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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.
