Accuretic is a fixed-combination tablet which combines the antihypertensive actions of an angiotensin-converting enzyme (ACE) inhibitor, quinapril HCl, and a diuretic, hydrochlorothiazide. In clinical studies, administration of this combination produced greater reductions in blood pressure than the single agents given alone.

Pharmacokinetics and Metabolism: Quinapril: Following oral administration of quinapril, peak plasma concentrations of quinapril occur within 1 hour. Based on the recovery of quinapril and its metabolites in urine, the extent of absorption is at least 60%. Following absorption, quinapril is de-esterified to its major active metabolite, quinaprilat (quinapril diacid), a potent ACE inhibitor, and to minor inactive metabolites. Quinapril has an apparent half-life in plasma of approximately 1 hour. Peak plasma quinaprilat concentrations occur approximately 2 hours after an oral dose of quinapril. Quinaprilat is eliminated primarily by renal excretion and has an effective accumulation half-life of approximately 3 hours. Quinaprilat has an elimination half-life in plasma of approximately 2 hours with a prolonged terminal phase of 25 hours. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins.

Pharmacokinetic studies in patients with end-stage renal disease or chronic hemodialysis or continuous ambulatory peritoneal dialysis indicate that dialysis has little effect on the elimination of quinapril and quinaprilat.

The disposition of quinapril and quinaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until creatinine clearance is 60 mL/min or less. With creatinine clearance less than 60 mL/min, peak and trough quinaprilat concentrations increase, apparent half-life increases, and time to steady-state may be delayed. The elimination of quinaprilat may be reduced in elderly patients (>65 years) and in those with heart failure; this reduction is attributable to decrease in renal function (See Dosage). Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired de-esterification of quinapril.

The rate and extent of quinapril absorption are diminished moderately (approximately 25 to 30%) when administered during a high-fat meal. However, no effect on quinapril absorption occurs when taken during a regular meal.

Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier.

Hydrochlorothiazide: After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours; the extent of absorption is approximately 50 to 80%. 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. Hydrochlorothiazide crosses the placental but not the blood-brain barrier.

Quinapril/Hydrochlorothiazide: Concomitant administration of quinapril and hydrochlorothiazide has little or no effect on the bioavailability or the pharmacokinetics of either drug.

Pharmacodynamics: Quinapril: Quinapril is a nonpeptide, nonsulphydryl ACE inhibitor. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor angiotensin II. After absorption, quinapril is rapidly de-esterified to quinaprilat (quinapril diacid), its principal active metabolite. Its primary mode of action is to inhibit circulating and tissue ACE, thereby decreasing vasopressor activity and aldosterone secretion. Although the decrease in aldosterone is small, it results in a small increase in serum K(see Precautions). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.

ACE is identical to kininase II. Thus, quinapril may interfere with the degradation of bradykinin, a potent peptide vasodilator. However, it is not known whether this system contributes to the therapeutic effects of quinapril.

The antihypertensive effect of quinapril outlasts its inhibitory effect on circulating ACE in animal studies. Tissue ACE inhibition more closely correlates with the duration of antihypertensive effects and this may be related to enzyme-binding characteristics as shown for quinapril on purified tissue ACE from human kidney and heart.

Administration of 10 to 40 mg of quinapril to patients with essential 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 to 4 weeks of therapy in some patients. At the recommended doses, antihypertensive effects are maintained throughout the 24-hour dosing interval in most patients. While the dose response relationship is relatively flat, a dose of 40 mg was somewhat more effective at trough than 10 to 20 mg, and twice daily dosing tended to give a somewhat lower blood pressure than once daily dosing with the same total daily dose. The antihypertensive effect of quinapril was maintained during long-term therapy with no evidence of loss of effectiveness.

Hemodynamic assessments in patients with essential 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 and cardiac index. There was an increase in renal blood flow that was not significant. Little or no change in glomerular filtration rate or filtration fraction was observed.

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.

The antihypertensive effect of angiotensin-converting enzyme inhibitors is generally lower in black patients than in non-blacks.

Hydrochlorothiazide: Hydrochlorothiazide 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 calcium excretion.

As a result of its diuretic effect, hydrochlorothiazide increases plasma renin activity, 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.

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.

Quinapril/Hydrochlorothiazide: When quinapril and hydrochlorothiazide are given together, the antihypertensive effects are approximately additive.

For the treatment of essential hypertension in patients for whom combination therapy is appropriate.

In using Accuretic, consideration should be given to the risk of angioedema (see Warnings, Angioedema).

