Quinaretic

Quinaretic is a 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 empirical formula is C25H30N2O5.HCl and its structural formula is:

M.W. = 474.98

Quinapril hydrochloride 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 empirical formula is C7H8ClN3O4S2 and its structural formula is:

M.W. = 297.72

Hydrochlorothiazide is a white to off-white, crystalline powder which is slightly soluble in water but freely soluble in sodium hydroxide solution.

Quinaretic is available for oral use as fixed combination tablets in three strengths of quinapril with hydrochlorothiazide: 10 mg with 12.5 mg (Quinaretic 10/12.5), 20 mg with 12.5 mg (Quinaretic 20/12.5), and 20 mg with 25 mg (Quinaretic 20/25).

Inactive ingredients: Carnauba wax powder, crospovidone, FD&C Yellow #6 Aluminum Lake, lecithin, magnesium hydroxide, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, talc, titanium dioxide and xanthum gum.

General

Derangements of Serum Electrolytes:

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 potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes.

Treatment with thiazide diuretics has been associated with hypokalemia, hyponatremia, and hypochloremic alkalosis. These disturbances have sometimes been manifest as one or more of dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, and vomiting. Hypokalemia can also sensitize or exaggerate the response of the heart to the toxic effects of digitalis. The risk of hypokalemia is greatest in patients with cirrhosis of the liver, in patients experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes, and in patients receiving concomitant therapy with corticosteroids or ACTH.

The opposite effects of quinapril and hydrochlorothiazide on serum potassium will approximately balance each other in many patients, so that no net effect upon serum potassium will be seen. In other patients, one or the other effect may be dominant. Initial and periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Chloride deficits secondary to thiazide therapy are generally mild and require specific treatment only under extraordinary circumstances (eg, in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of salt, except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Calcium excretion is decreased by thiazides. In a few patients on prolonged thiazide therapy, pathological changes in the parathyroid gland have been observed, with hypercalcemia and hypophosphatemia. More serious complications of hyperparathyroidism (renal lithiasis, bone resorption, and peptic ulceration) have not been seen.

Thiazides increase the urinary excretion of magnesium, and hypomagnesemia may result.

Other Metabolic Disturbances: Thiazide diuretics tend to reduce glucose tolerance and to raise serum levels of cholesterol, triglycerides, and uric acid. These effects are usually minor, but frank gout or overt diabetes may be precipitated in susceptible patients.

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.

Information for Patients

Angioedema: Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose. Patients receiving Quinaretic should be told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until after consulting with the prescribing physician.

Pregnancy: Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to ACE inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.

Symptomatic Hypotension: A patient receiving Quinaretic should be cautioned that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. The patient should be told that if syncope occurs, Quinaretic should be discontinued until the physician has been consulted.

All patients should be cautioned 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.

Patients planning to undergo major surgery and/or general or spinal anesthesia should be told to inform their physicians that they are taking an ACE inhibitor.

Hyperkalemia: A patient receiving Quinaretic should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.

Neutropenia: Patients should be told to promptly report any indication of infection (eg, sore throat, fever) which could be a sign of neutropenia.

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.

Laboratory Tests

The hydrochlorothiazide component of Quinaretic may decrease serum PBI levels without signs of thyroid disturbance.

Therapy with Quinaretic should be interrupted for a few days before carrying out tests of parathyroid function.

Drug Interactions

Potassium Supplements and Potassium-Sparing Diuretics: As noted above ("Derangements of Serum Electrolytes"), the net effect of Quinaretic may be to elevate a patient's serum potassium, to reduce it, or to leave it unchanged. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be given with caution, and the patient’s serum potassium should be monitored frequently.

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 Quinaretic, a thiazide diuretic is coadministered with the ACE inhibitor. Quinaretic and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended.

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.

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.

• Quinapril treatment did not affect the pharmacokinetics of digoxin.

• 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.

• 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 (eg, norepinephrine)-possible decreased response to pressor amines, but not sufficient to preclude their therapeutic use.

• Skeletal Muscle Relaxants, Nondepolarizing (eg, tubocurarine)-possible increased responsiveness to the muscle relaxant.

• Nonsteroidal Antiinflammatory Drugs-the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics may be reduced by concurrent administration of nonsteroidal antiinflammatory agents.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies have not been conducted in animals with Quinaretic.

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/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).

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 μg/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.

Pregnancy

Pregnancy Categories C (first trimester) and D (second and third trimesters): See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

Nursing Mothers

Because quinapril and hydrochlorothiazide are secreted in human milk, caution should be exercised when Quinaretic 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 Quinaretic, taking into account the importance of the drug to the mother.

Geriatric Use

Clinical studies of quinapril HCl/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.

Pediatric Use

Safety and effectiveness of Quinaretic in children have not been established.