Tanatril

Tanatril

imidapril

Manufacturer:

Mitsubishi Tanabe Pharma

Distributor:

Pharmaforte
Full Prescribing Info
Contents
Imidapril hydrochloride.
Description
(See Table 1.)

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Non-proprietary name: Imidapril hydrochloride (JAN); Imidapril (INN).
Chemical name: (-)-(4S)-3-[(2S)-2[[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride.
Molecular formula: C20H27N3O6.HCl: 441.91.
Imidapril hydrochloride occurs as a white crystal. It is odorless or has a slightly characteristic odor.
It is freely soluble in methanol, soluble in water, sparingly soluble in ethanol (99.5), and practically insoluble in ethyl acetate, in chloroform, in diethyl ether and in hexane.
Action
Pharmacology: Imidapril hydrochloride is a prodrug which is hydrolyzed in the body after oral administration to form the di-carboxylic acid form (imidaprilat), an active angiotensin converting enzyme inhibitor. Imidaprilat inhibits the activity of ACE, an enzyme widely distributed in blood and endothelial cell of many tissues. The antihypertensive effect of imidapril hydrochloride 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.
Angiotensin converting enzyme inhibition: The active metabolite imidaprilat competitively inhibits the activity of ACE preparation derived from swine renal cortex and human serum in a dose-dependent manner.
In rats, orally administered imidapril hydrochloride and imidaprilat inhibits dose-dependently the elevation of blood pressure induced by angiotensin-I in a dose-dependent manner.
Antihypertensive action: Orally administered imidapril hydrochloride 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 hydrochloride in SHR for 2 weeks had stable antihypertensive effects and had no effect on the heart rate.
Repeated oral administration of 5 to 10 mg of imidapril hydrochloride 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 intravenous or intraduodenal administration of imidapril hydrochloride or imidaprilat.
In SHR, long-term treatment with imidapril hydrochloride for 9 to 10 weeks prevented the genetic hypertensive development and cardiac hypertrophy due to the hypertension.
Pharmacodynamics: 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 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 84.0% (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 hydrochloride is metabolized to 4 metabolites, which were detected and identified, in addition to unchanged imidapril hydrochloride. The di-carboxylic acid form (imidaprilat) alone is pharmacologically active among the 4 metabolites.
Absorption: Following single oral administration of 10 mg of imidapril hydrochloride in healthy subjects, imidapril hydrochloride reached the peek plasma concentration is about 2 hours and was eliminated from the plasma with a half-life of about 2 hours. Imidaprilat, the active metabolite of imidapril, reached the peak plasma concentration (about 15 ng/mL) 6 to 8 hours after administration, and was gradually eliminated from the plasma with a half-life of about 8 hours.
Metabolism and excretion: Following single oral administration of 10 mg of imidapril hydrochloride in healthy subjects, 25.5% of the dosage was excreted in the urine within 24 hours. (See figure.)

