Acuitel FC

Hypertension

For the treatment of all grades of essential hypertension. Acuitel FC Tablets are effective as monotherapy or concomitantly with diuretics in patients with hypertension.

Congestive Heart Failure

For the treatment of congestive heart failure when given concomitantly with a diuretic and/or cardiac glycoside. Treatment of congestive heart failure with Acuitel FC Tablets should always be initiated under close medical supervision.

Hypertension

Acuitel FC is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with Acuitel FC.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Acuitel FC may be used alone or in combination with thiazide diuretics.

Heart Failure

Acuitel FC is indicated in the management of heart failure as adjunctive therapy when added to conventional therapy including diuretics and/or digitalis.

In using Acuitel FC, consideration should be given to the fact that another ACE inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease. Available data are insufficient to show that Acuitel FC does not have a similar risk (see WARNINGS).

Angioedema in black patients: Black patients receiving ACE inhibitor monotherapy have been reported to have a higher incidence of angioedema compared to non-blacks. It should also be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks.

For oral use.

Adults

Hypertension

Monotherapy: The recommended initial dosage is 10 mg once daily in uncomplicated hypertension. Depending upon clinical response, patient's dosage may be titrated (by doubling the dose allowing adequate time for dosage adjustment) to a maintenance dosage of 20 to 40 mg/day given as a single dose or divided into 2 doses. Long-term control is maintained in most patients with a single daily dosage regimen. Patients have been treated with dosages up to 80 mg/day.

Concomitant Diuretics: In order to determine if excess hypotension will occur, an initial dosage of 2.5 mg of Acuitel FC Tablets is recommended in patients who are being treated with a diuretic. After this the dosage of Acuitel FC Tablets should be titrated (as described above) to the optimal response.

Congestive Heart Failure

In order to closely monitor patients for symptomatic hypotension, a single 2.5 mg initial dosage is recommended. After this, patients should be titrated to an effective dose: (up to 40 mg/day) given in 1 or 2 doses with concomitant diuretic and/or cardiac glycoside therapy. Patients are usually maintained effectively on doses of 10-20 mg/day given with concomitant therapy. Take either with or without food. The dose should always be taken at about the same time of day to help increase compliance.

Severe Heart Failure

In the treatment of severe or unstable congestive heart failure, Acuitel FC Tablets should always be initiated in hospital under close medical supervision.

Other patients who may also be considered to be at higher risk and should have treatment initiated in hospital include: patients who are on high dose loop diuretics (e.g.> 80 mg frusemide) or on multiple diuretic therapy, have hypovolaemia, hyponatraemia (serum sodium < 130 mmol/l) or systolic blood pressure < 90 mm Hg, are on high dose vasodilator therapy, have a serum creatinine > 150 µmol/l or are aged 70 years or over.

Take either with or without food. The dose should always be taken at about the same time of day to help increase compliance.

Elderly/Renal Impairment (over 65 years of age)

In elderly patients and in patients with a creatinine clearance of less than 40 ml/min, an initial dosage in essential hypertension of 2.5 mg is recommended followed by titration to the optimal response.

Paediatric population

Hypertension

Monotherapy

The recommended initial dosage of Acuitel FC in patients not on diuretics is 10 or 20 mg once daily. Dosage should be adjusted according to blood pressure response measured at peak (2–6 hours after dosing) and trough (predosing). Generally, dosage adjustments should be made at intervals of at least 2 weeks. Most patients have required dosages of 20, 40, or 80 mg/day, given as a single dose or in two equally divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients an increase in dosage or twice daily administration may be warranted. In general, doses of 40–80 mg and divided doses give a somewhat greater effect at the end of the dosing interval.

Concomitant Diuretics

If blood pressure is not adequately controlled with Acuitel FC monotherapy, a diuretic may be added. In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of Acuitel FC. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued 2 to 3 days prior to beginning therapy with Acuitel FC (see WARNINGS). Then, if blood pressure is not controlled with Acuitel FC alone, diuretic therapy should be resumed.

If the diuretic cannot be discontinued, an initial dose of 5 mg Acuitel FC should be used with careful medical supervision for several hours and until blood pressure has stabilized.

The dosage should subsequently be titrated (as described above) to the optimal response (see WARNINGS, PRECAUTIONS, and DRUG INTERACTIONS).