Quinapril should normally be used in those patients in whom treatment with a diuretic or a beta-blocker was found ineffective or has been associated with unacceptable adverse effects. Quinapril can also be tried as an initial agent in those patients in whom use of diuretics and/or beta-blockers is contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects.

Accuretic is not indicated for initial therapy. Patients in whom quinapril and hydrochlorothiazide are initiated simultaneously can develop symptomatic hypotension (see Warnings, Hypotension and Precautions, Drug Interactions).

Patients should be titrated on the individual drugs. If the fixed combination represents the dosage determined by this titration, the use of Accuretic may be more convenient in the management of patients. If during maintenance therapy dosage adjustment is necessary, it is advisable to use individual drugs.

When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected, Accuretic should be discontinued as soon as possible (see Warnings, Pregnancy and Information for the Patient).

Patients who are hypersensitive to any component of this product (see Supplied) and patients with a history of angioedema related to previous treatment with an ACE inhibitor. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Angioedema: Angioedema has been reported in patients treated with ACE inhibitors, including quinapril. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with Accuretic should be discontinued immediately, the patient treated appropriately 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, although antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis or larynx likely to cause airway obstruction, appropriate therapy (including but not limited to 0.3 to 0.5 mL of s.c. epinephrine solution 1:1 000) should be administered promptly (see Adverse Effects).

The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in non-black patients.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see Contraindications).

Hypotension: Symptomatic hypotension has occurred after administration of quinapril, usually after the first or second dose or when the dose was increased. It is more likely to occur in patients who are volume-depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In patients with ischemic heart or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident (see Adverse Effects). Because of the potential fall in blood pressure in these patients, therapy with Accuretic should be started under close medical supervision. Such patients should be followed closely for the first weeks of treatment and whenever the dose of Accuretic is increased. In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.

If hypotension occurs, the patient should be placed in supine position and, if necessary, receive an i.v. infusion of 0.9% sodium chloride. A transient hypotensive response is not a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion. If symptoms persist, the dosage should be reduced or the drug discontinued.

Neutropenia/Agranulocytosis: Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Agranulocytosis did occur during quinapril treatment in one patient with a history of neutropenia during previous captopril therapy. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and/or renal disease.

Azotemia: Azotemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotemia and oliguria occur, Accuretic should be discontinued.

Impairment of Liver Function: Hepatitis (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with other ACE inhibitors in patients with or without pre-existing liver abnormalities. In most cases the changes were reversed on discontinuation of the drug.

Elevations of liver enzymes and/or serum bilirubin have been reported for Accuretic (see Adverse Effects). Should the patient receiving Accuretic experience any unexplained symptoms particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigation be carried out. Discontinuation of Accuretic should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. Accuretic should be used with particular caution in patients with pre-existing liver abnormalities. In such patients baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.

Hypersensitivity to Hydrochlorothiazide: Sensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported in patients treated with hydrochlorothiazide.

Pregnancy : ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, Accuretic should be discontinued as soon as possible.

In rare cases (probably less than 0.1% of pregnancies) in which no alternative to ACE inhibitor therapy will be found, the mothers should be apprised of the potential hazards to their fetuses. Serial ultrasound examinations should be performed to assess fetal development and well-being and the volume of amniotic fluid.

If oligohydramnios is observed, quinapril should be discontinued unless it is considered life-saving to the mother. A non-stress test (NST) and/or a biophysical profiling (BPP) may be appropriate, depending on the week of pregnancy. If concerns regarding fetal well-being still persist, a contraction stress test (CST) should be considered. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with a history of in utero exposure 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. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit. Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat.

Human Data: It is not known whether quinapril exposure limited to the first trimester of pregnancy can adversely affect fetal outcome. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation and hypoplastic lung development. Prematurity, intrauterine growth retardation and patent ductus arteriosus have also been reported, although is not clear whether these occurrences were due to the ACE-inhibitor exposure.

Thiazides cross the placental barrier and appear in cord blood. Although studies in humans have not been done, effects to the fetus may include fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which have occurred in the adult.

Animal Data: 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 hydrochloride was not teratogenic in rabbits; however, maternal and embryo toxicity were seen in some rabbits at doses as low as 0.5 mg/kg/day and 1 mg/kg/day, respectively.

No adverse effects on fertility or reproduction were observed in rats at quinapril dose levels up to 100 mg/kg/day (60 times the maximum daily human dose).

Renal Impairment: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia and, rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.

Use of Accuretic should include appropriate assessment of renal function.

Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 mL/min or below (i.e., moderate or severe renal insufficiency).

