DailyMed Label: QUINAPRIL HYDROCHLORIDE/HYDROCHLOROTHIAZIDE

DailyMed Label: QUINAPRIL HYDROCHLORIDE/HYDROCHLOROTHIAZIDE

2024

DailyMed Prescription

QUINAPRIL HYDROCHLORIDE/HYDROCHLOROTHIAZIDE

QUINAPRIL HYDROCHLORIDE/HYDROCHLOROTHIAZIDE

Aurobindo Pharma Limited

NDC: 65862-161

NDC: 65862-162

NDC: 65862-163

NDC: 65862-161

NDC: 65862-162

NDC: 65862-163

NDC: 65862-161

NDC: 65862-161

NDC: 65862-162

NDC: 65862-162

NDC: 65862-163

NDC: 65862-163

Quinapril and hydrochlorothiazide tablets, USP are fixed-combination tablet that combines an angiotensin-converting enzyme (ACE) inhibitor, quinapril hydrochloride, and a thiazide diuretic, hydrochlorothiazide. 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 . HCl and its structural formula is: Quinapril hydrochloride USP is a white to off-white amorphous powder that is freely soluble in aqueous solvents. Hydrochlorothiazide is chemically described as: 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its molecular formula is C 7 H 8 ClN 3 O 4 S 2 and its structural formula is: Hydrochlorothiazide USP is a white to off-white, crystalline powder which is slightly soluble in water but freely soluble in sodium hydroxide solution. Quinapril and hydrochlorothiazide tablets, USP are available for oral use as fixed combination tablets in three strengths of quinapril with hydrochlorothiazide: 10 mg (equivalent to 10.832 mg quinapril hydrochloride USP) with 12.5 mg (quinapril and hydrochlorothiazide 10/12.5), 20 mg (equivalent to 21.664 mg quinapril hydrochloride USP) with 12.5 mg (quinapril and hydrochlorothiazide 20/12.5), and 20 mg (equivalent to 21.664 mg quinapril hydrochloride USP) with 25 mg (quinapril and hydrochlorothiazide 20/25). The strength of the quinapril hydrochloride component is in terms of quinapril. Inactive ingredients: lactose monohydrate, magnesium carbonate, crospovidone, povidone, magnesium stearate, hypromellose, hydroxypropyl cellulose, polyethylene glycol 400, titanium dioxide, iron oxide red and iron oxide yellow. Quinapril Hydrochloride Chemical Structure Hydrochlorothiazide Chemical Structure

Hypertension Quinapril and hydrochlorothiazide tablets 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 and hydrochlorothiazide tablets. 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. This fixed combination is not indicated for the initial therapy of hypertension (see DOSAGE AND ADMINISTRATION ). In using quinapril and hydrochlorothiazide tablets, 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 does not have a similar risk (see WARNINGS: Neutropenia/Agranulocytosis ). 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.

As individual monotherapy, quinapril is an effective treatment of hypertension in once-daily doses of 10 mg to 80 mg and hydrochlorothiazide is effective in doses of 12.5 mg to 50 mg. In clinical trials of quinapril/hydrochlorothiazide combination therapy using quinapril doses of 2.5 mg to 40 mg and hydrochlorothiazide doses of 6.25 mg to 25 mg, the antihypertensive effects increased with increasing dose of either component. The side effects (see WARNINGS ) of quinapril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of quinapril and hydrochlorothiazide will be associated with both sets of dose-independent side effects, but regimens that combine low doses of hydrochlorothiazide with quinapril produce minimal effects on serum potassium. In clinical trials of quinapril and hydrochlorothiazide tablets, the average change in serum potassium was near zero in subjects who received HCTZ 6.25 mg in the combination, and the average subject who received 10 mg to 40 mg/12.5 mg to 25 mg experienced a milder reduction in serum potassium than that experienced by the average subject receiving the same dose of hydrochlorothiazide monotherapy. To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. Therapy Guided by Clinical Effect Patients whose blood pressures are not adequately controlled with quinapril monotherapy may instead be given quinapril and hydrochlorothiazide tablets 10 mg/12.5 mg or 20 mg/12.5 mg. Further increases of either or both components could depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2 to 3 weeks have elapsed. Patients whose blood pressures are adequately controlled with 25 mg of daily hydrochlorothiazide, but who experience significant potassium loss with this regimen, may achieve blood pressure control with less electrolyte disturbance if they are switched to quinapril and hydrochlorothiazide tablets 10 mg/12.5 mg or 20 mg/12.5 mg. Replacement Therapy For convenience, patients who are adequately treated with 20 mg of quinapril and 25 mg of hydrochlorothiazide and experience no significant electrolyte disturbances may instead wish to receive quinapril and hydrochlorothiazide tablets 20 mg/25 mg. Use in Renal Impairment Regimens of therapy with quinapril and hydrochlorothiazide tablets need not take account of renal function as long as the patient’s creatinine clearance is >30 mL/min/1.73 m 2 (serum creatinine roughly ≤3 mg/dL or 265 µmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides. Therefore, quinapril and hydrochlorothiazide tablets are not recommended for use in these patients.