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Accumulation: The plasma concentration of imidaprilat reached the steady state 3 to 5 days after the initiation of repeated oral administration of 10 mg of imidapril hydrochloride once a day for seven days in healthy subjects; there was no sign of accumulation. In patients with impaired renal function, peak plasma imidaprilat 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 for oral use is 5 mg to 10 mg of imidapril hydrochloride once a day. The dosage may be adjusted depending on the patient's age and symptoms. 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 the drug.
Patients with a history of angioedema (Angioedema due to drug such as angiotensin converting enzyme (ACE) inhibitors, etc., hereditary angioedema, acquired angioedema, idiopathic angioedema, etc.) [Angioedema associated with dyspnea may occur].
Patients undergoing apheresis by an adsorber using dextran sulfate immobilized cellulose, tryptophan immobilized polyvinyl alcohol or polyethylene terephthalate [shock may occur.] (See Interactions).
Patients who undergo hemodialysis with acrylonitrile methallyl sulfonate sodium membrane (AN69) [Anaphylactoid symptom may occur.] (See Interactions).
Pregnant women or women who may possibly be pregnant. [See Use in Pregnancy & Lactation].
Patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 vm2) being treated with aliskiren fumarate (excluding patients with markedly uncontrolled blood pressure even after antihypertensive treatment with other drugs) [Increased risks for nonfatal stroke, renal impairment, hyperkalemia, and hypotension have been reported.] (See Important Precautions under Precautions).
Special Precautions
In patients with serious renal impairment whose creatinine clearance levels are less than 30 mL/min. or serum creatinine levels are greater than 3 mg/dL, the drug should be administered with care; consider decreasing the usual dosage to the 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 Pharmacology: Pharmacokinetics under Actions and Careful Administration as follows.)
Careful Administration (TANATRIL should be administered with care in the following patients): Patients with renal impairment. [See Dosage & Administration and Clinically significant adverse reactions under Adverse Reactions].
Patients with bilateral or unilateral renal artery stenosis. [See Important Precautions as follows].
Patients with cerebrovascular disorders. [Excessive hypotension may cause cerebral blood flow insufficiency which may worsen patient's condition.]
Elderly patients. [See Use in the Elderly as follows].
Patients with Hyperkalemia [see Important Precautions as follows].
Important Precautions: Since the following patients may experience transient excessive hypotension after initiation of therapy with TANATRIL, the administration should be initiated with a reduced dosage; gradually increase the dosage 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); Patients on strict dietary salt restriction.
Since dizziness or light-headed may occur due to hypotensive effect, patients should be cautioned against engaging in potentially hazardous activities requiring alertness, such as driving a car, working at heights, or operating machinery, etc.
Administration is not recommended within 24 hours prior to surgery.
In patient with bilateral or unilateral renal artery stenosis, renal function may be aggravated rapidly due to decreased renal blood flow and decreased glomerular filtration pressure. TANATRIL should not be used in these patients except the treatment with this product is judged to be essential.
In patients with hyperkalemia, the symptom may be aggravated. This product should not be used in these patients except the treatment with this product is judged to be essential. In patients whose serum potassium levels tend to increase due to renal impairment and/or poorly controlled diabetes mellitus, etc. hyperkalemia may occur. Serum potassium levels should be monitored carefully.
Dual blockade of renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see Interactions).
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Other Precautions: It has been reported that the concomitant use of angiotensin converting enzyme inhibitors with insulin or hypoglycemic agents may easily cause hypoglycemia.
Use in Pregnancy & Lactation: TANATRIL is contraindicated in pregnant women or women who may possibly be pregnant. [Oligoamnios, fetal or neonatal death and hypotension, renal failure, hyperkalemia and cranial hypoplasia in the neonatal have been reported in hypertensive patients receiving angiotensin converting enzyme (ACE) inhibitors during mid or late pregnancy. Limb contractures and craniofacial deformities in the neonatal, presumably ascribable to oligoamnios, have also been reported.]
Woman who become pregnant while receiving TANATRIL should be informed of potential hazard to the foetus and treatment with TANATRIL should be discontinued.
Lactating mothers should not receive the drug. If use of the drug is judged to be essential, breast feeding should be discontinued during treatment. [It has been reported that imidapril hydrochloride is excreted in breast milk in animal experiments (rats).]