Hyperkalemia: Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately 2% of patients receiving quinapril. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in less than 0.1% of hypertensive patients. Risk factors for the development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia (See Precautions, Drug Interactions : Agents Increasing Serum Potassium, and Adverse Effects). The addition of a potassium-sparing diuretic to Accuretic, which contains a diuretic, is not recommended.

Patients with Impaired Liver Function: Accuretic 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. Also, since the metabolism of quinapril to quinaprilat is normally dependent upon hepatic esterase, patients with impaired liver function could develop markedly elevated plasma levels of quinapril.

Valvular Stenosis: There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

Metabolism: Hyperuricemia may occur, or acute gout may be precipitated, in certain patients receiving thiazide therapy.

Thiazides may decrease serum PBI levels without signs of thyroid disturbance.

Increase in cholesterol, triglyceride and glucose levels may be associated with thiazide diuretic therapy. Overt diabetes may be precipitated in susceptible individuals.

Initial and periodic determination of serum electrolytes 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 (see Precautions, Hyperkalemia). Conversely, treatment with thiazide diuretics has been associated with hyperkalemia. The opposite effects of hydrochlorothiazide and quinapril on serum potassium may approximately balance each other in many patients so that no net effect will be seen. In other patients, one or the other effect may be dominant.

In addition to hypokalemia, treatment with thiazide diuretics has also been associated with hyponatremia and hypochloremic alkalosis. These disturbances have sometimes been manifest as one or more of the following: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain 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, 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. 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, especially in hot weather; appropriate therapy is water restriction rather than administration of salt, except when the hyponatremia is life-threatening. In actual salt depletion, replacement of salt is the therapy of choice.

Thiazides may decrease calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hypoparathyroidism. 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.

Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, ACE inhibitors will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Systemic Lupus Erythematosus: Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. 

Cough: A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of quinapril, has been reported. Such possibility should be considered as part of the differential diagnosis of the cough. 

Lactation: Quinapril and quinaprilat are secreted in trace amounts in human milk. Thiazides appear in human milk. Caution should be exercised when Accuretic is given to a nursing mother and, in general, nursing should be interrupted. 

Children: The safety and effectiveness of Accuretic in children have not been established; therefore, use in this age group is not recommended. 

Anaphylactoid Reactions during Membrane Exposure: Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent. 

Anaphylactoid Reactions during LDL Apheresis: Rarely, patients receiving ACE inhibitors during low density lipoprotein apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding the ACE inhibitor therapy prior to each apheresis. 

Anaphylactoid Reactions during Desensitization: There have been isolated reports of patients experiencing sustained life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitizing treatment with hymenoptera (bees, wasps) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge to an ACE inhibitor. 

Drug Interactions : Concomitant Diuretic Therapy: Patients concomitantly taking ACE inhibitors and diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy. The possibility of hypotensive effects after the first dose of quinapril can be minimized by either discontinuing the diuretic or increasing the salt intake (except in patients with heart failure) prior to initiation of treatment with quinapril. If it is not possible to discontinue the diuretic, the starting dose of quinapril should be reduced and the patient should be closely observed for several hours following initial dose and until blood pressure has stabilized (see Warnings and Dosage). 

Agents Increasing Serum Potassium: Since quinapril decreases aldosterone production, elevation of serum potassium may occur. Potassium-sparing diuretics, such as spironolactone, triamterene or amiloride, or potassium supplements, should be given only for documented hypokalemia and with caution and frequent monitoring of serum potassium since they may lead to a significant increase in serum potassium. Salt substitutes which contain potassium should also be used with caution.

Agents Affecting Sympathetic Activity: Agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents) may be used with caution. Beta-adrenergic blocking drugs add some further antihypertensive effect to quinapril.

Tetracycline: Concomitant administration of tetracycline with quinapril reduced the absorption of tetracycline in healthy volunteers (by 28 to 37%) due to the presence of magnesium carbonate as an excipient in the formulation. This interaction should be considered with concomitant use of Accuretic and tetracycline or other drugs which interact with magnesium.

Lithium: In general, lithium should not be given with diuretics or ACE inhibitors. Diuretic agents and ACE inhibitors reduce the renal clearance of lithium and add a high risk of lithium toxicity.

Cardiac Glycosides: Thiazide diuretics may enhance digitalis toxicity associated with hypokalemia or hypomagnesemia.

Alcohol, Barbiturates, or Narcotics: Potentiation of orthostatic hypotension may occur in the presence of hydrochlorothiazide.

Antidiabetic Drugs: Dosage adjustment of oral hypoglycemic agents and insulin may be required.

