Accuzide

Accuzide

quinapril + hydrochlorothiazide

Manufacturer:

Pfizer

Distributor:

Zuellig
Full Prescribing Info
Contents
Quinapril hydrochloride, hydrochlorothiazide.
Description
Each film-coated tablet contains 20 mg Quinapril and 12.5 mg of hydrochlorothiazide.
Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) is a fixed-combination tablet that combines an angiotensin-converting enzyme inhibitor, quinapril hydrochloride, and a 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 molecular weight is 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 molecular weight is 297.72.
Hydrochlorothiazide is a white to off-white, crystalline powder which is slightly soluble in water, but freely soluble in sodium hydroxide solution.
Quinapril 20 mg/Hydrochlorothiazide 12.5 mg is available for oral use as fixed-combination tablets.
Action
Pharmacologic Category: Antihypertensive.
Pharmacology: Pharmacodynamics: Quinapril/hydrochloride (Accuzide) is a fixed-combination tablet that combines an ACE inhibitor, quinapril hydrochloride, and a diuretic, hydrochlorothiazide.
In clinical studies, concomitant administration of quinapril and hydrochlorothiazide produced greater reductions in blood pressure than the single agents given alone. Concomitant administration of quinapril and hydrochlorothiazide has no effect on the pharmacokinetics of either drug.
As a result of its diuretic effect, hydrochlorothiazide increases plasma renin activity (PRA), increases aldosterone secretion, decreases serum potassium, and increases urinary potassium loss. Administration of quinapril inhibits the renin-angiotensin-aldosterone axis and tends to attenuate the potassium decrease associated with hydrochlorothiazide.
Mechanism of Action: Quinapril is rapidly deesterified to quinaprilat (quinapril diacid, the principal metabolite), which, in human and animal studies, is a potent ACE inhibitor. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II which is involved in vascular control and function through many different mechanisms, including stimulation of aldosterone secretion by the adrenal cortex. The mode of action of quinapril in humans and animals is to inhibit circulating and tissue ACE activity, thereby decreasing vasopressor activity and aldosterone secretion. Removal of angiotensin II negative feedback on renin secretion leads to increased 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 monotherapy 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.
In animal studies, the antihypertensive effect of quinapril outlasts its inhibitory effect on circulating ACE, whereas tissue ACE inhibition more closely correlates with the duration of its antihypertensive effects.
Administration of 10 mg to 80 mg of quinapril to patients with mild to severe hypertension results in a reduction of both sitting and standing blood pressure with minimal effect on heart rate. Antihypertensive activity commences within 1 hour, with peak effects usually achieved by 2 to 4 hours after dosing. Achievement of maximum blood pressure-lowering effects may require 2 weeks of therapy in some patients. At the recommended doses, antihypertensive effects are maintained in most patients throughout the 24-hour dosing interval and continued during long-term therapy.
Hemodynamic assessments in patients with hypertension have indicated 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, GFR, or filtration fraction.
The mechanism underlying the antihypertensive activity of diuretics is unknown. During chronic administration, peripheral vascular resistance is reduced; however, this may be secondary to changes in sodium balance.
Hydrochlorothiazide is a diuretic which acts directly on the kidney to increase excretion of sodium and chloride and an accompanying volume of water. Hydrochlorothiazide also increases the excretion of potassium and bicarbonate and decreases excretion of calcium. Chronic treatment with hydrochlorothiazide elevates PRA two- to six-fold.
After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 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 and 15 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours.
Hydrochlorothiazide crosses the placental but not the blood-brain barrier.
Concomitant therapy with thiazide-type diuretics gives a blood pressure-lowering effect greater than that seen with either agent alone.
Pharmacokinetics: Following oral administration, peak plasma quinapril concentrations are observed within 1 hour. Based on the recovery of quinapril and its metabolites in the urine, the extent of absorption is approximately 60%. The absorption of hydrochlorothiazide is somewhat slower (1-2.5 hours) and more complete (50%-80%). Thirty-eight percent of orally administered quinapril is systemically available as quinaprilat. Quinapril has an elimination half-life in plasma of approximately 1 hour. Peak plasma quinaprilat concentrations are observed approximately 2 hours following an oral dose of quinapril. Quinaprilat is eliminated primarily by renal excretion and has an effective accumulation half-life of 3 hours. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins.