Pediatric Use: The 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 reduce dose (e.g., 2.5 mg) with careful monitoring of the patient's condition.
TANATRIL is mainly excreted by the kidney. Since there is a possibility of persistent elevated blood concentration in elderly patients, who often have impaired renal function, adverse reactions are more likely to occur and the action of the drug may be enhanced.
An excessive reduction in blood pressure is undesirable in elderly patients. (Cerebral infarction, etc., may occur).
Use In Pregnancy & Lactation
TANATRIL is contraindicated in pregnant women or women who may possibly be pregnant. [Oligoamnios, fetal or neonatal death and hypotension, renal failure, hyperkalemia and cranial hypoplasia in the neonatal have been reported in hypertensive patients receiving angiotensin converting enzyme (ACE) inhibitors during mid or late pregnancy. Limb contractures and craniofacial deformities in the neonatal, presumably ascribable to oligoamnios, have also been reported.]
Woman who become pregnant while receiving TANATRIL should be informed of potential hazard to the foetus and treatment with TANATRIL should be discontinued.
Lactating mothers should not receive the drug. If use of the drug is judged to be essential, breast feeding should be discontinued during treatment. [It has been reported that imidapril hydrochloride is excreted in breast milk in animal experiments (rats).]
Adverse Reactions
CLINICAL STUDIES (clinical trial): Adverse reactions were reported in 50 (5.83%) of 858 patients treated. The major adverse reaction were cough in 23 (2.68%), pharynx discomfort in 4 (0.47%), stomach discomfort in 2 (0.23%), palpitation in 2 (0.23%), etc.
Among abnormal laboratory test values reported, 56 (6.53%) were suspected as related to TANATRIL, including increased ALT (GPT) in 15 (2.03%) of 739 patients, increased AST (GOT) in 13 (1.76%) of 739, increased creatinine in 6 (0.83%) of 722 patients, etc.
Drug use-results survey (October 1993 to September 1999): Adverse reactions were reported in 390 (6.75%) of 5,774 patients. The major adverse reactions were cough in 275 (4.76%), hypotension in 15 (0.26%), dizziness in 13 (0.23%), headache in 11 (0.19%), pharynx strange sensation and/or discomfort in 8 (0.14%), lightheadness in 8 (0.14%), rash in 7 (0.12%), etc.
Clinically significant adverse reactions (rarely: <0.1%, no adverb: incidence is unknown due to spontaneous report): Angioedema, manifested as swelling of the face, tongue, glottis and larynx accompanied by dyspnea, may occur. If any of these sign are observed, the drug should be discontinued immediately and appropriate measures, such as administration of antihistaminic agents, adrenal cortex hormone agents, etc. and maintaining the airway, should be taken.
Severe thrombocytopenia may occur. In case, administration should be discontinued immediately and appropriate therapeutic measures should be taken.
Since acute renal failure and exacerbation of renal impairment may occur, the patient’s clinical condition should be closely monitored by performing renal function test. If any abnormalities are observed, appropriate measures, such as discontinuing administration, should be taken.
Severe hyperkalemia may occur. The patients should be observed carefully. If any abnormalities are observed, appropriate therapeutic measures should be taken immediately.
Erythroderma (Exfoliative dermatitis), oculo-muco-cutaneous syndrome (Steven Johnson syndrome), and pemphigus-like symptoms may occur. If symptoms such as erythema, blisters, pruritus, fever, enanthema, etc. are observed, the drug should be discontinued and appropriate measures should be taken.
Clinically significant adverse reactions (similar drugs): It has been reported that pancytopenia may occur with the use of other angiotensin converting enzyme inhibitors. If symptoms are observed, the drug should be discontinued immediately and appropriate measures taken.
It has been reported that pancreatitis may occur with the use of other angiotensin converting enzyme inhibitors. If increase in blood concentration of amylase, lipase, etc. is observed, appropriate measures, such as discontinuing administration, should be taken.
Others adverse reactions: If any adverse reactions are observed, appropriate measures, such as discontinuing administration, should be taken. (See Table 2.)

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Drug Interactions
Contraindications for coadministration (TANATRIL should not be coadministered with the following drugs, etc.): (See Table 3.)

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Precautions for coadministration (TANATRIL should be administered with care when coadministered with the following drugs.): (See Table 4.)

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Clinical trial data has shown that dual blockade of renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see Contraindications and Precautions).
Caution For Usage
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 such as mediastinitis.)
Storage
Store at below 30°C. Avoid humidity after opening.
ATC Classification
C09AA16 - imidapril ; Belongs to the class of ACE inhibitors. Used in the treatment of cardiovascular disease.
Presentation/Packing
Tab 5 mg x 3 x 10's, 10 x 10's. 10 mg x 3 x 10's, 10 x 10's.
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