AMPRACE (enalapril maleate) is the maleate salt of enalapril, a derivative of two amino acids, L-alanine and L-proline. Following oral administration, enalapril is rapidly absorbed and then hydrolysed to enalaprilat, which is a specific, long-acting, angiotensin converting enzyme inhibitor.

DESCRIPTION

AMPRACE tablets contain the maleate salt of enalapril, the ethyl ester of the parent diacid, enalaprilat. Enalapril maleate is chemically described as (S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline, (Z)-2-butenedioate salt (1:1). It lacks a sulphydryl group. Its empirical formula is C20 H28 N2 O5.C4 H4 O4, and its structural formula is:

Enalapril maleate is a white to off-white crystalline powder with a molecular weight of 492.53. It is sparingly soluble in water, soluble in ethanol, and freely soluble in methanol and dimethylformamide. AMPRACE Tablets (10 mg and 20 mg) contain the following excipients; sodium bicarbonate, lactose, starch-maize, starch-pregelatinised maize, magnesium stearate. The 10 mg tablets also contain iron- oxide red, while the 20 mg tablets contain iron-oxide red and iron-oxide yellow.

CLINICAL PHARMACOLOGY

Enalapril maleate is a pro-drug which when administered orally is hydrolysed to release the active converting enzyme inhibitor enalaprilat. The liver appears to be the main site for this conversion.

Oral enalapril is rapidly absorbed, with peak serum concentrations of enalapril occurring within one hour. Based on urinary recovery, the extent of absorption of enalapril from oral AMPRACE is approximately 60%. The oral bioavailability of enalaprilat is approximately 40%. Protein binding is approximately 50%. Following absorption, oral enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent angiotensin converting enzyme inhibitor. Peak serum concentrations of enalaprilat occur 3 to 4 hours after an oral dose of AMPRACE. Excretion of enalaprilat is primarily renal. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact enalapril. Except for conversion to enalaprilat, there is no evidence for significant metabolism of AMPRACE. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently associated with binding to angiotensin converting enzyme (ACE). In subjects with normal renal function, steady state serum concentrations of enalaprilat were achieved by the fourth day of administration of AMPRACE. The plasma concentration time profile of enalaprilat was complex with several exponentials including a very prolonged terminal phase (t1/2>30 hr). The effective half-life for accumulation of enalaprilat following multiple doses of oral AMPRACE is 11 hours. The absorption of oral AMPRACE is not influenced by the presence of food in the gastrointestinal tract. The extent of absorption and hydrolysis of enalapril are similar for the various doses in the recommended therapeutic range.

Administration of AMPRACE to patients with hypertension results in a reduction of both supine and standing blood pressure without a significant increase in heart rate. Symptomatic postural hypotension is infrequent. In some patients the development of optimal blood pressure reduction may require several weeks of therapy. Abrupt withdrawal of AMPRACE has not been associated with rapid increase in blood pressure. Effective inhibition of ACE activity usually occurs 2 to 4 hours after oral administration of an individual dose of enalapril. Onset of antihypertensive activity was usually seen at one hour, with peak reduction of blood pressure achieved by 4 to 6 hours after administration. The duration of effect is dose-related. However, at recommended doses, antihypertensive and haemodynamic effects have been shown to be maintained for at least 24 hours. In haemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of AMPRACE there was an increase or no change in renal blood flow; glomerular filtration rate was unchanged. However, in patients with low pretreatment glomerular filtration rates, the rates were usually increased. When given together with thiazide-type diuretics, the blood pressure lowering effects of AMPRACE are at least additive. AMPRACE may reduce or prevent the development of thiazide-induced hypokalaemia. In patients with congestive heart failure on therapy with digitalis and diuretics, treatment with oral or parenteral AMPRACE was associated with decreases in peripheral resistance and blood pressure. Cardiac output increased, while heart rate (usually elevated in patients with congestive heart failure) decreased. Pulmonary capillary wedge pressure was also reduced. Exercise tolerance and severity of congestive heart failure, as measured by New York Heart Association criteria, improved. These actions continued during chronic therapy. In a multicentre, placebo-controlled clinical trial (SOLVD), 2,569 patients with all degrees of symptomatic heart failure and ejection fraction 35% were randomised to placebo or enalapril and followed for up to 55 months (SOLVD-Treatment). A second multicentre trial used the SOLVD protocol for a study of patients with minimal or no symptoms of heart failure. SOLVD-Prevention patients, who had left ventricular ejection fraction 35% and no history of symptomatic heart failure were randomised to placebo (n=2117) or enalapril (n=2111) and followed for up to 5 years. These patients had little or no limitation of exercise tolerance due to dyspnoea or fatigue at randomisation and did not require treatment with digitalis, diuretics or vasodilators for heart failure at entry into the trial. The majority of patients in the trial had a history of ischaemic heart disease. A history of myocardial infarction was present in 80% of patients, current angina pectoris in 34% and a history of hypertension in 37%. Patients who had a recent myocardial infarction (ie. within the preceding 30 days) were not included in the SOLVD trials. In patients with left ventricular ejection fractions of less than 35%, AMPRACE has been shown to retard the progression of heart failure, reduce hospitalisations for heart failure and reduce the risk of myocardial infarction. In addition, in patients who have significant symptoms of heart failure (New York Heart Association Classes 2-4) and also left ventricular ejection fractions of less than 35%, AMPRACE has been shown to improve survival and reduce hospitalisations for unstable angina pectoris.