In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine clearance decreases. Pharmacokinetic studies in patients with end-stage renal disease on chronic hemodialysis or continuous ambulatory peritoneal dialysis indicate that dialysis has little effect on the elimination of quinapril and quinaprilat. The elimination of quinaprilat is also reduced in elderly patients (≥65 years) and correlates well with their level of renal function. (See Dosage & Administration.)
Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier.
Pharmacokinetics in the Elderly: Elderly patients exhibited increased area under the plasma concentration time curve (AUC) and peak levels for quinaprilat compared to values observed in younger patients; this appeared to be related to decreased renal function rather than to age itself. Of the total number of patients who received quinapril hydrochloride/Hydrochlorothiazide (Accuzide) in clinical trials, 15% were 65 years and older, while 1.5% were 75 years or older. Overall differences in effectiveness or safety were not observed between these patients and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.
Toxicology: Preclinical Safety Data: Carcinogenicity, mutagenicity, and fertility studies have not been conducted in animals with Quinapril/Hydrochlorothiazide (Accuzide).
Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or 100 mg/kg/day (50-60 times the maximum human daily dose) for 104 weeks. Neither quinapril nor quinaprilat was 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 times the maximum daily human dose).
No fetotoxic or teratogenic effects were observed in rats at quinapril doses as high as 300 mg/kg/day (180 times the maximum daily human dose), despite maternal toxicity at 150 mg/kg/day. Offspring body weights were reduced in rats treated late in gestation and during lactation with doses of 25 mg/kg/day or more. Quinapril was not teratogenic in rabbits; however, as noted with other ACE inhibitors, maternal toxicity and embryotoxicity were seen in some rabbits at doses as low as 0.5 mg/kg/day and 1 mg/kg/day, respectively.
Hydrochlorothiazide was not mutagenic in vitro in the Ames microbial mutagen test at a maximum concentration of 5 mg/plate using strains TA98 and TA100. Urine samples from patients treated with hydrochlorothiazide did not have mutagenic activity in the Ames test. Hydrochlorothiazide induced sister chromatid exchanges but not chromosomal aberrations in Chinese hamster ovary cells with or without metabolic activation. Hydrochlorothiazide induced mutations in mouse lymphoma cells at high concentrations. The ability of a number of drugs to induce nondisjunction and crossing-over was measured using Aspergillus nidulans. A large number of drugs, including hydrochlorothiazide, induce nondisjunction.
Indications/Uses
Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) is indicated for the treatment of hypertension in patients for whom combination therapy with quinapril and a diuretic is appropriate.
Dosage/Direction for Use
For patients not currently receiving a diuretic, whether or not they have been receiving quinapril monotherapy, the recommended initial dosage of Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) is 10/6.25 mg. The usual maintenance dosage is 20/12.5 mg.
The dosage range of this combination product Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) allows the flexibility to titrate the individual components as clinically indicated.
In patients who are currently being treated with a diuretic, the recommended initial dose of quinapril is 5 mg to minimize the potential for excessive blood pressure reduction. The dosage should be titrated to achieve the desired reduction in blood pressure. If titration results in doses similar to that in the combination product, Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) may be substituted.
Dosage Adjustment in Renal Impairment: Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) should not be used as initial therapy in patients with renal impairment (creatinine clearance <60 mL/min). For patients with mild renal insufficiency (creatinine clearance 30-60 mL/min), begin therapy with 5 mg of quinapril and titrate as appropriate.
Patients requiring the addition of a diuretic may have their dosage titrated using Quinapril hydrochloride/Hydrochlorothiazide (Accuzide). The initial starting dose is 10/6.25 mg. Control of blood pressure may be maintained with usual doses of Quinapril hydrochloride/Hydrochlorothiazide (Accuzide).
When concomitant diuretic therapy is required in patients with severe renal impairment (<30 mL/min), a loop diuretic rather than a thiazide diuretic is preferred for use with quinapril. Therefore, for patients with severe renal dysfunction, Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) is not recommended.
