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 molecular formula is C25H30N2O5•HCl and its structural formula is:

Quinapril hydrochloride USP is a white to off-white powder, with a pink cast at times that is freely soluble in aqueous solvents.



Quinapril tablets, USP contain 5 mg, 10 mg, 20 mg, or 40 mg of quinapril for oral administration. Each tablet also contains colloidal silicon dioxide, crospovidone, hydroxypropyl cellulose, hypromellose, iron oxide red, lactose monohydrate, magnesium carbonate, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide.

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 quinapril hydrochloride alone resulted in mean increases in potassium of 0.07 mmol/L (see PRECAUTIONS). 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. Quinapril hydrochloride was an effective antihypertensive in all races studied, although it was somewhat less effective in blacks (usually a 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.



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 to 30%) when quinapril 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 quinapril hydrochloride, 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 to 80 mg doses and 40 to 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 (see DOSAGE AND ADMINISTRATION). 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.



Pharmacodynamics and Clinical Effects



Hypertension



Single doses of 20 mg of quinapril hydrochloride 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 to 80 mg.



Administration of 10 to 80 mg of quinapril hydrochloride 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 (see WARNINGS). 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 to 2 weeks. In multiple-dose studies, 10 to 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 to 11/3 to 7 mm Hg. The trough effect represents about 50% of the peak effect. While the dose-response relationship is relatively flat, doses of 40 to 80 mg were somewhat more effective at trough than 10 to 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 quinapril hydrochloride 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 quinapril hydrochloride with a thiazide diuretic gives a blood-pressure lowering effect greater than that seen with either agent alone.



In patients with hypertension, quinapril hydrochloride 10 to 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.



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 quinapril hydrochloride 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 after 6 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.

Hypertension



Quinapril tablets, USP are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with quinapril tablets, USP.



Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).



Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.



Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.



Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.



Quinapril tablets, USP may be used alone or in combination with thiazide diuretics.



Heart Failure



Quinapril tablets, USP are indicated in the management of heart failure as adjunctive therapy when added to conventional therapy including diuretics and/or digitalis.



In using quinapril tablets, USP consideration should be given to the fact that another ACE inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease. Available data are insufficient to show that quinapril tablets, USP do not have a similar risk (see WARNINGS).



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.

Quinapril tablets are contraindicated in patients who are hypersensitive to this product and in patients with a history of angioedema related to previous treatment with an ACE inhibitor.

Quinapril tablets are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer quinapril tablets are within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor (see WARNINGS and PRECAUTIONS).

Do not co-administer quinapril tablets with aliskiren in patients with diabetes

Hypertension

Quinapril hydrochloride has been evaluated for safety in 4960 subjects and patients. Of these, 3203 patients, including 655 elderly patients, participated in controlled clinical trials. Quinapril hydrochloride 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 quinapril hydrochloride are shown below.

Heart Failure

Quinapril hydrochloride has been evaluated for safety in 1222 quinapril hydrochloride 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 quinapril hydrochloride are shown below.

See PRECAUTIONS, Cough.

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% (except as noted) of the patients with CHF or hypertension treated with quinapril hydrochloride (with or without concomitant diuretic) in controlled or uncontrolled trials (N=4847) and less frequent, clinically significant events seen in clinical trials or postmarketing 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

Metabolism and Nutrition Disorders:  hyponatremia



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

Angioedema

Angioedema has been reported in patients receiving quinapril hydrochloride (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 quinapril hydrochloride should be discontinued and appropriate therapy instituted immediately. (See WARNINGS.)

Clinical Laboratory Test Findings

Hematology

(See WARNINGS)

Hyperkalemia

(See PRECAUTIONS)

Creatinine and Blood Urea Nitrogen

Increases (>1.25 times the upper limit of normal) in serum creatinine and blood urea nitrogen were observed in 2% and 2%, respectively, of all patients treated with quinapril hydrochloride alone. Increases are more likely to occur in patients receiving concomitant diuretic therapy than in those on quinapril hydrochloride alone. These increases often remit on continued therapy. In controlled studies of heart failure, increases in blood urea nitrogen and serum creatinine were observed in 11% and 8%, respectively, of patients treated with quinapril hydrochloride; most often these patients were receiving diuretics with or without digitalis.

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 (e.g., 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.

Hypertension



Monotherapy



The recommended initial dosage of quinapril tablets 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 to 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 to 80 mg and divided doses give a somewhat greater effect at the end of the dosing interval.



Concomitant Diuretics



If blood pressure is not adequately controlled with quinapril tablets 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 quinapril tablets. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued 2 to 3 days prior to beginning therapy with quinapril tablets (see WARNINGS). Then, if blood pressure is not controlled with quinapril tablets alone, diuretic therapy should be resumed.



If the diuretic cannot be discontinued, an initial dose of 5 mg quinapril tablets 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 (see WARNINGS, PRECAUTIONS

and  Drug Interactions).



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.



Elderly (≥65 years)



The recommended initial dosage of quinapril tablets in elderly patients is 10 mg given once daily followed by titration (as described above) to the optimal response.



Heart Failure



Quinapril tablets are 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 quinapril tablets 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 (see WARNINGS) prohibit reaching this dose.



Following the initial dose of quinapril tablets, 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.



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 quinapril tablets 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 (see DOSAGE AND ADMINISTRATION, Heart Failure, WARNINGS, and PRECAUTIONS, Drug Interactions).



If the initial dose is well tolerated, quinapril tablets 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.

Quinapril tablets, USP are supplied as follows:



Quinapril Tablets USP, 5 mg are brown colored, oval shaped film-coated tablets, debossed with “5” and “2” on either side of the scoreline on one side and “H” on the other side.

            Bottles of 30                                                               NDC 63187-874-30

            Bottles of 60                                                               NDC 63187-874-60

            Bottles of 90                                                           NDC 63187-874-90

Dispense in well-closed containers as defined in the USP.



Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light.



Manufactured for:

Aurobindo Pharma USA, Inc.

2400 Route 130 North

Dayton, NJ 08810



Manufactured by:

Aurobindo Pharma Limited

Unit-VII (SEZ)

Mahaboob Nagar (Dt)-509302

India

Repackaged by:

Proficient Rx LP

Thousand Oaks, CA 91320

Revised: 05/2017

NDC 63187-874-30

Quinapril

Tablets, USP

5 mg           

Rx only       30 Tablets