Harnal D

Harnal D

tamsulosin

Manufacturer:

Astellas

Distributor:

Firma Chun Cheong
/
DKSH
Full Prescribing Info
Contents
Tamsulosin HCl.
Description
Active Ingredient (in each tablet): Tamsulosin Hydrochloride 0.2mg.
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: About 230°C (decomposition).
Tamsulosin hydrochloride is a white crystal. 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).
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.
Action
Pharmacology: Pharmacological Effects: Effects in humans: In a receptor binding assay using human prostate preparations, this product was 2.2 times more potent than prazosin hydrochloride and 40 times more so than phentolamine mesylate in α1-receptor blocking activity.
Effects in animals: Blockade of α-adrenergic receptors: In a receptor binding assay using isolated rat cerebral membrane and an in vitro experiment using isolated rabbit aorta, 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 vitro experiments using isolated rabbit aorta, isolated rat vas deferens and isolated guinea pig intestine, tamsulosin hydrochloride proved to be 5,400 to 24,000 times more selective for α1-receptors than for α2-receptors.
Effect on the lower urinary tract (urethra and urinary bladder) and prostate: In a receptor binding assay using isolated smooth muscle from rabbit urethra, prostate and urinary bladder base, 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 anesthetized dogs, the drug inhibited the α1-agonist (phenylephrine)-induced increase in intraurethral 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.
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.
Clinical Studies: 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 in easing the symptoms of benign prostatic hyperplasia. (See Table 1.)

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Pharmacokinetics: Plasma concentration: When a single dose of Harnal D 0.2 mg Tablet or Harnal 0.2 mg Capsule is orally administered to healthy male adults using a cross-over method, the plasma concentration of unchanged tamsulosin hydrochloride is shown as follows. (See figure and Table 2.)

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The plasma concentration of the unchanged drug reached its peak 7 to 8 h after a single oral administration of 0.1 to 0.6 mg Harnal Capsules to healthy male adults. The half-life was 9.0 to 11.6 h. The Cmax 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.
Pharmacokinetic parameters for Harnal Capsules for clinical dosing: See Table 3.

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Harnal 0.2 mg 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. However, 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.
Metabolism: In vitro experiments show Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6.
Excretion: Single doses of Harnal Capsules of 0.1 to 0.6 mg were orally administered to healthy male adults. The excretion rate of the unchanged drug in the urine up to 30 h after administration remained almost constant at 12 to 14%. No significant changes in the excretion rate after repeated administrations were observed.
(Note) The approved daily dose for this product is 0.2 mg.
Bioequivalence: When Harnal D Tablets or Harnal Capsules were orally administered to humans, the plasma concentration-time profile of the unchanged drug was almost equivalent between the two formulations, demonstrating their bioequivalence.
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 Cmax and AUG 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 Cmax and AUC of tamsulosin that had increased by a factor of 1.3 and 1.6, respectively.
Indications/Uses
Bladder outlet obstruction associated with benign prostatic hyperplasia.
Dosage/Direction for Use
The recommended adult oral dosage is 0.2 mg of tamsulosin hydrochloride once daily after meals.
The dosage may be adjusted depending on the patient's age and symptoms.
Contraindications
Patients with known hypersensitivity to Harnal D or any of its components.
Special Precautions
Careful Administration: Harnal D Tablets should be administered with care in the following patients.
(1) Patients with orthostatic hypotension [Symptoms may be exacerbated.]
(2) Patients with serious hepatic dysfunction [Plasma drug concentrations may be increased.]
(3) Patients with severe renal dysfunction [An increase in plasma drug concentrations may result. (See Pharmacology: Pharmacokinetics under Actions)]
(4) Elderly patients (see Use in the Elderly as follows)
(5) Patients who are taking phosphodiesterase-5 inhibitors (see Interactions)
(6) Patients with a past history of hypersensitivity to sulfonamide [An allergic reaction may occur.]
Important Precautions: (1) The tablets disintegrate in the mouth, but are not absorbed through the oral mucosa. Therefore. the patients should be instructed to swallow the dissolved tablet with saliva or a drink of water.
(2) Use with caution concerning dosage and administration. Overdosage may cause a decrease in blood pressure.
(3) Blood pressure in the orthostatic position may decrease. Patients must be watched for any changes in blood pressure occurring with postural change.
(4) This product does not eliminate the cause of the disease, but gives symptomatic relief. If the expected response does not result, surgical therapy or other alternative procedures should be considered.
(5) Since this product may induce symptoms such as dizziness, patients should be cautioned against performing hazardous activities, such as working at altitudes or driving a car.
(6) Before the start of treatment, patients should be asked whether they are taking any antihypertensive drugs. If any such drugs are used, blood pressure during treatment should be monitored closely. If a decrease in blood pressure is observed, the treatment should be discontinued, or other appropriate measures taken.
(7) Intraoperative Floppy Iris Syndrome (IFIS, a variant of small pupil syndrome) considered to be due to alpha-1 blocking action has been observed during cataract and glaucoma surgery in some patients on or previously treated with tamsulosin. Ophthalmologists should be aware of possible occurrence of IFIS during cataract and glaucoma surgery.
Use in the Elderly: Elderly patients are more likely to experience renal dysfunction. Such patients should be carefully monitored. If efficacy is not noted at 0.2 mg, the dose should not be increased further, and other appropriate measures must be taken.
Adverse Reactions
Adverse reactions (including abnormalities in clinical laboratory findings) to this product were observed in 104 (2.2%) of 4,724 patients investigated in the clinical trials until approval, and in drug-use results surveys for Harnal Capsules. The major adverse reactions were dizziness and stomach discomfort (At the end of latest reexamination: November 2003).
Clinically significant adverse reactions: Syncope / unconsciousness (Incidence unknown): Since transient unconsciousness etc. may appear with a decrease in blood pressure, patients should be carefully observed. If any abnormal findings are observed during treatment, administration should be discontinued and appropriate measures should be taken.
Hepatic function disorder or jaundice (Incidence unknown): Since increases of AST (GOT), ALT (GPT), or jaundice may appear, patients should be carefully observed. If any abnormal findings are observed during treatment, appropriate measures such as drug discontinuation should be taken.
Other adverse reactions: See Table 4.

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Drug Interactions
Precautions for coadministration: Harnal D Tablets should be administered with care when coadministered with the following drugs.
Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6 (see Pharmacology: Pharmacokinetics under Actions). (See Table 5.)

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Caution For Usage
Caution in dispensing: 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. [It has been reported that, if the PTP sheet is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, resulting in severe complications such as mediastinitis.]
Caution in oral administration: 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.]
The tablets can be soaked in saliva on the tongue, lightly mashed between the tongue and the hard palate, and then swallowed with saliva alone.
The tablets should not be taken without water if the patient is lying down.
Storage
Store in tight containers at room temperature.
ATC Classification
G04CA02 - tamsulosin ; Belongs to the class of alpha-adrenoreceptor antagonists. Used in the treatment of benign prostatic hypertrophy.
Presentation/Packing
XR tab 0.2 mg (white, extended-release, orally disintegrating, diameter 8.5 mm, thickness 4.2 mm, weight 0.20 g, identification code
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557) x 28's.
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