Other Antihypertensive Agents: Additive effects may occur.

Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia, may occur when administered with hydrochlorothiazide.

Pressor Amines, (e.g., norepinephrine): Possible decreased response to pressor amines may occur in the presence of a thiazide diuretic, but is not sufficient to preclude their use.

Nondepolarizing Neuromuscular Blocking Agents (e.g., d-tubocurarine): Hydrochlorothiazide may increase responsiveness to these drugs.

Nonsteroidal Anti-inflammatory Drugs: In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when Accuretic and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of Accuretic is obtained.

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.

Information to be Provided to the Patient: Note: As with many other drugs, certain advice to patients being treated with Accuretic 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.

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, such as swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing. They should immediately stop taking Accuretic and consult with their physician.

Pregnancy: Since the use of quinapril during pregnancy can cause injury and even death of the developing fetus, patients should be advised to report promptly to their physician if they become pregnant.

Hypotension: Patients should be cautioned to report light-headedness, especially during the first few days of Accuretic therapy. If actual syncope occurs, patients should be told to discontinue the drug and consult with their physician.

All patients should be cautioned that excessive perspiration and 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 their physician.

Agranulocytosis/Neutropenia: Patients should be told to report promptly to their physician any indication of infection (e.g., sore throat, fever) as this may be a sign of neutropenia.

Impaired Liver Function: Patients should be advised to return to their physician if they experience any symptoms possibly related to liver dysfunction. This would include “viral-like symptoms” in the first weeks to months of therapy (such as fever, malaise, muscle pain, rash or adenopathy which are possible indicators of hypersensitivity reactions) or if abdominal pain, nausea or vomiting, loss of appetite, jaundice, itching or any other unexplained symptoms occur during therapy.

Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician.

Surgery: Patients planning to undergo surgery and/or anesthesia should be told to inform their physician that they are taking an ACE inhibitor.

Accuretic has been evaluated for safety in 1 571 patients with essential hypertension, including 943 patients in controlled studies (see Table I), 345 patients in placebo-controlled trials and 517 patients who were treated with Accuretic for at least 1 year. Adverse reactions have been limited to those reported previously with quinapril or hydrochlorothiazide when used separately for the treatment of hypertension.

Serious or clinically significant adverse reactions observed in less than 0.2% of patients treated with quinapril and hydrochlorothiazide were: hematemesis, gout, syncope and angioedema. Therapy was discontinued in 2.1% of patients due to an adverse event. Headache (0.5%) and dizziness (0.3%) were the most frequent reasons for withdrawal.

The most frequent adverse experiences in controlled trials were headache (6.7%), dizziness (4.8%), cough (3.2%) and fatigue (2.9%). The cough is characteristically nonproductive, persistent and resolves after discontinuation of therapy (see Warnings, Angioedema and Hypotension).

Clinical adverse events, regardless of relationship to therapy, occurring in >0.5% to <1% of patients treated with quinapril plus hydrochlorothiazide in controlled and uncontrolled trials and less frequent clinically significant events seen in clinical trials or in postmarketing experience included: Cardiovascular: tachycardia, hypotension, palpitations.

Gastrointestinal: flatulence, dry mouth or throat, pancreatitis.

Respiratory: dyspnea, sinusitis.

Integumentary: erythema multiforme, exfoliative dermatitis, alopecia, pemphigus, pruritus, rash.

Nervous/Psychiatric: paresthesia, nervousness.

Urogenital: impotence, urinary tract infection.

Other: arthralgia, peripheral edema, hemolytic anemia.

Rare adverse events, not listed above, which have been reported with either hydrochlorothiazide, quinapril, or the combination, include: Cardiovascular: cerebrovascular accident, heart failure, atrial flutter, vasodilation, necrotizing angiitis, myocardial ischemia, heart arrest, transient ischemic attack. Orthostatic hypotension may occur, especially in elderly patients with reduced plasma volume, and may be potentiated by alcohol, barbiturates, or narcotics.

Gastrointestinal: anorexia, gastric irritation, cramping, constipation, jaundice (intrahepatic cholestatic), pancreatitis, sialadenitis, gastrointestinal hemorrhage, bloody stools.

Respiratory: respiratory distress including pneumonitis, asthma, hoarseness.

Integumentary: photosensitivity, rash, urticaria, Stevens-Johnson syndrome, eczema.

Nervous System: paresthesias, xanthopsia, confusion, amnesia, anxiety, facial paralysis, polyneuritis.

Hematological: leukopenia, thrombocytopenia, agranulocytosis, aplastic anemia, hemolytic anemia, purpura.

