging in hazardous activities, such as working at altitudes or driving a car.
Before the start of treatment, patients should be asked whether they are taking any antihypertensive agents. If any such drugs are used, changes in blood pressure should be monitored closely. If a decrease in blood pressure is observed, appropriate measures such as a reduction in the dose or discontinuation of this product should be taken. [See Precautions for Co-administration under Interactions.]
Other Precautions: Information Based on Clinical Uses: Intraoperative floppy iris syndrome has been reported in patients currently taking or having a history of treatment with α₁-blockers.
Precautions Concerning Patients with Specific Backgrounds: Patients with Complication or History of Diseases, etc.: Patients with orthostatic hypotension: Symptoms may be aggravated. [See Important Precautions as previously mentioned.]
Patients with a past history of hypersensitivity to sulfonamide: An allergic reaction may occur.
Patients with Renal Impairment: Patients with severe renal impairment: Plasma concentration of this product may be increased. [See Pharmacology: Pharmacokinetics: Patients with Specific Backgrounds: Patients with renal impairment under Actions.]
Patients with Hepatic Impairment: Patients with severe hepatic function disorder: Plasma concentrations of this product may be increased.
Use in the Elderly: Elderly patients often have reduced renal function. [See Precautions Concerning Dosage and Administration as previously mentioned and Pharmacology: Pharmacokinetics: Patients with Specific Backgrounds: Patients with renal impairment under Actions.]

Since the following adverse reactions may occur, patient should be observed carefully. If any abnormal findings are observed, appropriate measures such as drug discontinuation, etc. should be taken.
Clinically Significant Adverse Reactions: Syncope/unconsciousness (incidence unknown): Transient unconsciousness, etc. due to decreased blood pressure may occur.
Hepatic function disorder, jaundice (incidence unknown, each): AST increased, ALT increased or jaundice, etc. may occur.
Other Adverse Reactions: See Table 4.

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Precautions for Co-administration: This drug should be administered with caution when co-administered with the following.
Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6 [see Pharmacology: Pharmacokinetics: Drug Interaction under Actions]. (See Table 5.)

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Precautions Concerning Use: Precautions Concerning the Dispensing of the Drug: For drugs that are dispensed in a press-through package (PTP), instruct the patient to remove the drug from the package prior to taking this product. If the PTP sheet is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, resulting in severe complications such as mediastinitis.
Patients should be instructed not to chew the tablets. Prolonged release particles of tamsulosin hydrochloride are contained in this product. Crushing or chewing the tablets may destroy the prolonged release particles and may cause changes in pharmacokinetics.
Since the tablets can be soaked with saliva on the tongue and can be disintegrated, the tablet can be swallowed without using water. Also, this product can be taken with water.
The tablet should not be taken without water if the patient is in a lying position.
Precautions for Handling: For drugs that are dispensed in a press-through package (PTP), the quality of this product is maintained by an aluminum pack. After opening the aluminum pack, store away from moisture.

Stored in tight containers at room temperature.
Shelf Life: Three years.

Drugs for Bladder & Prostate Disorders

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

P₁S₁S₃