Renal Impairment

Kinetic data indicate that the apparent elimination half-life of quinaprilat increases as creatinine clearance decreases. Recommended starting doses, based on clinical and pharmacokinetic data from patients with renal impairment, are as follows:

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

Elderly (≥65 Years)

The recommended initial dosage of Acuitel FC in elderly patients is 10 mg given once daily followed by titration (as described above) to the optimal response.

Heart Failure

Acuitel FC is indicated as adjunctive therapy when added to conventional therapy including diuretics and/or digitalis. The recommended starting dose is 5 mg twice daily. This dose may improve symptoms of heart failure, but increases in exercise duration have generally required higher doses. Therefore, if the initial dosage of Acuitel FC is well tolerated, patients should then be titrated at weekly intervals until an effective dose, usually 20 to 40 mg daily given in two equally divided doses, is reached or undesirable hypotension, orthostatis, or azotemia (see WARNINGS) prohibit reaching this dose.

Following the initial dose of Acuitel FC, the patient should be observed under medical supervision for at least two hours for the presence of hypotension or orthostatis and, if present, until blood pressure stabilizes. The appearance of hypotension, orthostatis, or azotemia early in dose titration should not preclude further careful dose titration. Consideration should be given to reducing the dose of concomitant diuretics.

Dose Adjustments In Patients With Heart Failure And Renal Impairment Or Hyponatremia

Pharmacokinetic data indicate that quinapril elimination is dependent on level of renal function. In patients with heart failure and renal impairment, the recommended initial dose of Acuitel FC is 5 mg in patients with a creatinine clearance above 30 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 (see DOSAGE AND ADMINISTRATION, Heart Failure,WARNINGS, and PRECAUTIONS, DRUG INTERACTIONS).

If the initial dose is well tolerated, Acuitel FC 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.

- Second and third trimesters of pregnancy.

- History of angioedema related to previous treatment with ACE inhibitors.

- Hereditary or idiopathic angioneurotic oedema.

- Acuitel FC should not be used in patients with dynamic left ventricular outflow obstruction.

- The concomitant use of Acuitel FC with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²).

Acuitel FC is contraindicated in patients who are hypersensitive to this product and in patients with a history of angioedema related to previous treatment with an ACE inhibitor.

Do not co-administer Acuitel FC with aliskiren in patients with diabetes.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Acuitel FC Tablets should be used with caution in selected patients with aortic stenosis or outflow obstruction.

Sensitivity reactions:

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma, e.g., purpura, photosensitivity, urticaria, necrotising angiitis, respiratory distress including pneumonitis and pulmonary oedema, anaphylactic reactions.

Symptomatic hypotension:

Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients but it is a possible consequence of ACE inhibition. In hypertensive patients receiving Acuitel FC, hypotension is more likely to occur if the patient has been salt/volume-depleted e.g., by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or has severe renin-dependent hypertension.

If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses; however, lower doses of Acuitel FC or any concomitant diuretic therapy should be considered if this event occurs.

In patients with congestive heart failure, who are at risk of excessive hypotension, Acuitel FC therapy should be started at the recommended dose under close medical supervision; these patients should be followed closely for the first two weeks of treatment and whenever the dosage of Acuitel FC is increased.

Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

Impaired Renal Function

In patients with renal insufficiency, monitoring of renal function during therapy should be performed as deemed appropriate; although in the majority renal function will not alter or may improve.

The half-life of Acuitel FCat is prolonged as creatinine clearance falls. Patients with a creatinine clearance of <40 ml/min require a lower initial dosage of Acuitel FC. These patients' dosage should be titrated upwards based upon therapeutic response, and renal function should be closely monitored although initial studies do not indicate that Acuitel FC produces further deterioration in renal function.

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors including Acuitel FC, may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.

In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.

Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases >1.25 times the upper limit of normal) in blood urea and serum creatinine, usually minor and transient, especially when Acuitel FC has been given concomitantly with a diuretic. Increases in blood urea nitrogen and serum creatinine have been observed in 2% and 2%, respectively of hypertensive patients on Acuitel FC monotherapy and in 4% and 3%, respectively of hypertensive patients on Acuitel FC/HCTZ. These increases are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of a diuretic and/or Acuitel FC may be required.

There is insufficient experience in patients with severe renal impairment (creatinine clearance <10 ml/min). Treatment is therefore not recommended in these patients.

