NORPLUS Imidapril Hydrochloride / Hydrochlorothiazide 10mg / 12.5mg Tablet 1's
RXDRUG-DRP-10045-1pc
Discreet Packaging
FDA-registered Products
FDA-licensed Pharmacies
Indications/Uses
Treatment of hypertension.
Dosage/Direction for Use
Individualize dosage according to patient's clinical response.
Usual Recommended Oral Adult Dose: 1 tablet once a day.
Or, as prescribed by a physician.
Usual Recommended Oral Adult Dose: 1 tablet once a day.
Or, as prescribed by a physician.
Overdosage
Imidapril hydrochloride: Symptoms of overdosage with imidapril include severe hypotension, shock, stupor, bradycardia, electrolyte disturbances, and renal failure. After ingestion of an overdose, keep patient under close supervision, preferably in an intensive care unit. Monitor serum electrolytes and creatinine frequently. Measures to prevent absorption and hasten elimination such as gastric lavage, administration of adsorbents and sodium sulfate within 30 minutes after intake should be applied if ingestion is recent.
If hypotension occurs, place patient in the shock position and immediately give salt and volume supplementation. Treatment with angiotensin II should be considered. Bradycardia or extensive vagal reactions may be treated with atropine. The use of a pacemaker may be considered.
Imidapril and imidaprilat may be removed from the circulation by hemodialysis. The use of high-flux polyacrylonitrile membranes should be avoided.
Hydrochlorothiazide: The most common signs and symptoms of HCTZ overdose include electrolyte imbalance (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. Other features of overdose are lethargy, nausea and weakness. Lethargy may progress to coma within a few hours with minimal depression of respiratory and cardiovascular function without evidence of dehydration or serum electrolyte changes. Gastrointestinal irritation and hypermotility may occur, and temporary elevation of blood urea nitrogen has been reported.
In the treatment of thiazide overdosage, gastric contents may be evacuated taking caution to avoid aspiration, particularly in unconscious patients. If the patient is conscious, induction of vomiting with ipecac syrup is effective in removing the drug from the stomach. Do not administer cathartics since they tend to promote loss of fluid and electrolytes. Treatment is generally supportive. Monitor serum electrolyte and renal function. Replacement of fluid and electrolytes may be indicated. Measures may be required to maintain respiratory, cardiovascular and renal function. Gastrointestinal irritation is usually of short duration but may be treated symptomatically.
The degree to which HCTZ is removed by hemodialysis has not been established.
If hypotension occurs, place patient in the shock position and immediately give salt and volume supplementation. Treatment with angiotensin II should be considered. Bradycardia or extensive vagal reactions may be treated with atropine. The use of a pacemaker may be considered.
Imidapril and imidaprilat may be removed from the circulation by hemodialysis. The use of high-flux polyacrylonitrile membranes should be avoided.
Hydrochlorothiazide: The most common signs and symptoms of HCTZ overdose include electrolyte imbalance (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. Other features of overdose are lethargy, nausea and weakness. Lethargy may progress to coma within a few hours with minimal depression of respiratory and cardiovascular function without evidence of dehydration or serum electrolyte changes. Gastrointestinal irritation and hypermotility may occur, and temporary elevation of blood urea nitrogen has been reported.
In the treatment of thiazide overdosage, gastric contents may be evacuated taking caution to avoid aspiration, particularly in unconscious patients. If the patient is conscious, induction of vomiting with ipecac syrup is effective in removing the drug from the stomach. Do not administer cathartics since they tend to promote loss of fluid and electrolytes. Treatment is generally supportive. Monitor serum electrolyte and renal function. Replacement of fluid and electrolytes may be indicated. Measures may be required to maintain respiratory, cardiovascular and renal function. Gastrointestinal irritation is usually of short duration but may be treated symptomatically.
The degree to which HCTZ is removed by hemodialysis has not been established.
Administration
May be taken with or without food.
Contraindications
Hypersensitivity to imidapril hydrochloride, any ACE inhibitor, HCTZ, other sulfonamide derivatives, or to any component of the product.
History of angioneurotic edema associated with previous ACE inhibitor therapy.
Hereditary or idiopathic angioedema.
Pregnancy.
Breastfeeding.
Renal failure with or without hemodialysis.
Anuria.
Concomitant use with aliskiren in patients with diabetes mellitus, renal impairment [glomerular filtration rate (GFR) <60 mL/min/1.73 m2], hyperkalemia (>5 mmol/L) or congestive heart failure who are hypotensive.
History of angioneurotic edema associated with previous ACE inhibitor therapy.
Hereditary or idiopathic angioedema.
Pregnancy.
Breastfeeding.
Renal failure with or without hemodialysis.
Anuria.
Concomitant use with aliskiren in patients with diabetes mellitus, renal impairment [glomerular filtration rate (GFR) <60 mL/min/1.73 m2], hyperkalemia (>5 mmol/L) or congestive heart failure who are hypotensive.
Special Precautions
Fetal Toxicity: When pregnancy is detected, discontinue imidapril hydrochloride + HCTZ as soon as possible. Drugs that act directly on the renin-angiotensin-aldosterone system can cause injury and death to the developing fetus.
Imidapril Hydrochloride: Fetal Toxicity: The use of drugs that act on the renin-angiotensin-aldosterone system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue imidapril as soon as possible. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin-aldosterone system for a particular patient, apprise the mother of the potential risk to the fetus.
In patients taking imidapril during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. If oligohydramnios is observed, discontinue imidapril, unless it is considered lifesaving for the mother. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Closely observe infants with histories of in utero exposure to imidapril for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
Hypotension: Imidapril, like other ACE inhibitors, may cause a profound fall in blood pressure particularly after the first dose. Symptomatic hypotension is observed rarely in patients with uncomplicated hypertension. In hypertensive patients treated with imidapril, hypotension is more likely to occur if the patient has been volume-depleted (e.g., by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting). Symptomatic hypotension has also been observed in patients with heart failure (with or without associated renal insufficiency). This is most likely to occur in patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatremia or functional renal impairment. In these patients, treatment should be under medical supervision and patients should be monitored whenever the dose of imidapril and/or diuretic is adjusted. Apply similar considerations to patients with ischemic heart disease or cerebrovascular disease in whom an excessive fall in blood pressure may result in myocardial infarction or cerebrovascular accident.
If hypotension develops, place the patient in a supine position. Volume repletion with intravenous normal saline may be required. The appearance of hypotension after the initial dose does not preclude subsequent careful dose titration with imidapril after effective management.