Use in Elderly: Therapeutic effects 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.
Use in Children: Safety and effectiveness in pediatric patients have not been established.
Overdosage
No data are available for Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) with respect to overdosage in humans. The LD50 of Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) in combination ranges from 1063/664 mg/kg to 4640/2896 mg/kg in mice and rats.
The most likely clinical manifestation would be symptoms attributable to quinapril monotherapy overdosage, such as severe hypotension, which would usually be treated by infusion of intravenous normal saline solution.
The most common signs and symptoms observed for hydrochlorothiazide monotherapy overdosage are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.
No specific information is available on the treatment of overdosage with Quinapril hydrochloride/Hydrochlorothiazide (Accuzide). Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat.
Treatment is symptomatic and supportive consistent with established medical care.
Contraindications
Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) is contraindicated in patients who are hypersensitive to any component of this product, (i.e. Quinapril hydrochloride, Hydrochlorothiazide, Lactose monohydrate, Magnesium carbonate, Povidone, Crospovidone, Magnesium stearate, Opadry pink, Candelilla wax) including patients with a history of angioedema related to previous treatment with angiotensin-converting enzyme (ACE) inhibitors.
Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) is contraindicated in combination with sacubitril/valsartan due to the increased risk of angioedema.
Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) is also contraindicated in women who are pregnant, intend to become pregnant, or of childbearing potential who are not using adequate contraceptive measures. Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards to the fetus (see Use in Pregnancy & Lactation). Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
Do not administer Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) in combination with aliskiren: in patients with diabetes; in patients with moderate to severe kidney insufficiency (glomerular filtration rate [GFR] <60 mL/min/1.73 m2); in patients with hyperkalemia (>5 mmol/L); in congestive heart failure patients who are hypotensive.
Do not administer Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) in combination with angiotensin receptor blockers or other ACE inhibitors: in diabetic patients with end organ damage; in patients with moderate to severe kidney insufficiency (GFR <60 mL/min/1.73 m2); in patients with hyperkalemia (>5 mmol/L); in congestive heart failure patients who are hypotensive.
Special Precautions
Head and Neck Angioedema: Angioedema has been reported in patients treated with ACE inhibitors, including in 0.1% of patients receiving quinapril. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) should be discontinued immediately; the patient should be 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. Angioedema associated with laryngeal involvement may be fatal. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, emergency therapy, including, but not limited to, subcutaneous adrenalin (epinephrine) solution 1:1000 (0.3-0.5 mL), should be promptly administered.
Black patients receiving ACE inhibitor therapy have been reported to have a higher incidence of angioedema compared to non-black patients. 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-black patients. The incidence of angioedema in black and non-black patients during quinapril therapy has been calculated in two large open-label clinical trials evaluating the effectiveness of quinapril in the management of hypertension. In one study wherein 1656 black and 10,583 non-black patients were evaluated, the incidence of angioedema, regardless of association to quinapril treatment, was 0.3% in black patients and 0.39% in non-black patients. In the other study (1443 black and 9300 non-black patients), the incidence of angioedema was 0.55% in black patients and 0.17% in non-black patients.
Patients taking a concomitant mammalian target of rapamycin (mTOR) inhibitor (e.g. temsirolimus) or a concomitant dipeptidyl peptidase-IV (DPP-IV) inhibitor (e.g. vildagliptin) therapy or a neutral endopeptidase inhibitor may be at an increased risk for angioedema.
Caution should be used when starting an mTOR inhibitor or a DPP-IV inhibitor or a neutral endopeptidase inhibitor in a patient already taking an ACE inhibitor.
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 unrelated to ACE inhibitor therapy may be at an increased risk for angioedema while receiving an ACE inhibitor.
Anaphylactoid Reactions: Desensitization: Patients receiving ACE inhibitors during desensitizing treatment with hymenoptera venom have sustained life-threatening anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld, but they have reappeared upon inadvertent rechallenge.
Low-density lipoprotein apheresis: Patients undergoing low-density lipoprotein (LDL) apheresis with dextran-sulfate absorption when treated concomitantly with an ACE inhibitor have reported anaphylactoid reactions.