How enalapril, or converting enzyme inhibitors in general, lower blood pressure is not entirely clear. The mechanism most favoured is inhibition of the angiotensin converting enzyme (ACE), a peptidyl dipeptidase which catalyses the conversion of angiotensin I to the pressor substance angiotensin II. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback of renin release), and decreased aldosterone secretion. While the mechanism through which AMPRACE lowers blood pressure is believed to be primarily suppression of the renin-angiotensin- aldosterone system, which plays a major role in the regulation of blood pressure, AMPRACE is antihypertensive even in patients with low-renin hypertension. AMPRACE may also block the degradation of bradykinin, a potent vasodepressor peptide; however, the role that this plays in the therapeutic effect of AMPRACE remains to be elucidated.

CONTRAINDICATIONS

PRECAUTIONS

General

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including AMPRACE. This may occur at any time during treatment. In such cases AMPRACE should be promptly discontinued and the patient carefully observed until the swelling disappears. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to angioedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. 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 mL to 0.5 mL) and/or measures to ensure a patent airway should be promptly administered (see ADVERSE EFFECTS). The onset of angioedema associated with use of ACE inhibitors may be delayed for weeks or months. Patients may have multiple episodes of angioedema with long symptom-free intervals. Angioedema may occur with or without urticaria. Black patients receiving ACE inhibitors have been reported to have higher incidence of angioedema compared to non-blacks.

Rarely, patients receiving ACE inhibitors during desensitisation with hymenoptera venom have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitisation.

Excessive hypotension was rarely seen in uncomplicated hypertensive patients but is a possible consequence of enalapril use in severely salt/volume depleted persons such as those treated vigorously with diuretics or patients on dialysis or dietary salt restriction and those suffering from diarrhoea or vomiting (see PRECAUTIONS, Interactions with other medicines and ADVERSE EFFECTS). In patients with congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotaemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of enalapril and/or diuretic is increased. Similar considerations may 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. If hypotension occurs the patient should be placed in supine position and, if necessary, receive an intravenous infusion of normal saline. 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.

Another angiotensin converting enzyme inhibitor has been shown to cause agranulocytosis and bone marrow depression (including leucopenia/neutropenia). These reports generally involve patients who have pre-existing renal dysfunction and/or collagen vascular disease, some of whom have received concomitant immunosuppressant therapy. Most reports describe transient episodes for which a causal relationship to the ACE inhibitor could not be established. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. International marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded. It is recommended that periodic haematologic monitoring be considered in patients with diseases known to affect bone marrow function (e.g. renal dysfunction, collagen vascular disease, etc) and/or who are taking concomitant therapy known to be associated with bone marrow depression.

As a consequence of inhibiting the renin-angiotensin- aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including AMPRACE, may be associated with oliguria and/or progressive azotaemia and rarely with 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 were observed in 20 percent of patients. These increases were almost always reversible upon discontinuation of enalapril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when AMPRACE has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of AMPRACE and/or discontinuation of the diuretic may be required.

Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., AN 69) and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Evaluation of the hypertensive patient should always include assessment of renal function

As with all vasodilators, ACE inhibitors should be given with caution to patients with obstruction in the outflow tract of the left ventricle.

Elevated serum potassium (greater than 5.7 mmol/L) was observed in approximately one percent of hypertensive patients in clinical trials. In most cases these were isolated values which resolved despite continued therapy. Hyperkalaemia was a cause of discontinuation of therapy in 0.28 percent of hypertensive patients. Risk factors for the development of hyperkalaemia may include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amiloride), potassium supplements and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with AMPRACE. The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalaemia can cause serious, sometimes fatal, arrhythmias. If concomitant use of AMPRACE and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.

Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor should be told to closely monitor for hypoglycaemia, especially during the first month of combined use. (See Interactions with other medicines, Antidiabetics.)

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

A persistent non-productive, ticklish cough has been reported in some patients undergoing treatment with enalapril and other ACE inhibiting drugs. The cough is often worse when lying down. The cough is commoner in women (who account for about two thirds of reported cases). The patients who cough may have increased bronchial reactivity compared to those who do not cough. It may disappear in some patients with continued use, or diminish or disappear if the dose of the drug is reduced. In those in whom cough persists, the drug should be discontinued. The cough usually returns on rechallenge. No residual effects have been reported.

Use In Pregnancy

As with all ACE inhibitors, AMPRACE should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with AMPRACE and avoided during the treatment. If a patient intends to become pregnant, treatment with ACE inhibitors must be discontinued and replaced by another form of treatment. If a patient becomes pregnant while on ACE inhibitors, she must immediately inform her doctor to discuss a change in medication and further management. There are no adequate and well-controlled studies of enalapril in pregnant women. Data, however, show that enalapril crosses the human placenta. Post-marketing experience with all ACE inhibitors suggest that exposure in utero may be associated with hypotension and decreased renal perfusion in the foetus. ACE inhibitors have also been associated with foetal death in utero. There have been reports of foetal hypotension, renal failure, hyperkalaemia skull hypoplasia and death when ACE inhibitors have been used during the second and third trimesters of pregnancy. A historical cohort study in over 29,000 infants born to non-diabetic mothers has shown 2.7 times higher risk for congenital malformations in infants exposed to any ACE inhibitor during the first trimester compared to no exposure. The risk ratios for cardiovascular and central nervous system malformations were 3.7 times (95% confidence interval 1.89 to 7.3) and 4.4 times (95% confidence interval 1.37 to 14.02) respectively compared to no exposure. There is a potential risk of foetal hypotension, decreased birth weight and decreased renal perfusion or anuria in the foetus from in utero exposure to ACE inhibitors. Oligohydramnios in the mother has also been reported, presumably representing decreased renal function in the foetus and may result in limb contractures, craniofacial deformations and hypoplastic lung development. Any neonate exposed to enalapril in utero should be observed closely for adequate urine output, blood pressure and hyperkalaemia. If required, appropriate medical measures should be initiated including administration of fluids or dialysis to remove enalaprilat from the circulatory system. The maternal and fetal toxicity occurred in some rabbits at doses of 1 mg/kg/day or more. Saline supplementation prevented the maternal and fetal toxicity seen at doses of 3 and 10 mg/kg/day, but not at 30 mg/kg/day. Enalapril was not teratogenic in rabbits. There was no fetotoxicity or teratogenicity in rats treated with up to 200 mg/kg/day of enalapril. Fetotoxicity expressed as a decrease in average fetal weight occurred in rats given 1200 mg/kg/day of enalapril, but did not occur when these animals were supplemented with saline.

Use in Lactation

It is not known if AMPRACE is secreted in human milk. However, AMPRACE has been demonstrated to be secreted into the milk of lactating rats. In view of this and a lack of knowledge of the effects of enalapril on neonates, this product should not be used during lactation or else breast feeding should be discontinued.

Paediatric Use

Genotoxicity

Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E.coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow. There were no adverse effects on reproductive performance in male and female rats treated with 10 to 90 mg/kg/day of enalapril.