Renovascular Hypertension: An increased risk of severe hypotension and renal impairment has been observed in patients with renovascular hypertension and pre-existing bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney treated with ACE inhibitors. Loss of renal function may occur with only mild changes in serum creatinine. Treatment of these patients should be under strict medical supervision, with low doses, careful titration, and monitoring of renal function.
Renal Impairment: Changes in renal function may be anticipated in susceptible individuals due to inhibition of the renin-angiotensin-aldosterone system. Thus, imidapril should be used with caution in patients with impaired renal function. Reduced doses are required for patients with creatinine clearance between 30 to 80 mL/min. Due to limited data, imidapril should not be given to patients with creatinine clearance <30 mL/min. Close monitoring of renal function during treatment should be performed. Renal failure associated with ACE inhibitors has been reported mainly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. Some patients, with no apparent pre-existing renal disease, have developed minor and usually transient elevations in blood urea and serum creatinine when imidapril was coadministered with a diuretic. Reduction in imidapril dosage and/or discontinuation of the diuretic may be necessary. This situation should raise the possibility of underlying renal artery stenosis.
Kidney Transplantation: There is no data on the use of imidapril in patients with recent kidney transplantation.
Hemodialysis: Anaphylactoid reactions such as facial swelling, flushing, hypotension, and dyspnea have been seen in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Consider giving a different type of dialysis membrane or a different class of antihypertensive agent in these patients.
Hepatic Impairment: Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Discontinue the ACE inhibitor and take appropriate medical measures if marked elevations of hepatic enzymes or jaundice occur.
Psoriasis: Imidapril, as with other ACE inhibitors, should be used with caution in patients with psoriasis.
Angioneurotic Edema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients receiving ACE inhibitors, including imidapril. Symptoms may occur at any time during treatment. In such cases, immediately discontinue imidapril and institute appropriate monitoring until complete and sustained resolution of symptoms has occurred. Angioedema associated with laryngeal edema or tongue edema may be fatal. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, particularly those with a history of airway surgery. Appropriate therapy, which may include subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures to ensure a patent airway, should be administered promptly. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor. Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors.
Anaphylactoid Reactions during Desensitization: There have been isolated reports of patients experiencing sustained, life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitization treatment with hymenoptera (bees, wasps) venom. Discontinue imidapril before desensitization treatment.
Anaphylactoid Reactions during LDL-Apheresis: Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL)-apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily discontinuing ACE inhibitor therapy prior to apheresis.
Aortic Stenosis/Hypertrophic Cardiomyopathy: Use with caution in patients with left ventricular valvular and outflow tract obstruction.
Neutropenia/Agranulocytosis: Neutropenia/agranulocytosis, thrombocytopenia and anemia have been observed rarely in patients receiving ACE inhibitors, including imidapril. Imidapril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections which in a few instances did not respond to intensive antibiotic therapy. If imidapril is used in such patients, white blood cell count and differential counts should be performed prior to therapy, every 2 weeks during the first 3 months of imidapril therapy, and periodically thereafter. Patients should be instructed to report any sign of infection (e.g., sore throat, fever) during treatment. If neutropenia (neutrophils <1000/mm3) is detected or suspected, imidapril and other concomitant medication should be discontinued. In most patients, neutrophil counts rapidly return to normal upon discontinuing imidapril therapy.
Cough: Persistent nonproductive cough has been reported with all ACE inhibitors, presumably due to the inhibition of the degradation of endogenous bradykinin. Cough always resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
Surgery/Anesthesia: There are no data available on the use of imidapril under conditions of surgery or anesthesia. However, like other ACE inhibitors, imidapril may cause hypotension or even hypotensive shock in patients undergoing major surgery or during anesthesia. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
Hyperkalemia: Elevations in serum potassium have been observed in patients treated with ACE inhibitors, including imidapril. Risk factors for the development of hyperkalemia include: Renal insufficiency or worsening of renal function; Age (> 70 years old); Diabetes mellitus; Intercurrent events (i.e., dehydration, acute decompensation, metabolic acidosis); Concomitant use of potassium salts, potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene) or potassium supplements or those patients taking other drugs associated with increases in serum potassium (e.g., heparin).
Diabetic Complications: The blood glucose levels should be closely monitored for hypoglycemia in diabetic patients previously treated with oral antidiabetic agents or insulin, particularly during the first month of treatment with an ACE inhibitor.
Hydrochlorothiazide: Fluid/Electrolyte Imbalance: Serum electrolytes should be monitored regularly. Patients should be observed for clinical signs of fluid or electrolyte imbalance (e.g., volume depletion, hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia). Warning signs or symptoms of fluid and electrolyte imbalance include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances including nausea and vomiting.
Hypokalemia may develop, particularly with brisk diuresis, when liver cirrhosis is present, or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Although any chloride deficit is generally mild and usually does not require specific treatment, except under extraordinary situations (e.g., liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis. Dilutional hyponatremia may be seen in edematous patients in hot weather. Appropriate treatment is water restriction rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. Appropriate replacement therapy is the treatment of choice in actual salt depletion.
Renal Impairment: Use with caution in patients with renal disease resulting in severe renal impairment because HCTZ decreases glomerular filtration rate and may precipitate azotemia.
Hepatic Impairment: Use with caution in patients with hepatic disease or progressive liver disease since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Hypersensitivity Reaction: Hypersensitivity reactions to HCTZ may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. As a sulfonamide derivative, HCTZ can cause skin rashes and blood dyscrasias.
Systemic Lupus Erythematosus: Exacerbation or activation of systemic lupus erythematosus has been associated with the use of thiazide diuretics.
Metabolic and Endocrine Effects: Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.
Thiazides may decrease urinary calcium excretion and may cause intermittent and slight elevation of serum calcium. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Discontinue thiazides before taking parathyroid function test.
Thiazide diuretic therapy may increase cholesterol and triglyceride levels.
Thiazides have been reported to increase the urinary excretion of magnesium. This may result in hypomagnesemia.
Hyperuricemia may occur or acute gout may be precipitated in certain patients taking thiazide therapy.
Cardiovascular Effects: The antihypertensive effects of HCTZ may be enhanced in postsympathectomy patients.
Acute Myopia and Secondary Angle-closure Glaucoma: HCTZ, a sulfonamide, can cause an idiosyncratic reaction, resulting in transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Non-melanoma Skin Cancer: An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of HCTZ exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.
Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC.
Effects on Ability to Drive and Use Machines: Imidapril + HCTZ, like other antihypertensives, may cause dizziness or fatigue. Patients should exercise caution when driving vehicles or operating machinery.
Imidapril Hydrochloride: Fetal Toxicity: The use of drugs that act on the renin-angiotensin-aldosterone system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue imidapril as soon as possible. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin-aldosterone system for a particular patient, apprise the mother of the potential risk to the fetus.
In patients taking imidapril during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. If oligohydramnios is observed, discontinue imidapril, unless it is considered lifesaving for the mother. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Closely observe infants with histories of in utero exposure to imidapril for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
Hypotension: Imidapril, like other ACE inhibitors, may cause a profound fall in blood pressure particularly after the first dose. Symptomatic hypotension is observed rarely in patients with uncomplicated hypertension. In hypertensive patients treated with imidapril, hypotension is more likely to occur if the patient has been volume-depleted (e.g., by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting). Symptomatic hypotension has also been observed in patients with heart failure (with or without associated renal insufficiency). This is most likely to occur in patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatremia or functional renal impairment. In these patients, treatment should be under medical supervision and patients should be monitored whenever the dose of imidapril and/or diuretic is adjusted. Apply similar considerations to patients with ischemic heart disease or cerebrovascular disease in whom an excessive fall in blood pressure may result in myocardial infarction or cerebrovascular accident.
If hypotension develops, place the patient in a supine position. Volume repletion with intravenous normal saline may be required. The appearance of hypotension after the initial dose does not preclude subsequent careful dose titration with imidapril after effective management.
Renovascular Hypertension: An increased risk of severe hypotension and renal impairment has been observed in patients with renovascular hypertension and pre-existing bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney treated with ACE inhibitors. Loss of renal function may occur with only mild changes in serum creatinine. Treatment of these patients should be under strict medical supervision, with low doses, careful titration, and monitoring of renal function.
Renal Impairment: Changes in renal function may be anticipated in susceptible individuals due to inhibition of the renin-angiotensin-aldosterone system. Thus, imidapril should be used with caution in patients with impaired renal function. Reduced doses are required for patients with creatinine clearance between 30 to 80 mL/min. Due to limited data, imidapril should not be given to patients with creatinine clearance <30 mL/min. Close monitoring of renal function during treatment should be performed. Renal failure associated with ACE inhibitors has been reported mainly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. Some patients, with no apparent pre-existing renal disease, have developed minor and usually transient elevations in blood urea and serum creatinine when imidapril was coadministered with a diuretic. Reduction in imidapril dosage and/or discontinuation of the diuretic may be necessary. This situation should raise the possibility of underlying renal artery stenosis.
Kidney Transplantation: There is no data on the use of imidapril in patients with recent kidney transplantation.
Hemodialysis: Anaphylactoid reactions such as facial swelling, flushing, hypotension, and dyspnea have been seen in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Consider giving a different type of dialysis membrane or a different class of antihypertensive agent in these patients.
Hepatic Impairment: Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Discontinue the ACE inhibitor and take appropriate medical measures if marked elevations of hepatic enzymes or jaundice occur.
Psoriasis: Imidapril, as with other ACE inhibitors, should be used with caution in patients with psoriasis.
Angioneurotic Edema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients receiving ACE inhibitors, including imidapril. Symptoms may occur at any time during treatment. In such cases, immediately discontinue imidapril and institute appropriate monitoring until complete and sustained resolution of symptoms has occurred. Angioedema associated with laryngeal edema or tongue edema may be fatal. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, particularly those with a history of airway surgery. Appropriate therapy, which may include subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures to ensure a patent airway, should be administered promptly. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor. Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors.
Anaphylactoid Reactions during Desensitization: There have been isolated reports of patients experiencing sustained, life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitization treatment with hymenoptera (bees, wasps) venom. Discontinue imidapril before desensitization treatment.
Anaphylactoid Reactions during LDL-Apheresis: Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL)-apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily discontinuing ACE inhibitor therapy prior to apheresis.
Aortic Stenosis/Hypertrophic Cardiomyopathy: Use with caution in patients with left ventricular valvular and outflow tract obstruction.
Neutropenia/Agranulocytosis: Neutropenia/agranulocytosis, thrombocytopenia and anemia have been observed rarely in patients receiving ACE inhibitors, including imidapril. Imidapril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections which in a few instances did not respond to intensive antibiotic therapy. If imidapril is used in such patients, white blood cell count and differential counts should be performed prior to therapy, every 2 weeks during the first 3 months of imidapril therapy, and periodically thereafter. Patients should be instructed to report any sign of infection (e.g., sore throat, fever) during treatment. If neutropenia (neutrophils <1000/mm3) is detected or suspected, imidapril and other concomitant medication should be discontinued. In most patients, neutrophil counts rapidly return to normal upon discontinuing imidapril therapy.
Cough: Persistent nonproductive cough has been reported with all ACE inhibitors, presumably due to the inhibition of the degradation of endogenous bradykinin. Cough always resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
Surgery/Anesthesia: There are no data available on the use of imidapril under conditions of surgery or anesthesia. However, like other ACE inhibitors, imidapril may cause hypotension or even hypotensive shock in patients undergoing major surgery or during anesthesia. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
Hyperkalemia: Elevations in serum potassium have been observed in patients treated with ACE inhibitors, including imidapril. Risk factors for the development of hyperkalemia include: Renal insufficiency or worsening of renal function; Age (> 70 years old); Diabetes mellitus; Intercurrent events (i.e., dehydration, acute decompensation, metabolic acidosis); Concomitant use of potassium salts, potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene) or potassium supplements or those patients taking other drugs associated with increases in serum potassium (e.g., heparin).
Diabetic Complications: The blood glucose levels should be closely monitored for hypoglycemia in diabetic patients previously treated with oral antidiabetic agents or insulin, particularly during the first month of treatment with an ACE inhibitor.
Hydrochlorothiazide: Fluid/Electrolyte Imbalance: Serum electrolytes should be monitored regularly. Patients should be observed for clinical signs of fluid or electrolyte imbalance (e.g., volume depletion, hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia). Warning signs or symptoms of fluid and electrolyte imbalance include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances including nausea and vomiting.
