Generic Name: QUINAPRIL
Brand Name: Quinapril
- Substance Name(s):
- QUINAPRIL HYDROCHLORIDE
Anaphylactoid and Possibly Related Reactions Presumably because ACE 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.
Head and Neck Angioedema 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.
If 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 ).
Patients taking concomitant mammalian target of rapamycin (mTOR) inhibitor (e.g.
temsirolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema.
Intestinal Angioedema 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 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 ).
Anaphylactoid reactions during desensitization 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 during membrane exposure 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.
Hepatic Failure 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.
Hypotension 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 (see DOSAGE AND ADMINISTRATION ).
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.
Neutropenia/Agranulocytosis 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.
Fetal Toxicity Use of drugs that act on the renin-angiotensin 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 quinapril as soon as possible.
These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy.
Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.
Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.
Perform serial ultrasound examinations to assess the intra-amniotic environment.
If oligohydramnios is observed, discontinue quinapril, unless it is considered life-saving for the mother.
Fetal testing may be appropriate, based on the week of pregnancy.
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 quinapril for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use ).
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.
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.
Quinapril (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 C 25 H 30 N 2 O 5 •HCl and its structural formula is: Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in aqueous solvents.
Quinapril tablets USP contain 5 mg (equivalent to 5.416 mg Quinapril Hydrochloride), 10 mg (equivalent to 10.832 mg Quinapril Hydrochloride), 20 mg (equivalent to 21.664 mg Quinapril Hydrochloride), or 40 mg (equivalent to 43.328 mg Quinapril Hydrochloride) of quinapril for oral administration.
Each film-coated tablet also contains crospovidone, iron oxide yellow, lecithin, magnesium carbonate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, povidone, talc, titanium dioxide and xanthan gum.
Quinapril tablets USP are supplied as follows: 5-mg tablets: Yellow colored, oval shaped, film-coated tablets, debossed with ‘L’ and ‘U’ on either side of the breakline on one side and ‘F01’ on the other side.
NDC 68001-189-05 bottles of 90 tablets 10-mg tablets: Yellow colored, circular shaped, film-coated tablets, debossed with ‘LU’ on one side and ‘F02’ on the other side.
NDC 68001-188-05 bottles of 90 tablets 20-mg tablets: Yellow colored, round shaped, film-coated tablets, debossed with ‘LU’ on one side and ‘F03’ on the other side.
NDC 68001-187-05 bottles of 90 tablets 40-mg tablets : Yellow colored, round shaped, beveled edge film-coated biconvex tablets, debossed with ‘LU’ on one side and ‘F04’ on the other side.
NDC 68001-260-05 bottles of 90 tablets Dispense in well-closed containers as defined in the USP.
Storage: Store at 20 to 25°C (68 to 77°F) [See USP Controlled Room Temperature].
Protect from light.
INDICATIONS AND USAGE
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 is 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 does 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.
WARNING: FETAL TOXICITY • When pregnancy is detected, discontinue quinapril tablets as soon as possible.
• Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
See WARNINGS : Fetal Toxicity
DOSAGE AND ADMINISTRATION
Hypertension Monotherapy The recommended initial dosage of quinapril 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 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 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: Creatinine Clearance Maximum Recommended Initial Dose >60mL/min 10mg 30 to 60 mL/min 5mg 10 to 30 mL/min 2.5mg <10 mL/min Insufficient data for dosage recommendation 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 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 quinapril 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 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 , Heart Failure , 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.