Quinapril and hydrochlorothiazide   tablets are contraindicated in patients who are hypersensitive to quinapril or hydrochlorothiazide and in patients with a history of angioedema related to previous treatment with an ACE inhibitor. Quinapril and hydrochlorothiazide tablets are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer quinapril and hydrochlorothiazide tablets  within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor (see   WARNINGS  and  PRECAUTIONS ). Because of the hydrochlorothiazide components, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Do not co-administer quinapril and hydrochlorothiazide tablets with aliskiren: in patients with diabetes.

Serum Electrolyte Abnormalities In clinical trials, hyperkalemia (serum potassium ≥5.8 mmol/L) occurred in approximately 2% of patients receiving quinapril. In most cases, elevated serum potassium levels were isolated values which resolved despite continued therapy. Less than 0.1% of patients discontinued therapy due to hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of other drugs that raise serum potassium levels. Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. The risk of hyperkalemia may be increased in patients with renal insufficiency, diabetes mellitus or with concomitant use of drugs that raise serum potassium (see DRUG INTERACTIONS ). The risk of hypokalemia may be increased in patients with cirrhosis, brisk diuresis, or with concomitant use of drugs that lower serum potassium. Monitor serum electrolytes periodically. Other Metabolic Disturbances Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving  quinapril and hydrochlorothiazide. Cough Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. Surgery/Anesthesia In patients undergoing surgery or during anesthesia with agents that produce hypotension, quinapril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion. Angioedema Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose. Tell patients receiving quinapril and hydrochlorothiazide to immediately report any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to temporarily discontinue quinapril and hydrochlorothiazide until after consulting with the prescribing physician. Pregnancy Tell female patients of childbearing age about the consequences of exposure to quinapril and hydrochlorothiazide during pregnancy. Discuss treatment options with women planning to become pregnant. Ask patients to report pregnancies to their physicians as soon as possible. Symptomatic Hypotension Tell patients receiving quinapril and hydrochlorothiazide that lightheadedness can occur, especially during the first days of therapy, and to report it to the prescribing physician. Tell the patient if syncope occurs, discontinue quinapril and hydrochlorothiazide until the physician has been consulted. Tell patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure because of reduction in fluid volume, with the same consequences of lightheadedness and possible syncope. Tell patients planning to undergo major surgery and/ or general or spinal anesthesia to inform their physicians that they are taking an ACE inhibitor. Hyperkalemia Tell patients receiving quinapril and hydrochlorothiazide not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. Neutropenia Tell patients to promptly report any indication of infection (e.g., sore throat, fever) which could be a sign of neutropenia. Non-melanoma Skin Cancer: Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening. NOTE: As with many other drugs, certain advice to patients being treated with quinapril is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. The hydrochlorothiazide component of quinapril and hydrochlorothiazide  may decrease serum PBI levels without signs of thyroid disturbance. Therapy with quinapril and hydrochlorothiazide should be interrupted for a few days before carrying out tests of parathyroid function. Agents Increasing Serum Potassium Coadministration of quinapril and hydrochlorothiazide with other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients. Lithium Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. Because renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity is presumably raised further when, as in therapy with quinapril and hydrochlorothiazide, a thiazide diuretic is coadministered with the ACE inhibitor. Quinapril and hydrochlorothiazide and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. 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 and electrolytes in patients on quinapril and hydrochlorothiazide and other agents that affect the RAS. Do not co-administer aliskiren with quinapril and hydrochlorothiazide in patients with diabetes. Avoid concomitant use of aliskiren with quinapril and hydrochlorothiazide in patients with renal impairment (GFR <60 mL/min/1.73 m 2 ). Tetracycline and Other Drugs That Interact with Magnesium Simultaneous administration of tetracycline with quinapril 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 and tetracycline or other drugs that interact with magnesium. 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 and other agents showed: Multiple dose therapy with propranolol or cimetidine has no effect on the pharmacokinetics of single doses of quinapril. The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was not significantly changed by quinapril coadministration twice daily. Digoxin: Thiazide-induced electrolyte disturbances, i.e. hypokalemia, hypomagnesemia, increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events (See PRECAUTIONS ). No pharmacokinetic interaction was observed when single doses of quinapril and hydrochlorothiazide were administered concomitantly. When administered concurrently, the following drugs may interact with thiazide diuretics. Alcohol, Barbiturates, or Narcotics—potentiation of orthostatic hypotension may occur. Antidiabetic Drugs (oral hypoglycemic agents and insulin)—dosage adjustments of the antidiabetic drug may be required (See PRECAUTIONS ). Cholestyramine and Colestipol Resin—absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively. Corticosteroids, ACTH—intensified electrolyte depletion, particularly hypokalemia. Pressor Amines (e.g., norepinephrine)—possible decreased response to pressor amines, but not sufficient to preclude their therapeutic use. Skeletal Muscle Relaxants, Nondepolarizing (e.g., tubocurarine)—possible increased responsiveness to the muscle relaxant. Non-steroidal Anti-inflammatory Drugs—the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics may be reduced by concurrent administration of nonsteroidal anti-inflammatory agents. Carcinogenicity, mutagenicity, and fertility studies have not been conducted in animals with quinapril and hydrochlorothiazide. Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or 100 mg/kg/day (50 or 60 times the maximum human daily dose, respectively, on a mg/kg basis and 3.8 or 10 times the maximum human daily dose on a mg/m 2 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/m 2 , respectively). Under the auspices of the National Toxicology Program, rats and mice received hydrochlorothiazide in their feed for 2 years, at doses up to 600 mg/kg/day in mice and up to 100 mg/kg/day in rats. These studies uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in rats or female mice, but there was “equivocal” evidence of hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (the Ames test); in the Chinese hamster ovary (CHO) test for chromosomal aberrations; or in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO sister chromatid exchange (clastogenicity) test and in the mouse lymphoma cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43 to 1300 mcg/mL. Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using an unspecified concentration of hydrochlorothiazide. Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diets, to doses of up to 100 and 4 mg/kg/day, respectively, prior to mating and throughout gestation. Because quinapril and hydrochlorothiazide are secreted in human milk, caution should be exercised when quinapril and hydrochlorothiazide is administered to a nursing woman. Because of the potential for serious adverse reactions in nursing infants from hydrochlorothiazide and the unknown effects of quinapril in infants, a decision should be made whether to discontinue nursing or to discontinue quinapril and hydrochlorothiazide, taking into account the importance of the drug to the mother. Clinical studies of quinapril hydrochloride/hydrochlorothiazide 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. Neonates with a history of in utero exposure to quinapril and hydrochlorothiazide If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Removal of quinapril, which crosses the placenta, from the neonatal circulation is not significantly accelerated by these means. Safety and effectiveness of quinapril and hydrochlorothiazide   in children have not been established.