Hypokalemia may develop, particularly with brisk diuresis, when liver cirrhosis is present, or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Although any chloride deficit is generally mild and usually does not require specific treatment, except under extraordinary situations (e.g., liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis. Dilutional hyponatremia may be seen in edematous patients in hot weather. Appropriate treatment is water restriction rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. Appropriate replacement therapy is the treatment of choice in actual salt depletion.
Renal Impairment: Use with caution in patients with renal disease resulting in severe renal impairment because HCTZ decreases glomerular filtration rate and may precipitate azotemia.
Hepatic Impairment: Use with caution in patients with hepatic disease or progressive liver disease since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Hypersensitivity Reaction: Hypersensitivity reactions to HCTZ may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. As a sulfonamide derivative, HCTZ can cause skin rashes and blood dyscrasias.
Systemic Lupus Erythematosus: Exacerbation or activation of systemic lupus erythematosus has been associated with the use of thiazide diuretics.
Metabolic and Endocrine Effects: Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.
Thiazides may decrease urinary calcium excretion and may cause intermittent and slight elevation of serum calcium. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Discontinue thiazides before taking parathyroid function test.
Thiazide diuretic therapy may increase cholesterol and triglyceride levels.
Thiazides have been reported to increase the urinary excretion of magnesium. This may result in hypomagnesemia.
Hyperuricemia may occur or acute gout may be precipitated in certain patients taking thiazide therapy.
Cardiovascular Effects: The antihypertensive effects of HCTZ may be enhanced in postsympathectomy patients.
Acute Myopia and Secondary Angle-closure Glaucoma: HCTZ, a sulfonamide, can cause an idiosyncratic reaction, resulting in transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Non-melanoma Skin Cancer: An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of HCTZ exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.
Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC.
Effects on Ability to Drive and Use Machines: Imidapril + HCTZ, like other antihypertensives, may cause dizziness or fatigue. Patients should exercise caution when driving vehicles or operating machinery.
Use In Pregnancy & Lactation
ACE inhibitors should not be used during pregnancy. When pregnancy is diagnosed, immediately discontinue treatment with ACE inhibitors, and, if appropriate, alternative treatment should be started.
Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions that have occurred in adults.
Lactation: Imidapril, as with other ACE inhibitors, may be excreted in human milk. Thiazides appear in human milk. Discontinue breastfeeding or drug due to potential risk to breastfeeding infants, taking into consideration the importance of the drug to the mother.
Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions that have occurred in adults.
Lactation: Imidapril, as with other ACE inhibitors, may be excreted in human milk. Thiazides appear in human milk. Discontinue breastfeeding or drug due to potential risk to breastfeeding infants, taking into consideration the importance of the drug to the mother.
Adverse Reactions
Imidapril hydrochloride: Infections and infestations: Viral infection.
Blood and lymphatic system disorders: Agranulocytosis, anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia; individual cases of hemolytic anemia in patients with congenital deficiency of glucose-6-phosphate dehydrogenase (G6PD) have been reported with other ACE inhibitors.
Metabolism and nutrition disorders: Anorexia, hyperkalemia, hypoglycemia, thirst.
Psychiatric disorders: Depression, insomnia, sleep disorders, sleepiness.
Nervous system disorders: Cerebral hemorrhage, cerebrovascular disorders, confusion, disorder of balance, dizziness/postural dizziness, dysgeusia, headache, lightheadedness, paresthesia, somnolence, syncope, taste disturbance.
Eye disorders: Blurred vision.
Ear and labyrinth disorders: Tinnitus.
Cardiac disorders: Angina pectoris, arrhythmia, myocardial infarction, palpitations, tachycardia.
Vascular disorders: Severe hypotension after initiation of therapy or increase of dose; dizziness, feeling of weakness, impaired vision, and disturbance of consciousness (syncope) can also occur in association with hypotension; facial flushing, transient ischemic attack.
Respiratory, thoracic and mediastinal disorders: Cough, allergic alveolitis/eosinophilic pneumonia (very rare), angioedema involving the upper airways, bronchitis, bronchospasm, dyspnea, glossitis, hoarseness, pharynx discomfort, rhinitis, sinusitis, upper respiratory tract infection.
Gastrointestinal disorders: Abdominal pain, constipation, diarrhea, dry mouth, dyspepsia, epigastric pain, gastritis, ileus, intestinal angioedema, nausea, pancreatitis, queasy, stomach discomfort, vomiting.
Hepatobiliary disorders: Cholestatic icterus, hepatitis, jaundice.
Skin and subcutaneous tissue disorders: Allergic and hypersensitivity reactions such as rash, pruritus, exanthema, and urticaria; angioneurotic edema involving the face and oropharyngeal tissues; cutaneous symptoms accompanied by fever, myalgia, arthralgia, eosinophilia and/or increased antinuclear antibody (ANA) titers; alopecia, erythema multiforme, exfoliative dermatitis, pemphigus-like symptoms, photosensitivity reactions, psoriasis-like efflorescences, Stevens-Johnson syndrome, toxic epidermal necrolysis, blisters.
Renal and urinary disorders: Acute renal failure, aggravation of renal function disorder, renal impairment, proteinuria.
General disorders and administration site conditions: Chest discomfort, chest pain, edema (joint, peripheral), fatigue, feeling of weakness, malaise, numbness, pain in limbs, weariness.
Reproductive system and breast disorders: Impotence.
Investigations: Increased blood amylase, blood urea nitrogen, plasma creatinine, serum potassium, liver enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), γ-glutamyl transpeptidase (γ-GTP), serum bilirubin, creatine phosphokinase (CPK), eosinophil; decreased albumin, serum protein, erythrocyte, thrombocyte, leukocyte, hemoglobin, hematocrit, platelets, white blood cell count.
Hydrochlorothiazide: Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).
Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia, bone marrow failure, granulocytopenia (rare), hemolytic anemia, leukopenia, neutropenia, thrombocytopenia.
Immune system disorders: Hypersensitivity reactions, anaphylactic reactions.
Endocrine disorders: Worsening of diabetic control.
Metabolism and nutrition disorders: Anorexia, decreased appetite, electrolyte imbalance, hypercalcemia, hypercholesterolemia, hyperglycemia, hyperuricemia, hypochloremic alkalosis, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypovolemia.
Psychiatric disorders: Insomnia, nervousness.
Nervous system disorders: Cephalgia, dizziness, headache, lightheadedness, paresthesia, restlessness, vertigo .
Eye disorders: Acute myopia, secondary angle-closure glaucoma, transient blurred vision, visual impairment, xanthopsia.
