Quinapril

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 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.

DOSAGE AND ADMINISTRATION Hypertension Monotherapy The recommended initial dosage of quinapril tablets in patients not on diuretics is 10 mg 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 (pre-dosing). Generally, dosage adjustments should be made at intervals of at least 2 weeks. Most patients have required dosages of 20 mg/day, 40 mg/day 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 mg 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 hydrochloride tablet 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 and PRECAUTIONS, 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 greater than 60 mL/min 10 mg 30 mL/min to 60 mL/min 5 mg 10 mL/min to 30 mL/min 2.5 mg less than 10 mL/min Insufficient data for dosage recommendation Patients should subsequently have their dosage titrated (as described above) to the optimal response. Elderly (greater than or equal to 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 mg 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 mL/m …

CONTRAINDICATIONS 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. Quinapril hydrochloride is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer quinapril hydrochloride within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor (see WARNINGS and PRECAUTIONS ). Do not co-administer quinapril hydrochloride with aliskiren in patients with diabetes.

ADVERSE REACTIONS Hypertension Quinapril hydrochloride has been evaluated for safety in 4,960 subjects and patients. Of these, 3,203 patients, including 655 elderly patients, participated in controlled clinical trials. Quinapril hydrochloride has been evaluated for long-term safety in over 1,400 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 1,563 patients in placebo-controlled hypertension trials who were treated with quinapril hydrochloride are shown below. Adverse Events in Placebo-Controlled Trials Quinapril Hydrochloride (N=1,563) Incidence (Discontinuance) Placebo (N=579) Incidence (Discontinuance) Headache 5.6 (0.7) 10.9 (0.7) Dizziness 3.9 (0.8) 2.6 (0.2) Fatigue 2.6 (0.3) 1.0 Coughing 2.0 (0.5) 0.0 Nausea and/or Vomiting 1.4 (0.3) 1.9 (0.2) Abdominal Pain 1.0 (0.2) 0.7 Heart Failure Quinapril hydrochloride has been evaluated for safety in 1,222 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. Quinapril Hydrochloride (N=585) Incidence (Discontinuance) Placebo (N=295) Incidence (Discontinuance) Dizziness 7.7 (0.7) 5.1 (1.0) Coughing 4.3 (0.3) 1.4 Fatigue 2.6 (0.2) 1.4 Nausea and/or Vomiting 2.4 (0.2) 0.7 Chest Pain 2.4 1.0 Hypotension 2.9 (0.5) 1.0 Dyspnea 1.9 (0.2) 2.0 Diarrhea 1.7 1.0 Headache 1.7 1.0 (0.3) Myalgia 1.5 2.0 Rash 1.4 (0.2) 1.0 Back Pain 1.2 0.3 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 1.0% (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=4,847) 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 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 (S …

Drug Interactions Concomitant Diuretic Therapy As with other ACE inhibitors, patients on diuretics, especially those on recently instituted diuretic therapy, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with quinapril hydrochloride. The possibility of hypotensive effects with quinapril hydrochloride may be minimized by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with quinapril hydrochloride. If it is not possible to discontinue the diuretic, the starting dose of quinapril should be reduced (see DOSAGE AND ADMINISTRATION ). Agents Increasing Serum Potassium Coadministration of quinapril hydrochloride with other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients. Tetracycline and Other Drugs That Interact With Magnesium Simultaneous administration of tetracycline with quinapril hydrochloride reduced the absorption of tetracycline by approximately 28% to 37%, possibly due to the high magnesium content in quinapril tablets. This interaction should be considered if coprescribing quinapril hydrochloride and tetracycline or other drugs that interact with magnesium. Lithium Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity. Gold Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy. Non-steroidal Anti-inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including quinapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving quinapril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including quinapril may be attenuated by NSAIDs. Agents that inhibit mTOR or other drugs known to cause angioedema: Patients taking concomitant mTOR inhibitor (e.g., temsirolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema. Other Agents Drug interaction studies of quinapril hydrochloride with other agents showed: • Multiple dose therapy with propranolol or cimetidine has no effect on the pharmacokinetics of single doses of quinapril hydrochloride. • The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was not significantly changed by quinapril coadministration twice-daily. • Quinapril hydrochloride treatment did not affect the pharmacokinetics of digoxin. • No pharmacokinetic interaction was observed when single doses of quinapril hydrochloride and hydrochlorothiazide were administered concomitantly. • Co-administration of multiple 10 mg doses of atorvastatin with 80 mg of quinapril hydrochloride resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin. Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function …

DESCRIPTION Quinapril hydrochloride, USP 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 C 25 H 30 N 2 O 5 •HCI 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 quinapril hydrochloride, USP equivalent to 5 mg (equivalent to 5.42 mg Quinapril Hydrochloride), 10 mg (equivalent to 10.84 mg Quinapril Hydrochloride), 20 mg (equivalent to 21.66 mg Quinapril Hydrochloride), or 40 mg (equivalent to 43.33 mg Quinapril Hydrochloride) of quinapril for oral administration. Each tablet also contains magnesium carbonate, hydroxypropyl cellulose, crospovidone, magnesium stearate, polyethylene glycol, talc, FD&C yellow No. 6, FD&C red No. 40, titanium dioxide, FD&C blue No. 1, and polyvinyl alcohol. image description

OVERDOSAGE Doses of 1440 mg/kg 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.

HOW SUPPLIED 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 65862-617-30 Bottles of 90 NDC 65862-617-90 Bottles of 1,000 NDC 65862-617-99 Bottles of 15,000 NDC 65862-617-55 Cartons of 100 (10 x 10) Unit-dose Tablets NDC 65862-617-78 Quinapril Tablets USP, 10 mg are brown colored, triangular shaped film-coated tablets, debossed with “53” on one side and “H” on the other side. Bottles of 30 NDC 65862-618-30 Bottles of 90 NDC 65862-618-90 Bottles of 1,000 NDC 65862-618-99 Bottles of 15,000 NDC 65862-618-55 Cartons of 100 (10 x 10) Unit-dose Tablets NDC 65862-618-78 Quinapril Tablets USP, 20 mg are brown colored, circular shaped film-coated tablets, debossed with “D” on one side and “16” on the other side. Bottles of 30 NDC 65862-619-30 Bottles of 90 NDC 65862-619-90 Bottles of 1,000 NDC 65862-619-99 Bottles of 10,000 NDC 65862-619-19 Cartons of 100 (10 x 10) Unit-dose Tablets NDC 65862-619-78 Quinapril Tablets USP, 40 mg are brown colored, oval shaped film-coated tablets, debossed with “D” on one side and “17” on the other side. Bottles of 30 NDC 65862-620-30 Bottles of 90 NDC 65862-620-90 Bottles of 1,000 NDC 65862-620-99 Bottles of 3,000 NDC 65862-620-39 Cartons of 100 (10 x 10) Unit-dose Tablets NDC 65862-620-78 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. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 038, India Revised: 07/2020