Angioedema:

Angioedema has been reported in patients treated with angiotensin-converting enzyme inhibitors. If laryngeal stridor or angioedema of the face, tongue, or glottis occur, treatment 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; antihistamines may be useful in relieving symptoms. Angioedema associated with laryngeal involvement may be fatal. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, appropriate therapy e.g., subcutaneous adrenaline solution 1:1000 (0.3 to 0.5 ml) should be promptly administered.

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

Intestinal angioedema:

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Ethnic Differences

Black patients receiving ACE inhibitor therapy generally have a higher incidence of angioedema than non-black patients. It should also be noted that in controlled clinical trials, ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks.

Neutropenia/agranulocytosis:

ACE inhibitors have been rarely associated with agranulocytosis and bone marrow depression in patients with uncomplicated hypertension but more frequently in patients with renal impairment, especially if they also have collagen vascular disease. As with other ACE inhibitors, monitoring of white blood cell counts in patients with collagen vascular disease and/or renal diseases should be considered.

Agranulocytosis has been rarely reported during treatment with Acuitel FC. Monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered.

Desensitization:

Patients receiving ACE inhibitors during desensitising treatment with hymenoptera venom have sustained life threatening anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld, but they have reappeared upon inadvertent re-challenge.

Haemodialysis and LDL Apheresis:

Patients haemodialysed using high-flux polyacrylonitrile ('AN69') membranes are highly likely to experience anaphylactoid reactions if they are treated with ACE inhibitors. This combination should therefore be avoided, either by use of alternative antihypertensive drugs or alternative membranes for haemodialysis. Similar reactions have been observed during low-density lipoprotein apheresis with dextran-sulphate. This method should therefore not be used in patients treated with ACE inhibitors.

Impaired Hepatic Function:

Acuitel FC 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 Acuitel FC to Acuitel FCat is normally dependent upon hepatic esterase. Acuitel FCat concentrations are reduced in patients with alcoholic cirrhosis due to impaired de-esterification of Acuitel FC.

Rarely, ACE inhibitors have been associated with a syndrome beginning as a cholestatic jaundice and progressing to a fulminant hepatic necrosis (in some cases fatal). Patients who during ACE inhibitor therapy experience jaundice or clearly elevated hepatic enzymes should discontinue Acuitel FC and receive appropriate medical follow-up.

Cough:

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

Surgery/Anaesthesia:

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, Acuitel FC may block angiotensin II formation secondary to compensatory renin release.).

Diabetic patients:

In diabetic patients ACE inhibitors may enhance insulin sensitivity and have been associated with hypoglycaemia in patients treated with oral antidiabetic agents or insulin. Glycaemic control should be closely monitored particularly during the first month of treatment with an ACE inhibitor.

Pregnancy

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

WARNINGS

Anaphylactoid And Possibly Related Reactions

Presumably because ACE inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Acuitel FC) may be subject to a variety of adverse reactions, some of them serious.

Head And Neck Angioedema

Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors and has been seen in 0.1% of patients receiving Acuitel FC.

In two similarly sized U.S. postmarketing trials that, combined, enrolled over 3,000 black patients and over 19,000 non-blacks, angioedema was reported in 0.30% and 0.55% of blacks (in study 1 and 2 respectively) and 0.39% and 0.17% of non-blacks.

Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with Acuitel FC should be discontinued immediately, the patient treated in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, emergency therapy including, but not limited to, subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL) should be promptly administered (see ADVERSE REACTIONS).

Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema.

Intestinal Angioedema

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Patients With A History Of Angioedema

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).

Anaphylactoid Reactions During Desensitization

Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid Reactions During Membrane Exposure

Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

Hepatic Failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Hypotension Excessive hypotension is rare in patients with uncomplicated hypertension treated with Acuitel FC alone. Patients with heart failure given Acuitel FC commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. Caution should be observed when initiating therapy in patients with heart failure (see DOSAGE AND ADMINISTRATION). In controlled studies, syncope was observed in 0.4% of patients (N=3203); this incidence was similar to that observed for captopril (1%) and enalapril (0.8%).

Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include patients with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or cautiously increase salt intake (except in patients with heart failure) before initiating therapy with Acuitel FC in patients at risk for excessive hypotension who are able to tolerate such adjustments.

In patients at risk of excessive hypotension, therapy with Acuitel FC should be started under close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of Acuitel FC and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular accident.

If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of Acuitel FC, which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of Acuitel FC or concomitant diuretic may be necessary.