Cardiac disorders: Cardiac arrhythmias.
Vascular disorders: Hypotension/orthostatic hypotension.
Respiratory, thoracic and mediastinal disorders: Respiratory distress (including pneumonitis and pulmonary edema).
Gastrointestinal disorders: Constipation, cramping, diarrhea, gastric irritation, gastrointestinal discomfort, nausea, pancreatitis, sialadenitis, spasms, vomiting.
Hepatobiliary disorders: Jaundice (intrahepatic cholestatic jaundice).
Skin and subcutaneous tissue disorders: Alopecia, cutaneous lupus erythematosus, erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, necrotizing angiitis (vasculitis and cutaneous vasculitis), photosensitivity reactions, purpura, rash, reactivation of cutaneous lupus erythematosus, urticaria.
Musculoskeletal and connective tissue disorders: Muscle cramps, muscle spasm.
Renal and urinary disorders: Glycosuria, interstitial nephritis, renal dysfunction, renal failure.
Reproductive system and breast disorders: Impotence.
General disorders and administration site conditions: Asthenia, fever, weakness.
Investigations: Increased total cholesterol, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C) and triglycerides.
Blood and lymphatic system disorders: Agranulocytosis, anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia; individual cases of hemolytic anemia in patients with congenital deficiency of glucose-6-phosphate dehydrogenase (G6PD) have been reported with other ACE inhibitors.
Metabolism and nutrition disorders: Anorexia, hyperkalemia, hypoglycemia, thirst.
Psychiatric disorders: Depression, insomnia, sleep disorders, sleepiness.
Nervous system disorders: Cerebral hemorrhage, cerebrovascular disorders, confusion, disorder of balance, dizziness/postural dizziness, dysgeusia, headache, lightheadedness, paresthesia, somnolence, syncope, taste disturbance.
Eye disorders: Blurred vision.
Ear and labyrinth disorders: Tinnitus.
Cardiac disorders: Angina pectoris, arrhythmia, myocardial infarction, palpitations, tachycardia.
Vascular disorders: Severe hypotension after initiation of therapy or increase of dose; dizziness, feeling of weakness, impaired vision, and disturbance of consciousness (syncope) can also occur in association with hypotension; facial flushing, transient ischemic attack.
Respiratory, thoracic and mediastinal disorders: Cough, allergic alveolitis/eosinophilic pneumonia (very rare), angioedema involving the upper airways, bronchitis, bronchospasm, dyspnea, glossitis, hoarseness, pharynx discomfort, rhinitis, sinusitis, upper respiratory tract infection.
Gastrointestinal disorders: Abdominal pain, constipation, diarrhea, dry mouth, dyspepsia, epigastric pain, gastritis, ileus, intestinal angioedema, nausea, pancreatitis, queasy, stomach discomfort, vomiting.
Hepatobiliary disorders: Cholestatic icterus, hepatitis, jaundice.
Skin and subcutaneous tissue disorders: Allergic and hypersensitivity reactions such as rash, pruritus, exanthema, and urticaria; angioneurotic edema involving the face and oropharyngeal tissues; cutaneous symptoms accompanied by fever, myalgia, arthralgia, eosinophilia and/or increased antinuclear antibody (ANA) titers; alopecia, erythema multiforme, exfoliative dermatitis, pemphigus-like symptoms, photosensitivity reactions, psoriasis-like efflorescences, Stevens-Johnson syndrome, toxic epidermal necrolysis, blisters.
Renal and urinary disorders: Acute renal failure, aggravation of renal function disorder, renal impairment, proteinuria.
General disorders and administration site conditions: Chest discomfort, chest pain, edema (joint, peripheral), fatigue, feeling of weakness, malaise, numbness, pain in limbs, weariness.
Reproductive system and breast disorders: Impotence.
Investigations: Increased blood amylase, blood urea nitrogen, plasma creatinine, serum potassium, liver enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), γ-glutamyl transpeptidase (γ-GTP), serum bilirubin, creatine phosphokinase (CPK), eosinophil; decreased albumin, serum protein, erythrocyte, thrombocyte, leukocyte, hemoglobin, hematocrit, platelets, white blood cell count.
Hydrochlorothiazide: Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).
Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia, bone marrow failure, granulocytopenia (rare), hemolytic anemia, leukopenia, neutropenia, thrombocytopenia.
Immune system disorders: Hypersensitivity reactions, anaphylactic reactions.
Endocrine disorders: Worsening of diabetic control.
Metabolism and nutrition disorders: Anorexia, decreased appetite, electrolyte imbalance, hypercalcemia, hypercholesterolemia, hyperglycemia, hyperuricemia, hypochloremic alkalosis, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypovolemia.
Psychiatric disorders: Insomnia, nervousness.
Nervous system disorders: Cephalgia, dizziness, headache, lightheadedness, paresthesia, restlessness, vertigo .
Eye disorders: Acute myopia, secondary angle-closure glaucoma, transient blurred vision, visual impairment, xanthopsia.
Cardiac disorders: Cardiac arrhythmias.
Vascular disorders: Hypotension/orthostatic hypotension.
Respiratory, thoracic and mediastinal disorders: Respiratory distress (including pneumonitis and pulmonary edema).
Gastrointestinal disorders: Constipation, cramping, diarrhea, gastric irritation, gastrointestinal discomfort, nausea, pancreatitis, sialadenitis, spasms, vomiting.
Hepatobiliary disorders: Jaundice (intrahepatic cholestatic jaundice).
Skin and subcutaneous tissue disorders: Alopecia, cutaneous lupus erythematosus, erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, necrotizing angiitis (vasculitis and cutaneous vasculitis), photosensitivity reactions, purpura, rash, reactivation of cutaneous lupus erythematosus, urticaria.
Musculoskeletal and connective tissue disorders: Muscle cramps, muscle spasm.
Renal and urinary disorders: Glycosuria, interstitial nephritis, renal dysfunction, renal failure.
Reproductive system and breast disorders: Impotence.
General disorders and administration site conditions: Asthenia, fever, weakness.
Investigations: Increased total cholesterol, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C) and triglycerides.
Drug Interactions
Imidapril hydrochloride: Potassium-sparing diuretics/potassium supplements/salt substitutes: May lead to significant increases in serum potassium. Use with caution and monitor serum potassium frequently.