Quinapril  and hydrochlorothiazide

Agents Increasing Serum Potassium Coadministration of quinapril and hydrochlorothiazide with other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients. Lithium Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. Because renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity is presumably raised further when, as in therapy with quinapril and hydrochlorothiazide, a thiazide diuretic is coadministered with the ACE inhibitor. Quinapril and hydrochlorothiazide and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. 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 and electrolytes in patients on quinapril and hydrochlorothiazide and other agents that affect the RAS. Do not co-administer aliskiren with quinapril and hydrochlorothiazide in patients with diabetes. Avoid concomitant use of aliskiren with quinapril and hydrochlorothiazide in patients with renal impairment (GFR <60 mL/min/1.73 m 2 ). Tetracycline and Other Drugs That Interact with Magnesium Simultaneous administration of tetracycline with quinapril 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 and tetracycline or other drugs that interact with magnesium. 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 and other agents showed: Multiple dose therapy with propranolol or cimetidine has no effect on the pharmacokinetics of single doses of quinapril. The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was not significantly changed by quinapril coadministration twice daily. Digoxin: Thiazide-induced electrolyte disturbances, i.e. hypokalemia, hypomagnesemia, increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events (See PRECAUTIONS ). No pharmacokinetic interaction was observed when single doses of quinapril and hydrochlorothiazide were administered concomitantly. When administered concurrently, the following drugs may interact with thiazide diuretics. Alcohol, Barbiturates, or Narcotics—potentiation of orthostatic hypotension may occur. Antidiabetic Drugs (oral hypoglycemic agents and insulin)—dosage adjustments of the antidiabetic drug may be required (See PRECAUTIONS ). Cholestyramine and Colestipol Resin—absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively. Corticosteroids, ACTH—intensified electrolyte depletion, particularly hypokalemia. Pressor Amines (e.g., norepinephrine)—possible decreased response to pressor amines, but not sufficient to preclude their therapeutic use. Skeletal Muscle Relaxants, Nondepolarizing (e.g., tubocurarine)—possible increased responsiveness to the muscle relaxant. Non-steroidal Anti-inflammatory Drugs—the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics may be reduced by concurrent administration of nonsteroidal anti-inflammatory agents.