Neutropenia/Agranulocytosis

Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen vascular disease, such as systemic lupus erythematosus or scleroderma. Agranulocytosis did occur during Acuitel FC treatment in one patient with a history of neutropenia during previous captopril therapy. Available data from clinical trials of Acuitel FC are insufficient to show that, in patients without prior reactions to other ACE inhibitors, Acuitel FC does not cause agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered.

Fetal Toxicity

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Acuitel FC as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Acuitel FC, unless it is considered life-saving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Acuitel FC for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use). No teratogenic effects of Acuitel FC were seen in studies of pregnant rats and rabbits. On a mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum recommended human dose.

PRECAUTIONS

General

Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensinaldosterone system, treatment with ACE inhibitors, including Acuitel FC, may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.

In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.

Some patients with hypertension or heart failure with no apparent preexisting renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when Acuitel FC has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction and/or discontinuation of any diuretic and/or Acuitel FC may be required.

Evaluation of patients with hypertension or heart failure should always include assessment of renal function (see DOSAGE AND ADMINISTRATION).

Hyperkalemia

In clinical trials, hyperkalemia (serum potassium ≥5.8 mmol/L) occurred in approximately 2% of patients receiving Acuitel FC. In most cases, elevated serum potassium levels were isolated values which resolved despite continued therapy. Less than 0.1% of patients discontinued therapy due to hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of other drugs that raise serum potassium levels. Monitor serum potassium in such patients (see PRECAUTIONS, DRUG INTERACTIONS).

Cough

Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent non-productive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery/Anesthesia

In patients undergoing major surgery or during anesthesia with agents that produce hypotension, Acuitel FC 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.

Dual Blockade Of The Renin-Angiotensin System (RAS)

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on Acuitel FC and other agents that affect the RAS.

Do not co-administer aliskiren with Acuitel FC in patients with diabetes. Avoid concomitant use of aliskiren with Acuitel FC in patients with renal impairment (GFR<60 mL/min/1.73 m²).

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or 100 mg/kg/day (50 to 60 times the maximum human daily dose, respectively, on an mg/kg basis and 3.8 to 10 times the maximum human daily dose when based on an mg/m² basis) for 104 weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also negative in the following genetic toxicology studies: in vitro mammalian cell point mutation, sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro chromosome aberration with V79 cultured lung cells, and in anin vivo cytogenetic study with rat bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100 mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/m² , respectively).

Nursing Mothers

Because Acuitel FC is secreted in human milk, caution should be exercised when this drug is administered to a nursing woman.

Pediatric Use

Neonates With A History Of In Utero Exposure To Acuitel FC:

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Removal of Acuitel FC, which crosses the placenta, from the neonatal circulation is not significantly accelerated by these means.

The safety and effectiveness of Acuitel FC in pediatric patients have not been established.

Geriatric Use

Clinical studies of Acuitel FC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

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.

The following undesirable effects have been observed during treatment with Acuitel FC and other ACE inhibitors with the following frequencies:

Very common (> 1/10)

Common (> 1/100 to < 1/10),

Uncommon (> 1/1,000, to <1/100),

Rare (>1/10,000 to < 1/1,000).

Very rare < 1/10,000,

Not known (cannot be estimated from the available data)

The most frequently reported adverse reactions found in controlled clinical trials were headache (7.2%), dizziness (5.5%), cough (3.9%), fatigue (3.5%), rhinitis (3.2%), nausea and/or vomiting (2.8%), and myalgia (2.2%).

* Pancreatitis has been reported rarely in patients treated with ACE inhibitors; in some cases this has proved fatal.

** Such increases are more likely to occur in patients receiving concomitant diuretic therapy than those on monotherapy with Acuitel FC. These observed increases will often reverse on continued therapy.

Rare cases of agranulocytosis have been reported, and also a syndrome including fever, serositis, vasculitis, myalgia, arthralgia/arthritis, positive ANA-titre, SR-elevation, eosinophilia, and leukocytosis.

Gynaecomastia and vasculitis have been reported with other ACE-inhibitors and it cannot be excluded that these unwanted effects are class specific.

Laboratory values: Transient increases in serum creatinine and urea values have been reported, especially in association with concomitant therapy with diuretics. Slight decreases in haemoglobin and haematocrit values have been reported for other ACE-inhibitors. It cannot be excluded that these observations are group specific.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Hypertension

Acuitel FC has been evaluated for safety in 4960 subjects and patients. Of these, 3203 patients, including 655 elderly patients, participated in controlled clinical trials. Acuitel FC has been evaluated for long-term safety in over 1400 patients treated for 1 year or more.