Nonsteroidal anti-inflammatory drugs [NSAIDs, i.e., selective cyclooxygenase-2 inhibitors (COX-2) inhibitors, aspirin >3 g/day]: Reduced antihypertensive effect of imidapril. Concurrent administration of ACE inhibitors and NSAIDs may result in an increased risk of worsening of renal function (including possible acute renal failure) and an increase in serum potassium, particularly in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Regularly monitor renal function after initiation of concomitant therapy and adequately hydrate patients.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): Dual blockade of the RAAS with ACE inhibitors, angiotensin II receptor antagonists or aliskiren is associated with increased risk of hypotension, hyperkalemia and changes in renal function (including acute renal failure) compared with monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on imidapril and other agents that affect the RAAS. Do not coadminister imidapril with aliskiren in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m2). Avoid concomitant use of ACE inhibitors and angiotensin II receptor antagonists in patients with diabetic nephropathy.
Non-potassium-sparing diuretics: Risk of sudden hypotension and/or acute renal impairment. Discontinue the diuretic before initiating imidapril, or initiate with a lower dose of imidapril and increase progressively. The diuretic can be reintroduced thereafter. Monitor renal function during the first few weeks of therapy.
Lithium: May decrease lithium excretion leading to lithium toxicity. Monitor serum lithium levels frequently.
Antidiabetic agents (e.g., insulin, hypoglycemic agents): ACE inhibitors may increase the hypoglycemic effect in diabetic patients receiving insulin or hypoglycemic agents.
Tricyclic antidepressants, neuroleptics: Increased antihypertensive effect and risk of orthostatic hypotension.
Rifampicin: May decrease the antihypertensive effect of imidapril.
Antacids: May decrease imidapril bioavailability.
Sympathomimetics: May decrease the antihypertensive effects of ACE inhibitors; patients should be carefully monitored to confirm that the desired effect is obtained.
Gold (sodium aurothiomalate): Nitroid reactions (including facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients receiving concomitant therapy with ACE inhibitor and injectable gold.
Neprilysin (NEP) inhibitors (e.g., sacubitril, racecadotril): Concomitant inhibition of NEP and ACE may increase the risk of angioedema. Sacubitril/valsartan must not be administered until 36 hours after discontinuing imidapril therapy. Imidapril therapy must not be started until 36 hours after the last dose of sacubitril/valsartan. Concomitant use of other NEP inhibitors (e.g., racecadotril) and imidapril may also increase the risk of angioedema. A careful benefit-risk assessment is needed before initiating treatment with NEP inhibitors in patients on imidapril.
Other antihypertensive agents and vasodilators (e.g., nitroglycerin, nitrates): Increased blood pressure lowering effect of imidapril.
Hydrochlorothiazide: Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension.
Amantadine: Increased risk of adverse effects.
Aminoglycoside antibiotics: Diuretic-induced volume depletion can potentiate aminoglycoside nephrotoxicity.
Anticholinergic agents (e.g., atropine, biperidine): May increase availability of thiazide diuretics by decreasing gastrointestinal motility and stomach emptying rate.
Antidiabetic agents (e.g., insulin, hypoglycemic agents): Dosage adjustment of the antidiabetic agent may be necessary as thiazides may impair glucose tolerance.
Diazoxide: May enhance the hyperglycemic effect of diazoxide.
Antigout (e.g., probenecid, sulfinpyrazone, allopurinol): Dosage adjustment of the antigout medication may be necessary as HCTZ may raise level of serum uric acid; may increase hypersensitivity reaction with allopurinol.
Calcium salts, Vitamin D supplements: Increased serum calcium levels due to decreased excretion.
Carbamazepine: Symptomatic hyponatremia may occur. Monitor electrolytes during concomitant use.
Cardiac glycosides (e.g., digitalis): Thiazide-induced hypokalemia or hypomagnesemia may favor the onset of digitalis-induced cardiac arrhythmias.
Cholestyramine and colestipol resins: HCTZ absorption is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind HCTZ and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.
Corticosteroids, ACTH, amphotericin B (parenteral), stimulant laxative, or glycyrrhizin (found in licorice): Intensified electrolyte depletion/electrolyte imbalance, particularly hypokalemia.
Cytotoxic agents (e.g., cyclophosphamide, methotrexate): Decreased renal excretion; increased myelosuppressive effects.
Ciclosporin: May increase the risk of hyperuricemia and gout-type complications.
Lithium: Increased serum lithium concentrations and increased risk of lithium toxicity. Monitor serum lithium levels during concomitant use.
Pressor amines (e.g., epinephrine): Possible decreased response to pressor amines but not sufficient to prevent their use.
NSAIDs including COX-2 Inhibitors: May reduce the diuretic, natriuretic and antihypertensive effects of diuretics in some patients.
Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant.
Selective serotonin reuptake inhibitors (e.g., citalopram, escitalopram, sertraline): May potentiate hyponatremia.
Topiramate: May increase topiramate serum concentrations; additive hypokalemia.
Iodinated contrast media: Increased risk of acute renal failure particularly when large doses of iodinated media are used.
Other antihypertensive agents: Additive effect.
Nonsteroidal anti-inflammatory drugs [NSAIDs, i.e., selective cyclooxygenase-2 inhibitors (COX-2) inhibitors, aspirin >3 g/day]: Reduced antihypertensive effect of imidapril. Concurrent administration of ACE inhibitors and NSAIDs may result in an increased risk of worsening of renal function (including possible acute renal failure) and an increase in serum potassium, particularly in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Regularly monitor renal function after initiation of concomitant therapy and adequately hydrate patients.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): Dual blockade of the RAAS with ACE inhibitors, angiotensin II receptor antagonists or aliskiren is associated with increased risk of hypotension, hyperkalemia and changes in renal function (including acute renal failure) compared with monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on imidapril and other agents that affect the RAAS. Do not coadminister imidapril with aliskiren in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m2). Avoid concomitant use of ACE inhibitors and angiotensin II receptor antagonists in patients with diabetic nephropathy.
Non-potassium-sparing diuretics: Risk of sudden hypotension and/or acute renal impairment. Discontinue the diuretic before initiating imidapril, or initiate with a lower dose of imidapril and increase progressively. The diuretic can be reintroduced thereafter. Monitor renal function during the first few weeks of therapy.
Lithium: May decrease lithium excretion leading to lithium toxicity. Monitor serum lithium levels frequently.
Antidiabetic agents (e.g., insulin, hypoglycemic agents): ACE inhibitors may increase the hypoglycemic effect in diabetic patients receiving insulin or hypoglycemic agents.
