Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1537
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Accupril (Tablet, Film Coated)
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Hypertension:<br/>Monotherapy: The recommended initial dosage of ACCUPRIL in patients not on diuretics is 10 or 20 mg once daily. Dosage should be adjusted according to blood pressure response measured at peak (2���6 hours after dosing) and trough (predosing). Generally, dosage adjustments should be made at intervals of at least 2 weeks. Most patients have required dosages of 20, 40, or 80 mg/day, given as a single dose or in two equally divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients an increase in dosage or twice daily administration may be warranted. In general, doses of 40���80 mg and divided doses give a somewhat greater effect at the end of the dosing interval.<br/>Concomitant Diuretics: If blood pressure is not adequately controlled with ACCUPRIL monotherapy, a diuretic may be added. In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of ACCUPRIL. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued 2 to 3 days prior to beginning therapy with ACCUPRIL . Then, if blood pressure is not controlled with ACCUPRIL alone, diuretic therapy should be resumed. If the diuretic cannot be discontinued, an initial dose of 5 mg ACCUPRIL should be used with careful medical supervision for several hours and until blood pressure has stabilized. The dosage should subsequently be titrated (as described above) to the optimal response .<br/>Renal Impairment: Kinetic data indicate that the apparent elimination half-life of quinaprilat increases as creatinine clearance decreases. Recommended starting doses, based on clinical and pharmacokinetic data from patients with renal impairment, are as follows: Patients should subsequently have their dosage titrated (as described above) to the optimal response.<br/>Elderly (���65 years): The recommended initial dosage of ACCUPRIL in elderly patients is 10 mg given once daily followed by titration (as described above) to the optimal response.<br/>Heart Failure: ACCUPRIL is indicated as adjunctive therapy when added to conventional therapy including diuretics and/or digitalis. The recommended starting dose is 5 mg twice daily. This dose may improve symptoms of heart failure, but increases in exercise duration have generally required higher doses. Therefore, if the initial dosage of ACCUPRIL is well tolerated, patients should then be titrated at weekly intervals until an effective dose, usually 20 to 40 mg daily given in two equally divided doses, is reached or undesirable hypotension, orthostatis, or azotemia prohibit reaching this dose. Following the initial dose of ACCUPRIL, the patient should be observed under medical supervision for at least two hours for the presence of hypotension or orthostatis and, if present, until blood pressure stabilizes. The appearance of hypotension, orthostatis, or azotemia early in dose titration should not preclude further careful dose titration. Consideration should be given to reducing the dose of concomitant diuretics.<br/>DOSE ADJUSTMENTS IN PATIENTS WITH HEART FAILURE AND RENAL IMPAIRMENT OR HYPONATREMIA: Pharmacokinetic data indicate that quinapril elimination is dependent on level of renal function. In patients with heart failure and renal impairment, the recommended initial dose of ACCUPRIL is 5 mg in patients with a creatinine clearance above 30 mL/min and 2.5 mg in patients with a creatinine clearance of 10 to 30 mL/min. There is insufficient data for dosage recommendation in patients with a creatinine clearance less than 10 mL/min . If the initial dose is well tolerated, ACCUPRIL may be administered the following day as a twice daily regimen. In the absence of excessive hypotension or significant deterioration of renal function, the dose may be increased at weekly intervals based on clinical and hemodynamic response.
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ACCUPRIL' (quinapril hydrochloride) is the hydrochloride salt of quinapril, the ethyl ester of a non-sulfhydryl, angiotensin-converting enzyme (ACE) inhibitor, quinaprilat. Quinapril hydrochloride is chemically described as [3S-[2[R*(R*)], 3R*]]-2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, monohydrochloride. Its empirical formula is CHNO���HCl and its structural formula is: Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in aqueous solvents. ACCUPRIL tablets contain 5 mg, 10 mg, 20 mg, or 40 mg of quinapril for oral administration. Each tablet also contains candelilla wax, crospovidone, gelatin, lactose, magnesium carbonate, magnesium stearate, synthetic red iron oxide, and titanium dioxide.