Hemodialysis: Clinical evidence has shown that patients hemodialyzed using certain high-flux membranes (such as polyacrylonitrile membranes) are likely to experience anaphylactoid reactions with concomitant ACE inhibitor treatment. This combination should be avoided, either by use of alternative antihypertensive drugs or alternative membranes for hemodialysis.
Dual Blockage of the Renin-Angiotensin System: Dual blockage of the renin-angiotensin system (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.
Routine combination therapy with RAS-acting agents is not recommended and should be limited to individually defined cases with close monitoring of renal function and blood potassium levels (see Contraindications).
Hypotension: Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) can cause symptomatic hypotension, usually not more frequently than either drug as monotherapy. Symptomatic hypotension was rarely seen in uncomplicated hypertensive patients treated with quinapril but is a possible consequence of ACE inhibitor therapy in salt/volume-depleted patients, such as those previously treated with diuretics, who have a dietary salt restriction, or who are on dialysis (see previously mentioned text).
Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) should be used cautiously in patients receiving concomitant therapy with other antihypertensive agents. The thiazide component of Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) may potentiate the action of other antihypertensive drugs, especially ganglionic or peripheral adrenergic-blocking drugs. The antihypertensive effects of the thiazide component may also be enhanced in the post sympathectomy patients.
In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy for hypertension may cause an excessive drop in blood pressure, which may be associated with oliguria, azotemia, and, in rare instances, acute renal failure and death in such patients. Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) therapy should be started under close medical supervision. Patients should be followed closely for the first 2 weeks of treatment and whenever the dosage is increased.
If symptomatic 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; however, lower doses of the drug should be considered if this event occurs.
Neutropenia/Agranulocytosis: ACE inhibitors have been rarely associated with agranulocytosis and bone marrow depression in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen vascular disease. Agranulocytosis has been rarely reported during treatment with quinapril. As with other ACE inhibitors, periodic monitoring of white blood cell counts in quinapril-treated patients with collagen vascular disease and/or renal disease should be considered.
Systemic Lupus Erythematosus: Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Fetal/Neonatal Morbidity and Mortality: See Use in Pregnancy & Lactation.
Impaired Renal Function: Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) should be used with caution in patients with severe renal disease. Thiazides may precipitate azotemia in such patients, and the effects of repeated dosing may be cumulative.
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors may be associated with oliguria and/or progressive azotemia and, rarely, acute renal failure and/or death (see Adverse Reactions).
The half-life of quinaprilat is prolonged as creatinine clearance falls. Patients with a creatinine clearance of <60 mL/min require a lower initial dosage of the drug (see Dosage & Administration). These patients' dosage should be titrated upwards based upon therapeutic response; renal function should be closely monitored, although initial studies do not indicate that the drug produces further deterioration in renal function.
Some quinapril-treated hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when quinapril has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction may be required. Evaluation of the hypertensive patient should always include assessment of renal function (see Dosage & Administration).
In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy (see Adverse Reactions).
Impaired Hepatic Function: Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. The metabolism of quinapril to quinaprilat is normally dependent upon hepatic esterase. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril.
Derangements of Serum Electrolytes: Serum electrolyte evaluation should be performed at appropriate intervals to detect possible electrolyte imbalance. As with other ACE inhibitors, patients on quinapril alone may have increased serum potassium levels. 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, potassium-containing salt substitutes, or other drugs known to raise serum potassium levels. The addition of a potassium-sparing diuretic to Quinapril hydrochloride/Hydrochlorothiazide (Accuzide), which contains a diuretic, is not recommended.
Conversely, treatment with thiazide diuretics has been associated with hypokalemia, hyponatremia, and hypochloremic alkalosis. These disturbances have sometimes been manifested as one or more of the following: Dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, confusion, seizures 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, experiencing a brisk diuresis, receiving inadequate oral intake of electrolytes, and receiving concomitant therapy with corticosteroids or adrenocorticotrophic hormone (ACTH) or with other drugs known to increase the risk of hypokalemia induced by thiazide diuretics.