Urogenital: dysuria, polyuria, impaired renal function, hematuria, glycosuria.

Special Senses: tinnitus, transient blurred vision, taste disturbance.

Other: muscle spasm, weakness, restlessness, chill, weight increase, dehydration, arthritis, allergy, face edema, fever, anaphylactic reactions, fracture.

Laboratory Deviations: WBC decreased, hyperglycemia, azotemia, hyperglycemia, transient hyperlipidemia, hyperuricemia.

Clinical Laboratory Test Findings: Creatinine, Blood 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 Accuretic (see Precautions).

Hepatic: Elevations of liver enzymes and/or serum bilirubin have occurred (see Precautions).

Glucose: Elevations in glucose values have occurred (see Precautions).

Triglyceride: Elevations in triglyceride values have occurred (see Precautions).

Serum Uric Acid: Elevations in serum uric acid values have occurred (see Precautions).

Hematology: Possibly clinically important increases and decreases in hematology parameters have occurred (see Warnings).

Other laboratory test values with clinically important deviations during controlled and uncontrolled trials included: magnesium, cholesterol, PBI, parathyroid function tests and calcium (see Precautions); hematology (see Warnings).

Symptoms and Treatment: No data are available regarding overdosage of Accuretic or quinapril in humans. The most likely clinical manifestation would be symptoms attributable to severe hypotension, which should be normally treated by i.v. volume expansion with 0.9% sodium chloride.

Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat.

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.

Dosage must be individualized. The fixed combination is not for initial therapy. The dose of Accuretic should be determined by titration of the individual components.

Once the patient has been successfully titrated with the individual components as described below, Accuretic may be substituted if the titrated doses and dosing schedule can be achieved by the fixed combination (see Indications and Warnings). In some patients, a twice daily administration may be required.

Patients do not generally require hydrochlorothiazide in excess of 50 mg daily, particularly when combined with other antihypertensive agents.

Monotherapy: The recommended initial dose of quinapril in patients not on diuretics is 10 mg once daily. An initial dose of 20 mg once daily can be considered for patients without advanced age, renal impairment, or concomitant heart failure and who are not volume-depleted (see Precautions, Hypotension). Dosage should be adjusted according to blood pressure response, generally at intervals of 2 to 4 weeks. A dose of 40 mg daily should not be exceeded.

In some patients treated once daily, the antihypertensive effect may diminish towards the end of the dosing interval. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, either twice daily administration with the same total daily dose, or an increase in dose should be considered. If blood pressure is not controlled with quinapril alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of quinapril.

Concomitant Diuretic Therapy: Symptomatic hypotension occasionally may occur following the initial dose of quinapril and is more likely in patients who are currently being treated with a diuretic. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with quinapril to reduce the likelihood of hypotension (see Warnings). If the diuretic cannot be discontinued, an initial dose of 5 mg of quinapril should be used with careful medical supervision for several hours and until blood pressure has stabilized. The dosage of quinapril should subsequently be titrated (as described above) to the optimal response.

Dosage Adjustment in Renal Impairment: For use in hemodialysis patients, see Precautions, Anaphylactoid Reactions during Membrane Exposure. Quinapril should be administered on days when dialysis is not performed.

Patients should subsequently have dosage titrated (as described above) to the optimal response as described under Monotherapy.

When concomitant diuretic therapy is required in patients with severe renal impairment, a loop diuretic rather than a thiazide is preferred for use with quinapril. Therefore, for patients with severe renal dysfunction, Accuretic is not recommended.

Geriatrics: The recommended initial dosage of quinapril is 10 mg once daily (depending on renal function) followed by titration to the optimal response as described above under Monotherapy.

10/12.5: Each pink, scored, elliptical, biconvex, film-coated tablet contains: quinapril 10 mg and hydrochlorothiazide 12.5 mg. Nonmedicinal ingredients: candelilla wax, crospovidone, lactose, magnesium carbonate, magnesium stearate, povidone, synthetic red iron oxide, synthetic yellow iron oxide and titanium dioxide. Blisters of 28.

20/12.5: Each pink, scored, triangular, biconvex, film-coated tablet contains: quinapril 20 mg and hydrochlorothiazide 12.5 mg. Nonmedicinal ingredients: candelilla wax, crospovidone, lactose, magnesium carbonate, magnesium stearate, povidone, synthetic red iron oxide, synthetic yellow iron oxide and titanium dioxide. Blisters of 28.

Store at controlled room temperature 15 to 30°C. Dispense in well-closed containers.