Tanatril達爽

Tanatril

imidapril

Manufacturer:

Mitsubishi Tanabe Pharma

Distributor:

Primal
Full Prescribing Info
Contents
Imidapril HCl.
Description
Imidapril HCl is (-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino]-propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride. Molecular Formula: C20H27N3O6·HCl. Molecular Weight: 441.91.
Imidapril HCl occurs as white crystals. It is odorless or has a slight characteristic odor. It is freely soluble in methanol, soluble in water, sparingly soluble in ethanol (99.5), and practically insoluble in ethyl acetate, chloroform, diethyl ether and hexane.
Action
Selective angiotensin-converting enzyme inhibitor.
Pharmacology: Imidapril HCl is a prodrug which is hydrolyzed after oral administration to form the dicarboxylic acid form (imidaprilat), an active angiotensin-converting enzyme inhibitor. Imidaprilat inhibits the activity of angiotensin-converting enzyme (ACE), an enzyme widely distributed in blood and endothelial cells of many tissues. The antihypertensive effects of imidapril HCl are caused by ACE inhibition and the subsequent reduction in the formation of angiotensin II, which either directly or indirectly results in dilatation of peripheral vessels and reduction of vascular resistance.
ACE Inhibition: The active metabolite imidaprilat competitively inhibits the activity of ACE preparations derived from swine renal cortex and human serum in a dose-dependent manner.
In rats, orally administered imidapril HCl and imidaprilat inhibits the elevation of blood pressure induced by angiotensin I in a dose-dependent manner.
Antihypertensive Action: Orally administered imidapril HCl had significant dose-dependent antihypertensive effects in spontaneously hypertensive rats (SHR) and in 2-kidney-1-clip Goldblatt hypertensive rats. It had slight hypotensive effects in normotensive rats, but it was not effective in DOCA/saline hypertensive rats.
Oral administration of imidapril in SHR for 2 weeks had stable antihypertensive effects and had no effect on heart rate.
Repeated oral administration of 5-10 mg of imidapril HCl once a day in patients with essential hypertension had stable antihypertensive effects and had no effect on the circadian variation of blood pressure.
Other Actions: Renal blood flow and glomerular filtration rate significantly increased in dogs after IV or intraduodenal administration of imidapril HCl or imidaprilat.
In SHR, long-term treatment with imidapril for 9-10 weeks prevented genetic hypertension development and cardiac hypertrophy due to hypertension.
Clinical Studies: Tanatril was evaluated by clinical trials, including double-blind comparative clinical trials, at 133 institutions.
Essential Hypertension (mild to moderate): In clinical studies including a double-blind comparative clinical trial, Tanatril was effective in 80.8% (361/447) of the patients with mild to moderate essential hypertension.
Patients with Severe Hypertension and Hypertensive Patients with Renal Impairment: In clinical studies involving patients with severe hypertension and hypertensive patients with renal impairment, Tanatril was effective in 100% (19/19) of the patients with severe hypertension and 84% (21/25) of the hypertensive patients with renal impairment.
Renal Parenchymal Hypertension: In a clinical study involving patients with renal parenchymal hypertension, Tanatril was effective in 80.6% (25/31) of the patients.
Pharmacokinetics: Imidapril HCl is metabolized to 4 metabolites, which were detected and identified, in addition to unchanged imidapril HCl. The dicarboxylic acid form (imidaprilat) alone is pharmacologically active.
Absorption: Following single oral administration of 10 mg of imidapril HCl in healthy subjects, imidapril HCl reached the peak plasma concentration in about 2 hrs and was eliminated from the plasma with a half-life of about 2 hrs. Imidaprilat reached the peak plasma concentration (about 15 ng/mL) 6-8 hrs after administration, and was gradually eliminated from the plasma with a half-life of about 8 hrs.
Metabolism and Excretion: Following single oral administration of 10 mg of imidapril HCl in healthy subjects, 25.5% of the dosage was excreted in the urine within 24 hrs.
Accumulation: Plasma concentration of imidaprilat reached the steady state 3-5 days after the initiation of repeated oral administration of 10 mg of imidapril HCl once a day for 7 days in healthy subjects; there was no sign of accumulation. In patients with impaired renal function, peak imidaprilat plasma levels increased, and its elimination from the plasma may be delayed.
Indications/Uses
Hypertension; renal parenchymal hypertension.
Dosage/Direction for Use
The usual adult dosage range for oral use is 5-10 mg once a day. The dosage may be adjusted according to patient's age and symptoms. (See Interactions.)
In patients with severe hypertension, hypertension with renal impairment, or renal parenchymal hypertension, the recommended initial dose is 2.5 mg once a day.
Contraindications
Patients with a history of hypersensitivity to any of the ingredients of Tanatril; patients with a history of angioedema due to an ACE inhibitor (angioedema associated with dyspnea may occur); patients who undergo LDL apheresis using dextran cellulose sulfate (shock may occur) (see Interactions); patients who undergo hemodialysis with acrylonitrile methallyl sulfonate sodium membrane (AN69) (anaphylactoid symptom may occur; see Interactions).
Use in pregnancy: Tanatril is contraindicated in pregnant women or women who may possibly be pregnant. Oligohydramnios, fetal or neonatal death, and hypotension, renal failure, hyperkalemia and cranial hypoplasia in the neonatal have been reported in hypertensive patients receiving ACE inhibitors during mid or late pregnancy. Limb contractures and craniofacial deformities in the neonatal, presumably ascribable to oligohydramnios, have also been reported.
