Accupril

Following oral administration of ACCUPRIL, peak plasma concentrations of quinapril occur within one 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 one hour. Peak plasma quinaprilat concentrations occur approximately 2 hours after an oral dose of ACCUPRIL. 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 on 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 25-30%) when ACCUPRIL tablets are 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.

Administration of 10 to 40 mg of ACCUPRIL 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 one 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 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 10-20 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 ACCUPRIL 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 which was not significant. Little or no change in glomerular filtration rate or filtration fraction was observed.

Quinapril has been shown to reduce microalbuminuria in patients with essential hypertension independently of changes in systemic blood pressure.

When ACCUPRIL is given together with thiazide-type diuretics, the antihypertensive effects are approximately additive.

Administration of ACCUPRIL to patients with congestive heart failure (CHF) reduces peripheral vascular resistance, systolic and diastolic blood pressure, pulmonary capillary wedge pressure, and increases cardiac output. The onset of effects was observed within one hour and maximal effects occurred at 1.25 to 4 hours after administration of ACCUPRIL. Peak hemodynamic effects correlated well with peak plasma levels of quinaprilat (1 to 4 hours after administration).

Exercise tolerance was improved with ACCUPRIL therapy.

The effect of ACCUPRIL on survival in patients with heart failure has not been evaluated.

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.

ACCUPRIL is indicated in the treatment of congestive heart failure as adjunctive therapy when added to diuretics and/or digitalis glycosides.

Treatment with ACCUPRIL should be initiated under close medical supervision.

ACCUPRIL (quinapril hydrochloride) is indicated in the treatment of essential hypertension. It is usually administered in association with other drugs, particularly thiazide diuretics.

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

ACCUPRIL 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. ACCUPRIL 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.

The safety and efficacy of ACCUPRIL in renovascular hypertension has not been established; therefore, use in this condition is not recommended.

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

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 ACCUPRIL 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 ACCUPRIL. If it is not possible to discontinue the diuretic, the starting dose of ACCUPRIL 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).

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

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

Patients should be cautioned to report light-headedness, especially during the first few days of ACCUPRIL therapy. If actual syncope occurs, the 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.

As with other drugs which eliminate sodium, the lithium elimination may be reduced. Therefore, the serum lithium levels should be monitored carefully if lithium salts are to be administered.

Cough has been reported with the use of ACE inhibitors, including quinapril. Characteristically, the cough is dry and persistent and usually disappears only after withdrawal or lowering of the dose of ACCUPRIL. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of the cough.

Angioedema, including laryngeal edema, may occur especially following the first dose of ACCUPRIL. 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 ACCUPRIL and consult with their physician.

The antihypertensive effect of ACCUPRIL is augmented by antihypertensive agents that cause renin release (e.g. diuretics).

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

In single dose pharmacokinetic studies, no important changes in pharmacokinetic parameters were observed when ACCUPRIL was used concomitantly with propranolol, hydrochlorothiazide, digoxin, or cimetidine. No change in prothrombin time occurred when ACCUPRIL and warfarin were given together.

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 ACCUPRIL (quinapril hydrochloride) should include appropriate assessment of renal function.

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.

Since ACCUPRIL 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.

Of the total number of subjects in clinical studies of ACCUPRIL, 21% were 65 and over. (There was no distinction between patients over 65 or over 75 years.) No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Elderly patients exhibited increased area under the plasma concentration time curve and peak levels for quinaprilat compared to values observed in younger patients; this appeared to relate to decreased renal function rather than to age itself.

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.

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

Patients should be advised to return to the physician if he/she experiences 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.

ACE inhibitors may reduce insulin resistance and may lead to hypoglycemia in diabetic patients on insulin or oral hypoglycemic agents; closer monitoring of diabetic patients may be required.

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.

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 ACCUPRIL (see Adverse Effects). Should the patient receiving ACCUPRIL 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 ACCUPRIL should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. ACCUPRIL 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.

Quinapril, when combined with a diuretic 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 dependant upon hepatic esterase. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril.

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, ACCUPRIL 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.

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 agents.

Driving and Operating Machinery: The ability to engage in activities such as operating machinery or operating a motor vehicle may be impaired, especially when initiating quinapril therapy.

Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately 2% of patients receiving ACCUPRIL. 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 and Adverse Effects).