Quinapril and Hydrochlorothiazide Tablets, USP 10 mg/12.5 mg are Pink colored, scored, oval shaped, biconvex, film-coated tablets debossed with ‘D’ on scored side and ‘18’ on other side.                     Bottles of 90               NDC 65862-161-90 Quinapril and Hydrochlorothiazide Tablets, USP 20 mg/12.5 mg are Pink colored, scored, round shaped, biconvex, film-coated tablets debossed with ‘D’ on scored side and ‘19’ on other side.                     Bottles of 30               NDC 65862-162-30                     Bottles of 90               NDC 65862-162-90 Quinapril and Hydrochlorothiazide Tablets, USP 20 mg/25 mg are Pink colored, round shaped, biconvex, film-coated tablets debossed with ‘D’ on one side and ‘20’ on other side.                     Bottles of 90               NDC 65862-163-90 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°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–500 032, India Revised: 05/2022

Mechanism of Action The principal metabolite of quinapril, quinaprilat, is an inhibitor of ACE activity in human subjects and animals. ACE is 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 non-blacks. 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. Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldolsterone link is mediated by angiotensin, so coadministration of an ACE inhibitor tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is unknown. Pharmacokinetics and Metabolism The rate and extent of absorption of quinapril and hydrochlorothiazide from quinapril and hydrochlorothiazide tablets are not different, respectively, from the rate and extent of absorption of quinapril and hydrochlorothiazide from immediate-release monotherapy formulations, either administered concurrently or separately. Following oral administration of quinapril monotherapy tablets, peak plasma quinapril concentrations are observed within 1 hour. Based on recovery of quinapril and its metabolites in urine, the extent of absorption is at least 60%. The absorption of hydrochlorothiazide is somewhat slower (1 to 2.5 hours) and more complete (50% to 80%). The rate of quinapril absorption was reduced by 14% when quinapril and hydrochlorothiazide tablets were administered with a high-fat meal as compared to fasting, while the extent of absorption was not affected. The rate of hydrochlorothiazide absorption was reduced by 12% when quinapril and hydrochlorothiazide tablets were administered with a high-fat meal, while the extent of absorption was not significantly affected. Therefore, quinapril and hydrochlorothiazide may be administered without regard to food. 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, there is an effective accumulation half-life of quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed approximately 2 hours postdose. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins. Hydrochlorothiazide is not metabolized. Its apparent volume of distribution is 3.6 to 7.8 L/kg, consistent with measured plasma protein binding of 67.9%. The drug also accumulates in red blood cells, so that whole blood levels are 1.6 to 1.8 times those measured in plasma. Some placental passage occurred when quinapril was administered to pregnant rats. Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier. Hydrochlorothiazide crosses the placenta freely but not the blood-brain barrier. 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. Hydrochlorothiazide is excreted unchanged by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 4 to 15 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours. 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 have little effect on the elimination of quinapril and quinaprilat. Elimination of quinaprilat is 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. In a study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 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. Pharmacodynamics and Clinical Effects Single doses of 20 mg of quinapril 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 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 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. Therapeutic effects of quinapril 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. In patients with hypertension, quinapril 10 to 40 mg was similar in effectiveness to captopril, enalapril, propranolol, and thiazide diuretics. After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours. Use of quinapril with a thiazide diuretic gives blood pressure lowering effect greater than that seen with either agent alone. In clinical trials of quinapril/hydrochlorothiazide using quinapril doses of 2.5 to 40 mg and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects were sustained for at least 24 hours, and increased with increasing dose of either component. Although quinapril monotherapy is somewhat less effective in blacks than in non-blacks, the efficacy of combination therapy appears to be independent of race. By blocking the renin-angiotensin-aldosterone axis, administration of quinapril tends to reduce the potassium loss associated with the diuretic. In clinical trials of quinapril and hydrochlorothiazide, the average change in serum potassium was near zero when 2.5 to 40 mg of quinapril was combined with hydrochlorothiazide 6.25 mg, and the average subject who received 10 to 20/12.5 to 25 mg experienced a milder reduction in serum potassium than that experienced by the average subject receiving the same dose of hydrochlorothiazide monotherapy.

NDC 65862-161-90 Rx only Quinapril and Hydrochlorothiazide Tablets, USP   10 mg/12.5 mg AUROBINDO            90 Tablets PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 10 mg/12.5 mg (90 Tablet Bottle)