Accuretic

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 of age) 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.

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.

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.

The presence of concentrations of ACE inhibitor have been reported in human milk. Thiazides appear in human milk. Use of ACE inhibitors is not recommended during breast-feeding.

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.

Serious Warning and Precautions

Accuretic should not be used during pregnancy. Patients should be advised to stop the medication and contact their physician as soon as possible if they discover that they are pregnant while taking Accuretic.

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 and Breast-feeding: Taking Accuretic during pregnancy can cause injury and even death to the developing fetus. This medicine should not be used during pregnancy. Patients should be advised to stop the medication and report to their doctor as soon as possible if they become pregnant while taking Accuretic. It is possible that Accuretic passes into breast milk. Patients should be advised not to breast-feed while taking Accuretic.

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.

Each pink, triangular, biconvex, film-coated tablet, with bisecting score and PD220 on one side 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.

Each pink, oval, biconvex, film-coated tablet, with bisecting score on both sides and PD222 on one side 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.

Each pink, round, biconvex, film-coated tablet with PD223 on one side contains: quinapril 20 mg and hydrochlorothiazide 25 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 25°C. Dispense in well-closed containers.

Quinapril is contraindicated in pregnancy (see Contraindications). 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.

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, and patent ductus arteriosus and other structural cardiac malformations, as well as neurological malformations, have also been reported following exposure in the first trimester of pregnancy.

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. If oligohydramnios is observed, a non-stress test (NST), and/or a biophysical profiling (BPP) may be appropriate, depending upon 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.

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 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).

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

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:

paresthesias, xanthopsia, confusion, amnesia, anxiety, facial paralysis, polyneuritis.

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).

WBC decreased, hyperglycemia, azotemia, transient hyperlipidemia, hyperuricemia.

paresthesia, nervousness.

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

tinnitus, transient blurred vision, taste disturbance.

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

respiratory distress including pneumonitis, asthma, hoarseness.

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

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

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.

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.

See Symptoms.

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.

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.