Adverse experiences were usually mild and transient.

In placebo-controlled trials, discontinuation of therapy because of adverse events was required in 4.7% of patients with hypertension.

Adverse experiences probably or possibly related to therapy or of unknown relationship to therapy occurring in 1% or more of the 1563 patients in placebo-controlled hypertension trials who were treated with Acuitel FC are shown below.

Adverse Events in Placebo-Controlled Trials

Heart Failure

Acuitel FC has been evaluated for safety in 1222 Acuitel FC treated patients. Of these, 632 patients participated in controlled clinical trials. In placebo-controlled trials, discontinuation of therapy because of adverse events was required in 6.8% of patients with congestive heart failure.

Adverse experiences probably or possibly related or of unknown relationship to therapy occurring in 1% or more of the 585 patients in placebo-controlled congestive heart failure trials who were treated with Acuitel FC are shown below.

See PRECAUTIONS, Cough.

Hypertension And/Or Heart Failure

Clinical adverse experiences probably, possibly, or definitely related, or of uncertain relationship to therapy occurring in 0.5% to 1.0% (except as noted) of the patients with CHF or hypertension treated with Acuitel FC (with or without concomitant diuretic) in controlled or uncontrolled trials (N=4847) and less frequent, clinically significant events seen in clinical trials or post-marketing experience (the rarer events are in italics) include (listed by body system):

General: back pain, malaise, viral infections, anaphylactoid reaction

Cardiovascular: palpitation, vasodilation, tachycardia, heart failure, hyperkalemia, myocardial infarction, cerebrovascular accident, hypertensive crisis, angina pectoris, orthostatic hypotension, cardiac rhythm disturbances, cardiogenic shock

Hematology: hemolytic anemia

Gastrointestinal: flatulence, dry mouth or throat, constipation, gastrointestinal hemorrhage, pancreatitis, abnormal liver function tests, dyspepsia

Metabolism and Nutrition Disorders: hyponatremia

Nervous/Psychiatric: somnolence, vertigo, syncope, nervousness, depression, insomnia, paresthesia

Integumentary: alopecia, increased sweating, pemphigus, pruritus, exfoliative dermatitis, photosensitivity reaction, dermatopolymyositis

Urogenital: urinary tract infection, impotence, acute renal failure, worsening renal failure

Respiratory: eosinophilic pneumonitis

Other: amblyopia, edema, arthralgia, pharyngitis, agranulocytosis, hepatitis, thrombocytopenia

Angioedema

Angioedema has been reported in patients receiving Acuitel FC (0.1%). Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis, and/or larynx occurs, treatment with Acuitel FC should be discontinued and appropriate therapy instituted immediately. (see WARNINGS.)

Clinical Laboratory Test Findings

Hematology: (See WARNINGS)

Hyperkalemia: (See PRECAUTIONS)

Creatinine and Blood Urea Nitrogen

Increases (>1.25 times the upper limit of normal) in serum creatinine and blood urea nitrogen were observed in 2% and 2%, respectively, of all patients treated with Acuitel FC alone. Increases are more likely to occur in patients receiving concomitant diuretic therapy than in those on Acuitel FC alone. These increases often remit 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 Acuitel FC; most often these patients were receiving diuretics with or without digitalis.

The oral LD50 of Acuitel FC in mice and rats ranges from 1440 to 4280 mg/kg.

No specific information is available on the treatment of overdosage with Acuitel FC. The most likely clinical manifestation would be symptoms attributable to severe hypotension, which should normally be treated by intravenous volume expansion.

Haemodialysis and peritoneal dialysis have little effect on the elimination of Acuitel FC and Acuitel FCat.

Treatment is symptomatic and supportive consistent with established medical care.

Doses of 1440 to 4280 mg/kg of quinapril cause significant lethality in mice and rats.

No specific information is available on the treatment of overdosage with quinapril. The most likely clinical manifestation would be symptoms attributable to severe hypotension.

Laboratory determinations of serum levels of quinapril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of quinapril overdose.

No data are available to suggest physiological maneuvers (eg, maneuvers to change pH of the urine) that might accelerate elimination of quinapril and its metabolites.

Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat. Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of quinapril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of quinapril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat quinapril overdose by infusion of normal saline solution.