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Mechanism of Action: Quinapril is deesterified to the principal metabolite, quinaprilat, which is an inhibitor of ACE activity in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of quinapril in hypertension and in congestive heart failure (CHF) appears to result primarily from the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation.Quinapril inhibits the elevation in blood pressure caused by intravenously administered angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine or epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex, thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by quinapril may result in a small increase in serum potassium. In controlled hypertension trials, treatment with ACCUPRIL alone resulted in mean increases in potassium of 0.07 mmol/L . Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA). While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with low renin hypertension. ACCUPRIL was an effective antihypertensive in all races studied, although it was somewhat less effective in blacks (usuallya predominantly low renin group) than in nonblacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of quinapril remains to be elucidated.<br/>Pharmacokinetics and Metabolism: Following oral administration, peak plasma quinapril concentrations are observed within one hour. Based on recovery of quinapril and its metabolites in urine, the extent of absorption is at least 60%. The rate and extent of quinapril absorption are diminished moderately (approximately 25���30%) when ACCUPRIL tablets are administered during a high-fat meal. Following absorption, quinapril is deesterified to its major active metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites. Following multiple oral dosing of ACCUPRIL, there is an effective accumulation half-life of quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed approximately 2 hours post-dose. Quinaprilat is eliminated primarily by renal excretion, up to 96% of an IV dose, and has an elimination half-life in plasma of approximately 2 hours and a prolonged terminal phase with a half-life of 25 hours. The pharmacokinetics of quinapril and quinaprilat are linear over a single-dose range of 5���80 mg doses and 40���160 mg in multiple daily doses. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins. In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine clearance decreases. There is a linear correlation between plasma quinaprilat clearance and creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or continuous ambulatory peritoneal dialysis has little effect on the elimination of quinapril and quinaprilat. Elimination of quinaprilat may be reduced in elderly patients (���65 years) and in those with heart failure; this reduction is attributable to decrease in renal function . Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril. Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier.<br/>Pharmacodynamics and Clinical Effects:<br/>Hypertension: Single doses of 20 mg of ACCUPRIL provide over 80% inhibition of plasma ACE for 24 hours. Inhibition of the pressor response to angiotensin I is shorter-lived, with a 20 mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20% inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of angiotensin II levels at 24 hours by doses of 20���80 mg. Administration of 10 to 80 mg of ACCUPRIL to patients with mild to severe hypertension results in a reduction of sitting and standing blood pressure to about the same extent with minimal effect on heart rate. Symptomatic postural hypotension is infrequent although it can occur in patients who are salt-and/or volume-depleted . Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is obtained in 1���2 weeks. In multiple-dose studies, 10���80 mg per day in single or divided doses lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect of about 5���11/3���7 mm Hg. The trough effect represents about 50% of the peak effect. While the dose-response relationship is relatively flat, doses of 40���80 mg were somewhat more effective at trough than 10���20 mg, and twice daily dosing tended to give a somewhat lower trough blood pressure than once daily dosing with the same total dose. The antihypertensive effect of ACCUPRIL continues during long-term therapy, with no evidence of loss of effectiveness. Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction produced by quinapril is accompanied by a reduction in total peripheral resistance and renal vascular resistance with little or no change in heart rate, cardiac index, renal blood flow, glomerular filtration rate, or filtration fraction. Use of ACCUPRIL with a thiazide diuretic gives a blood-pressure lowering effect greater than that seen with either agent alone. In patients with hypertension, ACCUPRIL 10���40 mg was similar in effectiveness to captopril, enalapril, propranolol, and thiazide diuretics. Therapeutic effects appear to be the same for elderly (���65 years of age) and younger adult patients given the same daily dosages, with no increase in adverse events in elderly patients.<br/>Heart Failure: In a placebo-controlled trial involving patients with congestive heart failure treated with digitalis and diuretics, parenteral quinaprilat, the active metabolite of quinapril, reduced pulmonary capillary wedge pressure and systemic vascular resistance and increased cardiac output/index. Similar favorable hemodynamic effects were seen with oral quinapril in baseline-controlled trials, and such effects appeared to be maintained during chronic oral quinapril therapy. Quinapril reduced renal hepatic vascular resistance and increased renal and hepatic blood flow with glomerular filtration rate remaining unchanged. A significant dose response relationship for improvement in maximal exercise tolerance has been observed with ACCUPRIL therapy. Beneficial effects on the severity of heart failure as measured by New York Heart Association (NYHA) classification and Quality of Life and on symptoms of dyspnea, fatigue, and edema were evident after6 months in a double-blind, placebo-controlled study. Favorable effects were maintained for up to two years of open label therapy. The effects of quinapril on long-term mortality in heart failure have not been evaluated.<br/>INDICATIONS AND USAGE:<br/>Hypertension: ACCUPRIL is indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics.<br/>Heart Failure: ACCUPRIL is indicated in the management of heart failure as adjunctive therapy when added to conventional therapy including diuretics and/or digitalis. In using ACCUPRIL, consideration should be given to the fact that another angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease. Available data are insufficient to show that ACCUPRIL does not have a similar risk .