Carcinogenicity

There was no evidence of a carcinogenic effect when enalapril was administered for 106 weeks to rats at doses up to 90 mg/kg/day. Enalapril has also been administered for 94 weeks to male and female mice at doses up to 90 mg and 180 mg/kg/day, respectively, and showed no evidence of carcinogenicity.

Effects on laboratory tests

Serum Electrolytes: Hyperkalaemia (see PRECAUTIONS), hyponatraemia. Creatinine, Blood Urea Nitrogen: In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.2 percent of patients with essential hypertension treated with AMPRACE alone. Increases are more likely to occur in patients receiving concomitant diuretics or in patients with renal artery stenosis (see PRECAUTIONS).

Haemoglobin and Haematocrit: Small decreases in haemoglobin and haematocrit (mean decreases of approximately 0.3g percent and 1.0 vol percent, respectively) occur frequently in hypertensive patients treated with AMPRACE but are rarely of clinical importance unless another cause of anaemia coexists. In clinical trials, less than 0.1 percent of patients discontinued therapy due to anaemia.

Other (Causal Relationship Unknown): In marketing experience, rare cases of pancreatitis, neutropenia, thrombocytopenia, agranulocytosis, and bone marrow depression have been reported. A few cases of haemolysis have been reported in patients with G6PD deficiency. Liver Function Tests: Elevations of liver enzymes and/or serum bilirubin have occurred.

INTERACTIONS WITH OTHER MEDICINES

Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimised by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide medical supervision for at least one hour after the initial dose (see PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

The antihypertensive effect of AMPRACE is augmented by antihypertensive agents that cause renin release (eg., diuretics).

AMPRACE has been used concomitantly with beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine and prazosin without evidence of clinically significant adverse interactions.

AMPRACE may attenuate potassium loss caused by thiazide-type diuretics. Risk factors for the development of hyperkalaemia include renal insufficiency and diabetes mellitus. Potassium-sparing diuretics (eg spironolactone, eplerenone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of AMPRACE with these agents is indicated because of demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.

Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood-glucose- lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment. In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored for hypoglycaemia, especially during the first month of treatment with an ACE inhibitor.

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

Non-Steroidal Anti-Inflammatory Drugs Including Selective Cyclooxygenase-2 Inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX- 2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors. In some patients with compromised renal function (e.g., elderly patients or patients who are volume- depleted, including those on diuretic therapy) who are being treated with non-steroidal anti- inflammatory drugs including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function, including possible renal failure. These effects are usually reversible. Therefore, the combination should be administered with caution in patients with compromised renal function. These interactions should be considered in patients taking NSAIDs including selective COX-2 inhibitors concomitantly with diuretics and ACE inhibitors. Therefore, the combination should be administered with caution, especially in the elderly.

Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs and thiazide diuretics The use of an ACE inhibiting drug (ACE-inhibitor or angiotensin receptor antagonist), an anti- inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed-combination products containing more than one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of drugs from these three classes should be used with caution particularly in elderly patients or those with pre- existing renal impairment.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin receptor blockers, ACE inhibitors, or direct renin inhibitors (such as aliskiren) is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on AMPRACE and other agents that affect the RAAS. Do not coadminister aliskiren with AMPRACE in patients with diabetes. Avoid use of aliskiren with AMPRACE in patients with renal impairment (GFR<60 mL/min). .

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including enalapril.

ADVERSE EFFECTS

AMPRACE has been evaluated for safety in more than 10,000 patients, including over 1000 patients treated for one year or more. AMPRACE has been found to be generally well tolerated in controlled clinical trials involving 2677 patients. The most frequent clinical adverse experiences in controlled trials were: headache (4.8 percent), dizziness (4.6 percent) and fatigue (2.8 percent). For the most part, adverse experiences were mild and transient in nature. Discontinuation of therapy was required in 6.0 percent of patients. In clinical trials, the overall frequency of adverse experiences was not related to total daily dosage within the range of 10 to 40 mg. The overall percentage of patients treated with AMPRACE reporting adverse experiences was comparable to placebo. Adverse experiences occurring in greater than one percent of patients treated with AMPRACE in controlled clinical trials are shown below:

Percent of Patients in Controlled Studies
	AMPRACE (n=2677 1 ) Incidence (discontinuation)	Placebo (n=230) Incidence
Headache	4.8 (0.3)	9.1
Dizziness	4.6 (0.4)	4.3
Fatigue	2.8(<0.1)	2.6
Diarrhoea	1.6 (0.2)	1.7
Rash	1.5 (0.3)	0.4
Hypotension	1.4 (0.3)	0.4
Cough 2	1.3 (0.2)	0.9
Nausea	1.3 (0.2)	1.7
Orthostatic Effects	1.3(<0.1)	0.0

Includes 363 patients treated for congestive heart failure receiving concomitant digoxin and diuretic therapy.

