QUINAPRIL HYDROCHLORIDE TABLETS, USP

Rx only

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, quinapril hydrochloride tablets, USP should be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

Quinapril hydrochloride, USP is the hydrochloride salt of quinapril, the ethyl ester of a non-sulfhydryl, angiotensin-converting enzyme (ACE) inhibitor, quinaprilat.

Quinapril hydrochloride, USP 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 C₂₅H₃₀N₂O₅•HCI and its structural formula is:

Quinapril hydrochloride, USP is a white to off-white amorphous powder that is freely soluble in aqueous solvents.

Quinapril hydrochloride tablets, USP contain 5 mg, 10 mg, 20 mg, or 40 mg of quinapril for oral administration. Each tablet also contains black iron oxide, candelilla wax powder, crospovidone, dibasic calcium phosphate, hypromellose 2910 3cP, hypromellose 2910 6cP, magnesium carbonate powder heavy, magnesium stearate, polyethylene glycol 400, polysorbate 80, povidone, red iron oxide, titanium dioxide and yellow iron oxide.

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 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 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 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.

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 quinapril is 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 quinapri, 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 (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.

Quinapril hydrochloride tablets, USP are indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics. In using quinapril hydrochloride tablets, USP, 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 quinapril hydrochloride tablets, USP do not have a similar risk (see WARNINGS).

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 hydrochbride tablets, USP 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.

Presumably because angiotensin-converting inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including quinapril) may be subject to a variety of adverse reactions, some of them serious.

Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors and has been seen in 0.1% of patients receiving quinapril.

In two similarly sized U.S. postmarketing trials that, combined, enrolled over 3,000 black patients and over 19,000 non-blacks, angioedema was reported in 0.30% and 0.55% of blacks (in study 1 and 2 respectively) and 0.39% and 0.17% of non-blacks.

Angioedema associated with laryngeal edema can be fatal. It laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with quinapril should be discontinued immediately, the patient treated in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, emergency therapy including, but not limited to, subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL) should be promptly administered (see ADVERSE REACTIONS).

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also CONTRAINDICATIONS).

Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

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. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Excessive hypotension is rare in patients with uncomplicated hypertension treated with quinapril alone. Patients with heart failure given quinapril commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. Caution should be observed when initiating therapy in patients with heart failure. In controlled studies, syncope was observed in 0.4% of patients (N=3203); this incidence was similar to that observed for captopril (1%) and enalapril (0.8%).

Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include patients with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or cautiously increase salt intake (except in patients with heart failure) before initiating therapy with quinapril in patients at risk for excessive hypotension who are able to tolerate such adjustments.

In patients at risk of excessive hypotension, therapy with quinapril should be started under close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of quinapril and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular accident.

If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of quinapril, which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops a dose reduction or discontinuation of quinapril or concomitant diuretic may be necessary.

Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen vascular disease, such as systemic lupus erythematosus or scleroderma. Agranulocytosis did occur during quinapril treatment in one patient with a history of neutropenia during previous captopril therapy. Available data from clinical trials of quinapril are insufficient to show that, in patients without prior reactions to other ACE inhibitors, quinapril does not cause agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered.

ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure.

These adverse effects do not appear to have resulted from intrauterine ACE inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of quinapril as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment.

If oligohydramnios is observed, quinapril should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Removal of quinapril, which cross the placenta, from the neonatal circulation is not significantly accelerated by these means.

No teratogenic effects of quinapril were seen in studies of pregnant rats and rabbits. On a mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum recommended human dose.

Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or 100 mg/kg/day (50 to 60 times the maximum human daily dose, respectively, on an mg/kg basis and 3.8 to 10 times the maximum human daily dose when based on an mg/m² basis) for 104 weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also negative in the following genetic toxicology studies: in vitro mammalian cell point mutation, sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro chromosome aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100 mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/m², respectively).

Because quinapril is secreted in human milk, caution should be exercised when this drug is administered to a nursing woman.

The safety and effectiveness of quinapril in pediatric patients have not been established.

Clinical studies of quinapril 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/or 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.

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

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 treated with quinapril (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 (uled by body system):

General: anaphylactoid reaction, back pain, dyspepsia, malaise, viral infections

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: anaphylactoid reaction, dyspepsia, flatulence, dry mouth or throat, constipation, gastrointestinal hemorrhage, pancreatitis, abnormal liver function tests

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

See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

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

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.

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

If the diuretic cannot be discontinued, an initial dose of 5 mg quinapril hydrochloride tablets, USP 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).

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.

The recommended initial dosage of quinapril in elderly patients is 10 mg given once daily followed by titration (as described above) to the optimal response. Following the initial dose of quinapril hydrochloride tablets, USP, 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, orthostasis, 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 quinapril 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 WARNINGS, and PRECAUTIONS, Drug Interactions).

If the initial dose is well tolerated, quinapril 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 hydrochloride tablets, USP are supplied as follows:

5-mg tablets: pink, film-coated, oval, standard convex tablets debossed with , bisect and "5" on one side and "531" on the other side.

NDC 62037-531 -90 bottles of 90 tablets
NDC 62037-531 -10 bottles of 1000 tablets

10-mg tablets: pink, film-coated, round, standard convex tablets debossed with and "10" on one side and "532" on the other side.

NDC 62037-532-90 bottles of 90 tablets
NDC 62037-532-10 bottles of 1000 tablets

20-mg tablets: pink, film-coated, round, standard convex tablets debossed with and "20" on one side and "533" on the other side.

NDC 62037-533-90 bottles of 90 tablets
NDC 62037-533-10 bottles of 1000 tablets

40-mg tablets: pink, film-coated, round, standard convex tablets debossed with and "40" on one side and "534" on the other side.

NDC 62037-534-90 bottles of 90 tablets
NDC 62037-534-10 bottles of 1000 tablets

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