Taking ACCUPRIL 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 medication and report to their physician as soon as possible if they become pregnant while taking ACCUPRIL. It is possible that ACCUPRIL passes into breast milk. Patients should be advised not to breast-feed while taking ACCUPRIL.

Serious Warnings and Precautions

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

Note: As with many other drugs, certain advice to patients being treated with ACCUPRIL 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.

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.

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 ACCUPRIL.

Each scored, brown, film-coated, elliptical tablet, debossed “” on one side and “5” on the other, contains: quinapril 5 mg. Nonmedicinal ingredients: candelilla wax, crospovidone, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium carbonate, magnesium stearate, polyethylene glycol, synthetic red iron oxide and titanium dioxide. Bottles of 90. Store at controlled room temperature, 15-30°C. Protect from moisture. Dispense in well-closed containers.

Each brown, film-coated, round tablet, debossed “” on one side and “20” on the other, contains: quinapril 20 mg. Nonmedicinal ingredients: candelilla wax, crospovidone, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium carbonate, magnesium stearate, polyethylene glycol, synthetic red iron oxide and titanium dioxide. Bottles of 90. Store at controlled room temperature, 15-30°C. Protect from moisture. Dispense in well-closed containers.

Each brown, film-coated, elliptical tablet, debossed “” on one side and “40” on the other, contains: quinapril 40 mg. Nonmedicinal ingredients: candelilla wax, crospovidone, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium carbonate, magnesium stearate, polyethylene glycol, synthetic red iron oxide and titanium dioxide. Bottles of 90. Store at controlled room temperature, 15-30°C. Protect from moisture. Dispense in well-closed containers.

Each brown, film-coated, triangular tablet, debossed “” on one side and “10” on the other, contains: quinapril 10 mg. Nonmedicinal ingredients: candelilla wax, crospovidone, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium carbonate, magnesium stearate, polyethylene glycol, synthetic red iron oxide and titanium dioxide. Bottles of 90. Store at controlled room temperature, 15-30°C. Protect from moisture. Dispense in well-closed containers.

Head and neck angioedema has been reported in patients treated with ACCUPRIL (quinapril hydrochloride). Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, ACCUPRIL 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 subcutaneous epinephrine solution 1:1000) 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).

Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Agranulocytosis did occur during ACCUPRIL 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.

No fetotoxic or teratogenic effects were observed in rats at 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 1 mg/kg/day.

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

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, ACCUPRIL 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 neurologic 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 testing (CST) should be considered. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Symptomatic hypotension has occurred after administration of ACCUPRIL, 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 ACCUPRIL should be started under close medical supervision (see Dosage). Such patients should be followed closely for the first weeks of treatment and whenever the dose of ACCUPRIL 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 intravenous 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. However, lower doses of ACCUPRIL and/or reduced concomitant diuretic therapy should be considered.

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.

flatulence, pancreatitis*.

See Warnings.

Constipation, tongue edema, GI hemorrhage, anorexia, bloody stools.

Allergy, face edema, chill, weight increase, dehydration.

Dysuria, polyuria, impaired renal function.

Tinnitus.

athralgia, edema (peripheral and generalized), hemolytic anemia*.

Dermatitis, urticaria, eczema, Stevens-Johnson syndrome.

Arthritis.

anaphylactoid reaction*; photosensitivity reaction*.

See Precautions.

Confusion, amnesia, anxiety, arthralgia.

Hematuria, WBC decreased, elevated BUN, hyperglycemia, azotemia.

Clinical adverse experiences probably, possibly, or definitely related, or of uncertain relationship to therapy occuring in 0.5% to ≤ 1.0% of the patients treated with quinapril (with or without concomitant diuretic) in controlled or uncontrolled clinical trials and less frequent events seen in clinical trials or post-marketing experience (indicated by a *) included:

urinary tract infection.

Adverse events occurring in <0.5% of patients with hypertension or congestive heart failure include:

Asthma, hoarseness.

Increases (>1.25 times the upper limit of normal) in serum creatinine and blood urea nitrogen were observed in 2% and 2%, respectively, of patients treated with ACCUPRIL alone. Increases are more likely to occur in patients receiving concomitant diuretic therapy than in those on ACCUPRIL alone. These increases often reversed on continued therapy. In controlled studies of heart failure, increases in blood urea nitrogen and serum creatinine were observed in 11% and 8%, respectively, of patients treated with ACCUPRIL. Most often these patients were receiving diuretics with or without digitalis.