Women who become pregnant while receiving Tanatril should be informed of the potential hazard to the foetus and the treatment with the drug should be discontinued.
Use in lactation: Lactating mothers should not receive Tanatril. If use of the drug is judged to be essential, breastfeeding should be discontinued during treatment. It has been reported that imidapril HCl is excreted in breast milk in animal experiments (rats).
Special Precautions
Tanatril should be administered with care in the following patients: Patients with Renal Impairment: In patients with serious renal impairment whose creatinine clearance levels are <30 mL/min or serum creatinine levels are >3 mg/dL, Tanatril should be administered with care by decreasing the dose by half or prolonging the time interval between administrations. (Excessive hypotension or further decrease in renal function may occur due to decrease in urinary excretion rate.) (See Pharmacokinetics under Actions.)
Patients with Bilateral Renal Arterial Stenosis: Renal dysfunction may be exacerbated.
Patients with Cerebrovascular Disorders: Excessive hypotension may cause cerebral blood flow insufficiency which may worsen patient's condition.
Since the following patients may experience transient excessive hypotension after initiation of therapy with Tanatril, the administration should be initiated with a reduced dosage; the dosage may be gradually increased while closely observing the patient's condition: Patients with severe hypertension; patients who undergo hemodialysis; patients on diuretic therapy, especially those in whom diuretic therapy has been recently initiated; and patients on strict dietary salt restriction.
Administration is not recommended within 24 hrs prior to surgery.
Use only pursuant to prescription or directions of a physician.
Precautions Regarding Dispensing: Since Tanatril is dispensed in a press-through package (PTP), instruct the patient to remove the drug from the package prior to use. 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 eg, mediastinitis.
Other Precautions: It has been reported that the concomitant use of ACE inhibitors with insulin or hypoglycemic agents may easily cause hypoglycemia.
Effects on the Ability to Drive or Operate Machinery: Since dizziness or lightheadedness may occur due to its hypotensive effect, patients should be cautioned against engaging in potentially hazardous activities requiring alertness eg, driving a car, working at heights or operating machinery, etc.
Use in children: Safety of Tanatril in children has not been established (no clinical experience).
Use in the elderly: Therapy should be instituted with special care, starting at a reduced dosage (eg, 2.5 mg) with careful monitoring of the patient's conditions.
Tanatril is mainly excreted by the kidney. Since there is a possibility of persistent elevated blood concentrations in elderly patients who often have impaired renal function, adverse reactions are more likely to occur and the action of Tanatril may be enhanced.
An excessive reduction in blood pressure is undesirable in elderly patients. (Cerebral infarction, etc, may occur.)
Adverse Reactions
Adverse reactions to Tanatril were reported in 442 (6.6%) of 6741 patients treated. The most frequently observed adverse reactions were cough 4.5%, dizziness 0.2%, hypotension 0.2%, headache 0.2%, pharynx discomfort 0.2%, rash 0.1%, etc. (Data collected from the time of approval up to November 1996.)
Abnormal laboratory findings suspected to be drug-related were reported in 47 patients (5.6%) of 832 patients treated. Frequently reported abnormal findings were increased SGOT (1.4%), increased SGPT (1.7%) and increased creatinine (0.7%). (At the time of approval.)
Clinically Significant Adverse Reactions (Rarely: <0.1%): Angioedema, manifested as swelling of the face, tongue, glottis and larynx accompanied by dyspnea, may occur rarely. If any of these signs are observed, Tanatril should be discontinued immediately and appropriate measures eg, administration of antihistaminic agents, adrenal cortex hormone agents, etc, and maintaining the airway should be taken.
Serious thrombocytopenia may occur rarely. If symptoms are observed, Tanatril should be discontinued immediately and appropriate measures taken.
Since acute renal failure (incidence <0.1%) and exacerbation of renal impairment may occur, the patient's clinical condition should be closely monitored by performing renal function tests. If any abnormalities are observed, appropriate measures eg, discontinuing administration, should be taken.
Clinically Significant Adverse Reactions (similar drugs): It has been reported that pancytopenia may occur with the use of other ACE inhibitors. If symptoms are observed, Tanatril should be discontinued immediately and appropriate measures taken.
It has been reported that pancreatitis may occur with the use of other ACE inhibitors. If an increase in blood concentration of amylase, lipase, etc, is observed, appropriate measures eg, discontinuing administration, should be taken.
Other Adverse Reactions: If any adverse reactions are observed, appropriate measures eg, discontinuing administration, should be taken. (See Table 1.)

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Drug Interactions
Contraindications for co-administration (Tanatril should not be co-administered with the following drugs): See Table 2.

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Precautions for co-administration (Tanatril should be administered with care when co-administered with the following drugs): See Table 3.

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Storage
Store at room temperature, in airtight containers. Avoid humidity.
ATC Classification
C09AA16 - imidapril ; Belongs to the class of ACE inhibitors. Used in the treatment of cardiovascular disease.
Presentation/Packing
Tab 10 mg x 100's.
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