Tricyclic antidepressants, neuroleptics: Increased antihypertensive effect and risk of orthostatic hypotension.
Rifampicin: May decrease the antihypertensive effect of imidapril.
Antacids: May decrease imidapril bioavailability.
Sympathomimetics: May decrease the antihypertensive effects of ACE inhibitors; patients should be carefully monitored to confirm that the desired effect is obtained.
Gold (sodium aurothiomalate): Nitroid reactions (including facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients receiving concomitant therapy with ACE inhibitor and injectable gold.
Neprilysin (NEP) inhibitors (e.g., sacubitril, racecadotril): Concomitant inhibition of NEP and ACE may increase the risk of angioedema. Sacubitril/valsartan must not be administered until 36 hours after discontinuing imidapril therapy. Imidapril therapy must not be started until 36 hours after the last dose of sacubitril/valsartan. Concomitant use of other NEP inhibitors (e.g., racecadotril) and imidapril may also increase the risk of angioedema. A careful benefit-risk assessment is needed before initiating treatment with NEP inhibitors in patients on imidapril.
Other antihypertensive agents and vasodilators (e.g., nitroglycerin, nitrates): Increased blood pressure lowering effect of imidapril.
Hydrochlorothiazide: Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension.
Amantadine: Increased risk of adverse effects.
Aminoglycoside antibiotics: Diuretic-induced volume depletion can potentiate aminoglycoside nephrotoxicity.
Anticholinergic agents (e.g., atropine, biperidine): May increase availability of thiazide diuretics by decreasing gastrointestinal motility and stomach emptying rate.
Antidiabetic agents (e.g., insulin, hypoglycemic agents): Dosage adjustment of the antidiabetic agent may be necessary as thiazides may impair glucose tolerance.
Diazoxide: May enhance the hyperglycemic effect of diazoxide.
Antigout (e.g., probenecid, sulfinpyrazone, allopurinol): Dosage adjustment of the antigout medication may be necessary as HCTZ may raise level of serum uric acid; may increase hypersensitivity reaction with allopurinol.
Calcium salts, Vitamin D supplements: Increased serum calcium levels due to decreased excretion.
Carbamazepine: Symptomatic hyponatremia may occur. Monitor electrolytes during concomitant use.
Cardiac glycosides (e.g., digitalis): Thiazide-induced hypokalemia or hypomagnesemia may favor the onset of digitalis-induced cardiac arrhythmias.
Cholestyramine and colestipol resins: HCTZ absorption is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind HCTZ and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.
Corticosteroids, ACTH, amphotericin B (parenteral), stimulant laxative, or glycyrrhizin (found in licorice): Intensified electrolyte depletion/electrolyte imbalance, particularly hypokalemia.
Cytotoxic agents (e.g., cyclophosphamide, methotrexate): Decreased renal excretion; increased myelosuppressive effects.
Ciclosporin: May increase the risk of hyperuricemia and gout-type complications.
Lithium: Increased serum lithium concentrations and increased risk of lithium toxicity. Monitor serum lithium levels during concomitant use.
Pressor amines (e.g., epinephrine): Possible decreased response to pressor amines but not sufficient to prevent their use.
NSAIDs including COX-2 Inhibitors: May reduce the diuretic, natriuretic and antihypertensive effects of diuretics in some patients.
Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant.
Selective serotonin reuptake inhibitors (e.g., citalopram, escitalopram, sertraline): May potentiate hyponatremia.
Topiramate: May increase topiramate serum concentrations; additive hypokalemia.
Iodinated contrast media: Increased risk of acute renal failure particularly when large doses of iodinated media are used.
Other antihypertensive agents: Additive effect.
Storage
Store at temperatures not exceeding 30°C.
Action
Angiotensin-converting enzyme (ACE) inhibitor, diuretic, antihypertensive.
Pharmacology: Pharmacodynamics: Imidapril HCl: Imidapril is an ester prodrug which is hydrolyzed after oral administration to form the active ACE inhibitor imidaprilat. Imidaprilat has potent ACE inhibitory effects, 1.2 times and 2.6 times that of enalaprilat and captopril, respectively.
The blood pressure lowering effect of imidapril is mainly due to ACE inhibition and consequent reduction in angiotensin II, resulting in dilatation of peripheral vessels and reduction in vascular resistance. The blood pressure lowering effect of imidapril is comparable to enalapril and 5-10 times more potent than that of captopril.
Imidapril decreases total peripheral vascular resistance without an increase in heart rate or cardiac contractility. Imidapril increases renal blood flow and reduces renal vascular resistance mainly due to dilatation of the efferent arteriole. Imidapril showed no specific effect on the central nervous, digestive, respiratory, smooth muscle, reproductive, urologic, hematologic and metabolic systems.
Hydrochlorothiazide: Hydrochlorothiazide (HCTZ), a thiazide diuretic, increases the excretion of water by inhibiting the reabsorption of sodium and chloride ions at the distal renal tubule. The excretion of potassium and magnesium is also increased while the elimination of calcium and uric acid is decreased. Thiazide diuretics usually do not affect the normal blood pressure. When chronically administered, thiazide diuretics decrease peripheral vascular resistance. The exact mechanism responsible for lowered peripheral resistance is not known; however, excretion of urinary sodium by the kidneys is required to achieve blood pressure reduction.
Indirectly, the diuretic action of HCTZ reduces plasma volume, with consequent increases in plasma renin activity, aldosterone secretion, urinary potassium loss and decreased serum potassium.
Diuresis begins with 2 hrs, peaks in about 4 hrs and lasts about 6-12 hrs after oral administration of HCTZ.
Pharmacokinetics: Imidapril HCl: About 70% of imidapril is absorbed from the gastrointestinal tract and reaches peak plasma concentration (Cmax) within 2 hrs after oral administration. Plasma imidapril concentrations decline monophasically with a t½ of about 2 hrs. A fat-rich meal significantly decreases imidapril absorption.
Imidapril undergoes de-esterification in the liver to form imidaprilat. Peak plasma imidaprilat concentrations are reached within 7 hrs, and decline biphasically with an initial t½ of 7-9 hrs and a terminal t½ of >24 hrs. The absolute bioavailability of imidaprilat is 42%. After multiple dosing, steady state imidaprilat concentrations are reached after 5 days. Protein-binding of imidapril and imidaprilat is 85% and 53%, respectively.
After single oral dosing, imidapril absorption appeared linear with doses of 10-240 mg based on plasma and urinary excretion data. Drug elimination is primarily via renal (40%) and hepatobiliary (50%) routes.