See PRECAUTIONS

Clinical adverse experiences occurring since the drug was marketed or in 0.5 to 1.0 percent of patients in the controlled trials are listed below and, within each category, are in order of decreasing severity.

Cardiovascular:

Myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see PRECAUTIONS, Hypotension), syncope, orthostatic hypotension, palpitations, chest pain, rhythm disturbances, angina pectoris, Raynaud's phenomenon.

Endocrine:

Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Gastrointestinal system:

Ileus, pancreatitis, hepatitis or cholestatic jaundice, abdominal pain, vomiting, dyspepsia, constipation, anorexia, stomatitis.

Metabolic:

Cases of hypoglycaemia in diabetic patients on oral antidiabetic agents or insulin have been reported (see Interactions with other medicines).

Nervous System/Psychiatric:

Depression, confusion, somnolence, insomnia, nervousness, paraesthesia, vertigo, dream abnormality.

Renal:

Renal failure, oliguria, renal dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Respiratory

: Bronchospasm/asthma, dyspnoea, rhinorrhoea, sore throat and hoarseness.

Other:

Vasculitis, muscle cramps, hyperhidrosis, impotence, pruritus, asthenia, photosensitivity, alopecia, flushing, taste alteration, tinnitus, glossitis, blurred vision, urticaria.

A symptom complex has been reported which may include fever, serositis, myalgia and arthralgia/arthritis; an elevated erythrocyte sedimentation rate (ESR), a positive ANA, eosinophilia and leukocytosis. Rash, photosensitivity or other dermatological manifestations may occur. These symptoms have disappeared after discontinuation of therapy.

Angioedema:

Angioedema has been reported in patients receiving AMPRACE (0.2 percent). Angioedema associated with laryngeal oedema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with AMPRACE should be discontinued and appropriate therapy instituted immediately (see PRECAUTIONS). In very rare cases, intestinal angioedema has been reported with angiotensin converting enzyme inhibitors including enalapril.

Hypotension:

Combining the results of clinical trials in patients with hypertension or congestive heart failure, hypotension (including postural hypotension, and other orthostatic effect) was reported in 2.3 percent of patients following the initial dose of enalapril or during extended therapy. In the hypertensive patients, hypotension occurred in 0.9 percent and syncope occurred in 0.5 percent of patients. Hypotension or syncope was a cause for discontinuation of therapy in 0.1 percent of hypertensive patients (see PRECAUTIONS).

DOSAGE AND ADMINISTRATION

In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of AMPRACE. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with AMPRACE to reduce the likelihood of hypotension (see PRECAUTIONS). If the patient's blood pressure is not controlled with AMPRACE alone, diuretic therapy may be resumed. If the diuretic cannot be discontinued an initial dose of 2.5mg (break the 5mg tablet) should be used under medical supervision for at least one hour to determine whether excess hypotension will occur (see PRECAUTIONS, Interactions with other medicines). The recommended initial dose in patients not on diuretics is 5 mg once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range is 10 to 40 mg per day administered in a single dose or two 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 should be considered. If blood pressure is not controlled with AMPRACE alone, a diuretic may be added. Concomitant administration of AMPRACE with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics may lead to increases of serum potassium (see PRECAUTIONS). To date there is insufficient experience with AMPRACE in the treatment of accelerated or malignant hypertension. AMPRACE, therefore, is not recommended in such situations.

Dosage in the Elderly (over 65 years) The starting dose should be 2.5 mg. Some elderly patients may be more responsive to AMPRACE than younger patients.

Since blood pressure and renal function in such patients may be particularly sensitive to ACE inhibition, therapy should be initiated with a lower starting dose (eg 5 mg or less). The dosage should then be adjusted according to the needs of the patient. Most patients may be expected to respond to 20 mg taken once daily. For patients with hypertension who have been treated recently with diuretics, caution is recommended (see next paragraph).