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 (e.g. 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 should be discontinued before performing tests for parathyroid function.
Thiazides increase the urinary excretion of magnesium, and hypomagnesemia may result (see previously mentioned text and Interactions).
Other Metabolic Disturbances: Thiazide diuretics 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.
Diabetes: Thiazide-induced hyperglycemia may compromise blood sugar control. Depletion of serum potassium augments glucose intolerance. Monitor glycemic control, supplement potassium, if necessary, to maintain appropriate serum potassium levels, and adjust diabetes medications as required (see Interactions.)
ACE inhibitors have been associated with hypoglycemia in diabetic patients on insulin or oral hypoglycemic agents; closer monitoring of diabetic patients may be required.
Cough: Cough has been reported with the use of ACE inhibitors, including quinapril. Characteristically, the cough is nonproductive, persistent, and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
Surgery/Anesthesia: Caution should be exercised when patients undergo major surgery or anesthesia since ACE inhibitors have been shown to block angiotensin II formation secondary to compensatory renin release. This may lead to hypotension, which can be corrected by volume expansion.
Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain, and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothizide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Non-melanoma Skin Cancer: An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide exposure has been observed in epidemiological studies. Photosensitizing actions of hydrochlorothiazide could act as a possible mechanism for NMSC.
Patients taking Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) should be monitored for SCC and BCC, especially those with a history of skin cancer and/or risk factors (see Adverse Reactions).
Information for Patients: Angioedema: Angioedema, including laryngeal edema, may occur with ACE inhibitors, especially following the first dose. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of the face, extremities, eyes, lips, and tongue and difficulty in swallowing or breathing) and to stop taking Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) until patients have consulted with the physician.
Hypotension: Patients should be cautioned to report lightheadedness, especially during the first few days of Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) therapy. If actual syncope occurs, patients should be told to discontinue therapy until patients have consulted with the physician.
All patients should be cautioned that inadequate fluid intake, excessive perspiration, or dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion, such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with the physician.
Surgery/Anesthesia: Patients planning to undergo any surgery and/or anesthesia should be told to inform the physician that they are taking an ACE inhibitor.
Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting the physician.
Neutropenia: Patients should be told to report promptly any indication of infection (e.g. sore throat, fever) as this could be a sign of neutropenia.
Skin Cancer: Patients taking Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and ultraviolet (UV) rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer.
NOTE: As with many other drugs, certain advice to patients being treated with Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) 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.
Effects on Ability to Drive or Use Machines: The ability to engage in activities, such as operating machinery or operating a motor vehicle may be impaired, especially when initiating Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) therapy.
Use in Pregnancy: Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) must not be used by women who are pregnant, intend to become pregnant, or could become pregnant and who are not using adequate contraceptive measures because of the potential of drug effects that may seriously injure or even cause fatality to a developing fetus (see Contraindications and Fetal/Neonatal Morbidity and Mortality as previously mentioned.)
Use In Pregnancy & Lactation
Pregnancy: Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) is contraindicated in pregnancy (see Contraindications). ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) should be discontinued.
Infants exposed to ACE inhibitors during pregnancy may be at increased risk for malformations of the cardiovascular system and central nervous system. There have also been reports of prematurity, hypotension, renal system disorders (including renal failure), skull hypoplasia, oligohydramnios, limb contractures, craniofacial deformities, hypoplastic lung development, intrauterine growth retardation, patent ductus arteriosus, fetal death and/or death in the newborn in association with the maternal use of ACE inhibitors. Patients and physicians should be aware that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants who may have been exposed in utero to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion.
Thiazides cross the placental barrier and appear in cord blood. Nonteratogenic effects to the fetus may include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have been occurred in the adult.
There are no adequate and well-controlled studies of Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) in pregnant women.
Nursing Mothers: ACE inhibitors, including quinapril, are secreted in human milk to a limited extent. Thiazides appear in human milk. Because of the potential for serious reactions in nursing infants, a decision should be made whether to discontinue Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) or discontinue nursing, taking into account the importance of the drug to the mother.