Hydrochlorothiazide: Hydrochlorothiazide is well absorbed from the gastrointestinal tract. Oral bioavailability is approximately 65-75%. After oral administration of HCTZ at doses of 12.5-100 mg, Cmax of 70-490 ng/mL are observed within 1-5 hrs of dosing.
Approximately 40-60% of the drug is bound to plasma proteins. HCTZ crosses the placenta, but not the blood-brain barrier and is distributed in breast milk. It appears to be preferentially bound to red blood cells.
HCTZ is not metabolized but is eliminated rapidly as unchanged drug in the urine. HCTZ's plasma half-life ranged from 5.6 to 15 hours when plasma levels were followed for at least 24 hours. At least 61% of an oral dose is eliminated unchanged within 24 hours.
Special Populations: Renal Impairment: Increased plasma levels and area under the curve (AUC) of imidapril and imidaprilat were reported in patients with renal impairment. There was a two-fold increase in the AUC of imidaprilat in patients with creatinine clearance 30 to 80 mL/min and an almost ten-fold increase in patients with creatinine clearance 10 to 29 mL/min.
In patients with renal impairment (mean creatinine clearance of 19 mL/min), the elimination half-life of HCTZ was prolonged to 20.7 hours.
Hepatic Impairment: In patients with hepatic impairment, the AUC of imidapril and imidaprilat were slightly higher than in normal subjects while the time to peak plasma concentration (Tmax) for both was similar in the two groups. The half-life of imidaprilat, but not that of imidapril, was significantly increased in patients with hepatic impairment.
Monitor patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Pharmacology: Pharmacodynamics: Imidapril HCl: Imidapril is an ester prodrug which is hydrolyzed after oral administration to form the active ACE inhibitor imidaprilat. Imidaprilat has potent ACE inhibitory effects, 1.2 times and 2.6 times that of enalaprilat and captopril, respectively.
The blood pressure lowering effect of imidapril is mainly due to ACE inhibition and consequent reduction in angiotensin II, resulting in dilatation of peripheral vessels and reduction in vascular resistance. The blood pressure lowering effect of imidapril is comparable to enalapril and 5-10 times more potent than that of captopril.
Imidapril decreases total peripheral vascular resistance without an increase in heart rate or cardiac contractility. Imidapril increases renal blood flow and reduces renal vascular resistance mainly due to dilatation of the efferent arteriole. Imidapril showed no specific effect on the central nervous, digestive, respiratory, smooth muscle, reproductive, urologic, hematologic and metabolic systems.
Hydrochlorothiazide: Hydrochlorothiazide (HCTZ), a thiazide diuretic, increases the excretion of water by inhibiting the reabsorption of sodium and chloride ions at the distal renal tubule. The excretion of potassium and magnesium is also increased while the elimination of calcium and uric acid is decreased. Thiazide diuretics usually do not affect the normal blood pressure. When chronically administered, thiazide diuretics decrease peripheral vascular resistance. The exact mechanism responsible for lowered peripheral resistance is not known; however, excretion of urinary sodium by the kidneys is required to achieve blood pressure reduction.
Indirectly, the diuretic action of HCTZ reduces plasma volume, with consequent increases in plasma renin activity, aldosterone secretion, urinary potassium loss and decreased serum potassium.
Diuresis begins with 2 hrs, peaks in about 4 hrs and lasts about 6-12 hrs after oral administration of HCTZ.
Pharmacokinetics: Imidapril HCl: About 70% of imidapril is absorbed from the gastrointestinal tract and reaches peak plasma concentration (Cmax) within 2 hrs after oral administration. Plasma imidapril concentrations decline monophasically with a t½ of about 2 hrs. A fat-rich meal significantly decreases imidapril absorption.
Imidapril undergoes de-esterification in the liver to form imidaprilat. Peak plasma imidaprilat concentrations are reached within 7 hrs, and decline biphasically with an initial t½ of 7-9 hrs and a terminal t½ of >24 hrs. The absolute bioavailability of imidaprilat is 42%. After multiple dosing, steady state imidaprilat concentrations are reached after 5 days. Protein-binding of imidapril and imidaprilat is 85% and 53%, respectively.
After single oral dosing, imidapril absorption appeared linear with doses of 10-240 mg based on plasma and urinary excretion data. Drug elimination is primarily via renal (40%) and hepatobiliary (50%) routes.
Hydrochlorothiazide: Hydrochlorothiazide is well absorbed from the gastrointestinal tract. Oral bioavailability is approximately 65-75%. After oral administration of HCTZ at doses of 12.5-100 mg, Cmax of 70-490 ng/mL are observed within 1-5 hrs of dosing.
Approximately 40-60% of the drug is bound to plasma proteins. HCTZ crosses the placenta, but not the blood-brain barrier and is distributed in breast milk. It appears to be preferentially bound to red blood cells.
HCTZ is not metabolized but is eliminated rapidly as unchanged drug in the urine. HCTZ's plasma half-life ranged from 5.6 to 15 hours when plasma levels were followed for at least 24 hours. At least 61% of an oral dose is eliminated unchanged within 24 hours.
Special Populations: Renal Impairment: Increased plasma levels and area under the curve (AUC) of imidapril and imidaprilat were reported in patients with renal impairment. There was a two-fold increase in the AUC of imidaprilat in patients with creatinine clearance 30 to 80 mL/min and an almost ten-fold increase in patients with creatinine clearance 10 to 29 mL/min.
In patients with renal impairment (mean creatinine clearance of 19 mL/min), the elimination half-life of HCTZ was prolonged to 20.7 hours.
Hepatic Impairment: In patients with hepatic impairment, the AUC of imidapril and imidaprilat were slightly higher than in normal subjects while the time to peak plasma concentration (Tmax) for both was similar in the two groups. The half-life of imidaprilat, but not that of imidapril, was significantly increased in patients with hepatic impairment.
Monitor patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
MedsGo Class
ACE Inhibitors/Direct Renin Inhibitors / Diuretics
Features
Brand
Norplus
Full Details
Dosage Strength
10 mg / 12.5 mg
Drug Ingredients
- Hydrochlorothiazide
- Imidapril
Drug Packaging
Tablet 1's
Generic Name
Imidapril Hydrochloride / Hydrochlorothiazide
Dosage Form
Tablet
Registration Number
DRP-10045
Drug Classification
Prescription Drug (RX)
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