Accupril (Quinapril hydrochloride) ® (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 (Quinapril hydrochloride) 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.

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 (Quinapril hydrochloride) alone resulted in mean increases in potassium of 0.07 mmol/L (see ). 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 (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.

Accupril (Quinapril hydrochloride) is 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.

Pregnancy Categories C (first trimester) and D (second and third trimesters): See .

Clinical studies of Accupril (Quinapril hydrochloride) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Elderly patients exhibited increased area under the plasma concentration time curve and peak levels for quinaprilat compared to values observed in younger patients; this appeared to relate to decreased renal function rather than to age itself.

Accupril (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. Accupril (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 Accupril (Quinapril hydrochloride) are shown below.

Accupril (Quinapril hydrochloride) has been evaluated for safety in 1222 Accupril (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 Accupril (Quinapril hydrochloride) are shown below.

See .

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 (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 post-marketing experience (the rarer events are in italics) include (listed by body system):

Nervous/Psychiatric:
See .

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.

Accupril (Quinapril hydrochloride) 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 (Quinapril hydrochloride) 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 ) prohibit reaching this dose.

Following the initial dose of Accupril (Quinapril hydrochloride) , 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.

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 (Quinapril hydrochloride) 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 , , and ).

If the initial dose is well tolerated, Accupril (Quinapril hydrochloride) 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.

Accupril (Quinapril hydrochloride) tablets are supplied as follows:

N0071-0527-23 bottles of 90 tabletsN0071-0527-40 10 × 10 unit dose blisters

N0071-0530-23 bottles of 90 tabletsN0071-0530-40 10 × 10 unit dose blisters

N0071-0532-23 bottles of 90 tabletsN0071-0532-40 10 × 10 unit dose blisters

N0071-0535-23 bottles of 90 tablets

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

NDC 0071-0527-23

NDC 0071-0530-23

NDC 0071-0532-23

NDC 0071-0535-23