ACCUPRIL (quinapril hydrochloride) monotherapy has been evaluated for safety in 2005 hypertensive patients enrolled in placebo-controlled clinical trials. These trials included 313 elderly patients. There was no increase in the incidence of adverse events in elderly patients given the same daily dosages. ACCUPRIL has been evaluated for long-term safety in over 1100 patients treated for one year or more. Adverse events were usually mild and transient in nature.

The most serious adverse event was angioedema (0.1%). Renal insufficiency (1 case), agranulocytosis (1 case) and mild azotemia (2 cases in CHF patients) have been reported. Myocardial infarction and cerebrovascular accident occurred, possibly secondary to excessive hypotension in high risk patients (see Warnings).

The most frequent adverse events in controlled clinical trials were headache (8.1%), dizziness (4.1%), cough (3.2%), fatigue (3.2%), rhinitis (3.2%), nausea and/or vomiting (2.3%), and abdominal pain (2.0%).

Discontinuation of therapy because of adverse events was required in 4.7% of patients treated with ACCUPRIL in placebo controlled trials.

alopecia*, exfoliative dermatitis*, pemphigus*.

thrombocytopenia*.

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

Anemia, including hemolytic anemia, agranulocytosis.

postural hypotension*, syncope*, vasodilation.

No data are available regarding overdosage of ACCUPRIL (quinapril hydrochloride) in humans. The most likely clinical manifestation would be symptoms attributable to severe hypotension, which should be normally treated by intravenous volume expansion with 0.9% sodium chloride. Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat.

See Symptoms.

ACCUPRIL is indicated as adjunctive therapy to diuretics, and/or cardiac glycosides. Therapy should be initiated under close medical supervision. Blood pressure and renal function should be monitored, both before and during treatment with ACCUPRIL, because severe hypotension and, more rarely, consequent renal failure have been reported (see Warnings and Precautions).

Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion. If possible, the dose of diuretic should be reduced before beginning treatment, to reduce the likelihood of hypotension. Serum potassium should also be monitored (see Precautions, Drug Interactions).

The recommended starting dose is 5 mg once daily, to be administered under close medical supervision to determine the initial effect on blood pressure. After the initial dose, the patient should be observed for at least two hours, or until the pressure has stabilized for at least an additional hour (see Warnings, Hypotension). This dose may improve symptoms of heart failure, but increases in exercise duration have generally required higher doses. Therefore, if the initial dosage of ACCUPRIL is well tolerated or after effective management of symptomatic hypotension following initiation of therapy, the dose should then be increased gradually to 10 mg once daily, then 20 mg once daily, and to 40 mg per day given in 2 equally divided doses, depending on the patient's response. The maximum daily dose is 40 mg.

The dose titration may be done at weekly intervals, as indicated by the presence of residual signs or symptoms of heart failure.

Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation and salt restriction. The dosage of other antihypertensive agents being used with ACCUPRIL may need to be adjusted.

Symptomatic hypotension occasionally may occur following the initial dose of ACCUPRIL 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 ACCUPRIL to reduce the likelihood of hypotension (see Warnings). If the diuretic cannot be discontinued, an initial dose of 5 mg ACCUPRIL should be used with careful medical supervision for several hours and until blood pressure has stabilized. The dosage of ACCUPRIL should subsequently be titrated (as described above) to the optimal response.

The recommended initial dose of ACCUPRIL 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 Warnings, Hypotension). Dosage should be adjusted according to blood pressure response, generally at intervals of two to four 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 ACCUPRIL alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of ACCUPRIL.

The recommended initial dosage of ACCUPRIL is 10 mg once daily (depending on renal function), followed by titration (as described above) to the optimal response.

Kinetic data indicate that ACCUPRIL elimination is dependent on the level of renal function. The recommended initial dose of ACCUPRIL is 5 mg in patients with a creatinine clearance of 30 to 60 mL/min and 2.5 mg in patients with a creatinine clearance of 10 to 30 mL/min. There is insufficient data for dosage recommendation in patients with a creatinine clearance less than 10 mL/min. If the initial dose is well tolerated, ACCUPRIL may be administered the following day as a twice daily regimen. In the absence of excessive hypotension or significant deterioration of renal function, the dose may be increased at weekly intervals based on clinical and hemodynamic response.