Therapy with AMPRACE must be started under close medical supervision. Blood pressure and renal function should be monitored closely both before and after starting treatment with AMPRACE (see PRECAUTIONS) because severe hypotension and (more rarely) consequent renal failure have been reported. 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. The initial dose of AMPRACE in patients with congestive heart failure (especially renally impaired or sodium- and/or volume-depleted patients) should be lower (2.5 mg or less), and it should be administered under close medical supervision to determine the initial effect on the blood pressure. The appearance of hypotension after the initial dose of AMPRACE does not imply that hypotension will recur during chronic therapy with AMPRACE and does not preclude continued use of the drug. In the absence of, or after effective management of, symptomatic hypotension following initiation of therapy with AMPRACE in congestive heart failure, the dose should be gradually increased, depending on the patient's response, to the usual maintenance dose (10 - 20 mg) given in a single or divided dose. This dose titration may be performed over a 2 to 4 week period, or more rapidly if indicated by the presence of residual signs and symptoms of heart failure. In clinical trials in which mortality and morbidity was reduced, dosage was divided in two doses.

In the SOLVD Prevention trial, the initial dose was 2.5 mg twice daily and titrated, as above (see DOSAGE & ADMINISTRATION, Congestive Heart Failure), to the usual maintenance dose of 20mg in two divided doses.

The usual dose of enalapril is recommended for patients with a creatinine clearance >30 mL/min (serum creatinine of up to approximately 3 mg/dL). For patients with creatinine clearance <30 mL/min (serum creatinine >3 mg/dL), the first dose is 2.5 mg once daily. The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.

Dosage on non dialysis days should be adjusted depending on blood pressure response.

OVERDOSAGE

Limited data are available with regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension, beginning some six hours after ingestion of tablets, concomitant with blockade of the renin-angiotensin system, and stupor, which can be treated, if necessary, by intravenous infusion of normal saline solution. Several hypertensive patients in clinical studies have received as much as 80 mg of enalaprilat intravenously over a fifteen minute period. No adverse effects, other than those associated with recommended dosages, were observed. Enalaprilat may be removed from the general circulation by haemodialysis. Contact the Poisons Information Centre on 131126 for management of overdose.

PRESENTATION AND STORAGE CONDITIONS

AMPRACE

5 mg, white, round biconvex compressed tablet, scored on one side and engraved 'A712' on the other. Supplied in blister packs of 30 tablets. *

AMPRACE

10 mg, rust-red, round biconvex compressed tablet, scored on one side and engraved 'A713' on the other. Supplied in blister packs of 30 tablets.

AMPRACE

20 mg, peach coloured, round biconvex compressed tablet engraved 'A714' on one side. Supplied in blister packs of 30 tablets.

NAME AND ADDRESS OF SPONSOR

Merck Sharp & Dohme (Australia) Pty Limited 54-68 Ferndell Street, South Granville NSW 2142

Renal Status	Creatinine Clearance mL/min	Initial Dose mg/day
Normal Renal Function	>80 mL/min	5 mg
Mild Impairment	< 80 >30 mL/min	5 mg
Moderate to Severe Impairment	< 30 mL/min	2.5 mg
Dialysis Patients	-	2.5 mg on dialysis days 3

AMPRACE(r)

INTRODUCTION

DESCRIPTION

CLINICAL PHARMACOLOGY

INDICATIONS

CONTRAINDICATIONS

PRECAUTIONS

General

Evaluation of the hypertensive patient should always include assessment of renal function

Use In Pregnancy

Use in Lactation

Paediatric Use

Genotoxicity

Carcinogenicity

Effects on laboratory tests

INTERACTIONS WITH OTHER MEDICINES

ADVERSE EFFECTS

DOSAGE AND ADMINISTRATION

OVERDOSAGE

PRESENTATION AND STORAGE CONDITIONS

AMPRACE

AMPRACE

AMPRACE

NAME AND ADDRESS OF SPONSOR

POISON SCHEDULE OF THE MEDICINE

This document was approved by the Therapeutic Goods Administration on 6 September 1995. Date of most recent amendment 03 April 2013.