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ACCUPRIL tablets are supplied as follows: 5-mg tablets: brown, film-coated, elliptical scored tablets, coded "PD 527" on one side and "5" on the other. N0071-0527-23 bottles of 90 tabletsN0071-0527-40 10��10 unit dose blisters 10-mg tablets: brown, film-coated, triangular tablets, coded "PD 530" on one side and "10" on the other. N0071-0530-23 bottles of 90 tabletsN0071-0530-40 10��10 unit dose blisters 20-mg tablets: brown, film-coated, round tablets, coded "PD 532" on one side and "20" on the other. N0071-0532-23 bottles of 90 tabletsN0071-0532-40 10��10 unit dose blisters 40-mg tablets: brown, film-coated, elliptical tablets, coded "PD 535" on one side and "40" on the other. N0071-0535-23 bottles of 90 tablets Dispense in well-closed containers as defined in the USP.<br/>Storage: Store at controlled room temperature 15�����30��C (59�����86��F). Protect from light.
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USE IN PREGNANCY: When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, ACCUPRIL should be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
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Doses of 1440 to 4280 mg/kg of quinapril cause significant lethality in mice and rats. No specific information is available on the treatment of overdosage with quinapril. The most likely clinical manifestation would be symptoms attributable to severe hypotension. Laboratory determinations of serum levels of quinapril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of quinapril overdose. No data are available to suggest physiological maneuvers (eg, maneuvers to change pH of the urine) that might accelerate elimination of quinapril and its metabolites. Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat. Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of quinapril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of quinapril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat quinapril overdose by infusion of normal saline solution.
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quinapril hydrochloride
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Accupril (Tablet, Film Coated)
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Hypertension: ACCUPRIL has been evaluated for safety in 4960 subjects and patients. Of these, 3203 patients, including 655 elderly patients, participated in controlled clinical trials. ACCUPRIL has been evaluated for long-term safety in over 1400 patients treated for 1 year or more. Adverse experiences were usually mild and transient. In placebo-controlled trials, discontinuation of therapy because of adverse events was required in 4.7% of patients with hypertension. Adverse experiences probably or possibly related to therapy or of unknown relationship to therapy occurring in 1% or more of the 1563 patients in placebo-controlled hypertension trials who were treated with ACCUPRIL are shown below.<br/>Heart Failure: ACCUPRIL has been evaluated for safety in 1222 ACCUPRIL treated patients. Of these, 632 patients participated in controlled clinical trials. In placebo-controlled trials, discontinuation of therapy because of adverse events was required in 6.8% of patients with congestive heart failure. Adverse experiences probably or possibly related or of unknown relationship to therapy occurring in 1% or more of the 585 patients in placebo-controlled congestive heart failure trials who were treated with ACCUPRIL are shown below. See PRECAUTIONS, Cough.<br/>Hypertension and/or Heart Failure: Clinical adverse experiences probably, possibly, or definitely related, or of uncertain relationship to therapy occurring in 0.5% to 1.0% (except as noted) of the patients with CHF or hypertension treated with ACCUPRIL (with or without concomitant diuretic) in controlled or uncontrolled trials (N=4847) and less frequent, clinically significant events seen in clinical trials or post-marketing experience (the rarer events are in italics) include (listed by body system): General: back pain, malaise, viral infections, anaphylactoid reaction Cardiovascular: palpitation, vasodilation, tachycardia, heart failure, hyperkalemia, myocardial infarction, cerebrovascular accident, hypertensive crisis, angina pectoris, orthostatic hypotension, cardiac rhythm disturbances, cardiogenic shock Hematology: hemolytic anemia Gastrointestinal: flatulence, dry mouth or throat, constipation, gastrointestinal hemorrhage, pancreatitis, abnormal liver function tests, dyspepsia Nervous/Psychiatric: somnolence, vertigo, syncope, nervousness, depression, insomnia, paresthesia Integumentary: alopecia, increased sweating, pemphigus, pruritus, exfoliative dermatitis, photosensitivity reaction, dermatopolymyositis Urogenital: urinary tract infection, impotence, acute renal failure, worsening renal failure Respiratory: eosinophilic pneumonitis Other: amblyopia, edema, arthralgia, pharyngitis, agranulocytosis, hepatitis, thrombocytopenia<br/>Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and Mortality.<br/>Angioedema: Angioedema has been reported in patients receiving ACCUPRIL (0.1%). Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis, and/or larynx occurs, treatment with ACCUPRIL should be discontinued and appropriate therapy instituted immediately.<br/>Clinical Laboratory Test Findings:
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Hypertension: ACCUPRIL is indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics.<br/>Heart Failure: ACCUPRIL is indicated in the management of heart failure as adjunctive therapy when added to conventional therapy including diuretics and/or digitalis. In using ACCUPRIL, consideration should be given to the fact that another angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease. Available data are insufficient to show that ACCUPRIL does not have a similar risk .<br/>Angioedema in black patients: Black patients receiving ACE inhibitor monotherapy have been reported to have a higher incidence of angioedema compared to non-blacks. It should also be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks.
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Accupril
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