Adverse Reactions
Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) has been evaluated for safety in 1571 patients in controlled and uncontrolled studies. In clinical trials with Quinapril hydrochloride/Hydrochlorothiazide (Accuzide), no adverse experience specific to the combination has been observed. Adverse experiences that have occurred have been limited to those previously reported with quinapril or hydrochlorothiazide. In controlled trials, the most frequent adverse experiences reported in at least 1% of patients with any combination of quinapril and hydrochlorothiazide were headache (6.7%), dizziness (4.8%), cough (3.2%), and fatigue (2.9%). It should be noted that, characteristically, the cough is nonproductive, persistent and resolves after discontinuation of therapy. Generally, adverse experiences were mild and transient in nature, and there was no relationship between side effects and age, sex, race, or duration of therapy (see Angioedema and Hypertension under Precautions). Discontinuation of therapy due to adverse effects was required in approximately 2% of patients. Headache (0.5%) was the most common reason for withdrawal followed by cough and nausea and/or vomiting (0.2%). Adverse experiences occurring in ≥1% of patients treated with Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) in controlled trials are shown as follows (N=943). (See Table.)

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Clinical adverse experiences probably, possibly, or definitely related or of uncertain relationship to therapy, occurring in 0.5% to <1.0% of patients treated with quinapril plus hydrochlorothiazide in controlled and uncontrolled trials and less frequently clinically significant events seen in clinical trials, post-marketing experience (indicated by *), or with hydrochlorothiazide included: Neoplasms benign, malignant and unspecified (including cysts and polyps): Basal cellcarcinoma, *squamous cell carcinoma (see Precautions)*.
Blood and lymphatic system disorders:
hemolytic anemia*, thrombocytopenia*.
Immune system disorders: anaphylactoid reaction*.
Psychiatric disorders: nervousness.
Nervous system disorders: paresthesia.
Cardiac disorders: palpitations, tachycardia.
Vascular disorders: hypotension, postural hypotension*, syncope*.
Respiratory, thoracic and mediastinal disorders: dyspnea, sinusitis.
Gastrointestinal disorders: dry mouth or throat, flatulence, pancreatitis*.
Hepatobiliary disorders: hepatitis*.
Skin and subcutaneous tissue disorders: alopecia*, erythema multiforme, exfoliative dermatitis*, pemphigus*, photosensitivity reaction*, pruritus, rash, (Hydrochlorothiazide) Stevens-Johnson syndrome.
Musculoskeletal and connective tissue disorders: arthralgia.
Renal and urinary disorders: urinary tract infection (see Precautions).
Eye disorders: acute myopia and acute angle closure glaucoma (see Precautions).
Reproductive system and breast disorders: impotence.
Congenital, familial, and genetic disorders: See Contraindications and Use in Pregnancy & Lactation.
General disorders and administration site conditions: peripheral edema.
Quinapril has been evaluated for safety in 4960 subjects and patients and was well tolerated. Of these, 3203 patients including 655 elderly patients participated in controlled clinical trials. Quinapril has been evaluated for long-term safety in over 1400 patients treated for 1 year or more.
Clinical Laboratory Test Findings: Serum Electrolytes: see Contraindications and Precautions.
Creatinine, Blood Urea Nitrogen: Increases (>1.25 times the upper limit of normal) in serum creatinine and blood urea nitrogen were observed in 3% and 4%, respectively, of patients treated with quinapril/hydrochlorothiazide (see Precautions).
Serum Uric Acid, Glucose, Magnesium, Cholesterol, Triglyceride, Protein-Bound Iodine (PBI), Parathyroid Function tests and Calcium: See Precautions.
Hematology: See Precautions.
Drug Interactions
Tetracycline and Other Drugs that Interact with Magnesium: Administration of tetracycline with quinapril reduced the absorption of tetracycline by approximately 28% to 37% in subjects. Decreased absorption is due to the presence of magnesium carbonate as an excipient in the quinapril formulation. This interaction should be considered when contemplating concurrent therapy with Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) and tetracycline or other drugs that interact with magnesium.
Lithium: Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy due to the sodium-losing effect of these agents. With Quinapril hydrochloride/Hydrochlorothiazide (Accuzide), the risk of lithium toxicity may be increased. Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) should be administered with caution, and frequent monitoring of serum lithium levels is recommended.
Nonsteroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors: In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of nonsteroidal anti-inflammatory agents/drugs (NSAIDs), including selective cyclooxygenase-2 (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.
Other Drugs Known to Cause Angioedema: Patients taking a concomitant mTOR inhibitor (e.g. temsirolimus) or a concomitant DPP-IV inhibitor (e.g. vildagliptin) therapy or a neutral endopeptidase inhibitor may be at an increased risk for angioedema. Caution should be used when starting an mTOR inhibitor or a DPP-IV inhibitor or a neutral endopeptidase inhibitor in a patient already taking an ACE inhibitor.
Other Agents: No clinically important pharmacokinetic interactions occurred when quinapril was used concomitantly with propranolol, hydrochlorothiazide, or cimetidine.
The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was not significantly changed by quinapril co-administration twice daily.
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.
Thiazide-induced hyperglycemia may compromise blood sugar control. Depletion of serum potassium augments glucose intolerance. Monitor glycemic control, supplement potassium, if necessary to maintain appropriate serum potassium levels, and adjust diabetes medications as required. (see Precautions.)
Other antihypertensive drugs: Additive effect or potentiation.
Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia.
Pressor amines (e.g., norepinephrine): Possible decreased response to pressor amines, but not sufficient to preclude their use.
Skeletal muscle relaxants, non-depolarizing (e.g. tubocurarine): Possible increased responsiveness to the muscle relaxant.
Nonsteroidal anti-inflammatory drugs: In some patients, the administration of a NSAID can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Therefore, when Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) is obtained.
Agents increasing serum potassium: Quinapril is an ACE inhibitor capable of lowering aldosterone levels, which in turn can result in potassium retention. Therefore, concomitant therapy of quinapril with potassium supplements, potassium-containing salt substitutes or other drugs known to raise serum potassium levels should be used with caution along with appropriate monitoring of serum potassium (see Precautions). Since Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) contains a diuretic, the addition of a potassium-sparing diuretic is not recommended. In patients who are elderly or have compromised renal function, co-administration of an ACE inhibitor with sulfamethoxazole/trimethoprim has been associated with severe hyperkalemia, which is thought to be due to trimethoprim. Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) and trimethoprim-containing products should therefore be co-administered with caution and with appropriate monitoring of serum potassium.
Digoxin: Thiazide-induced electrolyte disturbances, i.e. hypokalemia, hypomagnesemia, increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events. (See Precautions.)
Anion exchange resins: Absorption of hydrochlorothiazide is impaired in the presence of anion exchange resins, such as cholestyramine and colestipol. Single doses of the resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.
Dual blockage of the renin-angiotensin system: Dual blockage 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. Closely monitor blood pressure, renal function and electrolytes in patients on Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) and other agents that affect the RAS.
Do not administer Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) in combination with aliskiren in patients with diabetes, in patients with moderate to severe kidney insufficiency (GFR <60 mL/min/1.73 m2), in patients with hyperkalemia (>5 mmol/L) or in congestive heart failure patients who are hypotensive (see Contraindications).
Do not administer Quinapril hydrochloride/Hydrochlorothiazide (Accuzide) in combination with angiotensin receptor blockers or other ACE inhibitors in diabetic patients with end organ damage, in patients with moderate to severe kidney insufficiency (GFR <60 mL/min/1.73 m2), in patients with hyperkalemia (>5 mmol/L), or in congestive heart failure patients who are hypotensive (see Contraindications).
Gout medications (allopurinol, uricosurics, xanthine oxidase inhibitors): Thiazide-induced hyperuricemia may compromise control of gout by allopurinol and probenecid. The co-administration of HCTZ and allopurinol may increase the incidence of hypersensitivity reactions to allopurinol.
Storage
Store at temperatures not exceeding 30°C. Protect from light.
ATC Classification
C09BA06 - quinapril and diuretics ; Belongs to the class of ACE inhibitors in combination with diuretics. Used in the treatment of cardiovascular disease.
Presentation/Packing
FC tab 20/12.5 mg (pink, scored, triangular, biconvex) x 50's.
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