INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
HR-ENALAPRIL MALEATE

        59143

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

HR-ENALAPRIL MALEATE

HR-Enalapril maleate 2,5 (tablets)
HR-Enalapril maleate 5 (tablets)
HR-Enalapril maleate 10 (tablets)
HR-Enalapril maleate 20 (tablets)

COMPOSITION
HR-Enalapril maleate 2,5 - each tablet contains 2,5 mg enalapril maleate.
HR-Enalapril maleate 5 - each tablet contains 5 mg enalapril maleate.
HR-Enalapril maleate 10 - each tablet contains 10 mg enalapril maleate.
HR-Enalapril maleate 20 - each tablet contains 20 mg enalapril maleate.

PHARMACOLOGICAL CLASSIFICATION
A.7.1.3 Vascular medicines - other hypotensives

PHARMACOLOGICAL ACTION
Enalapril (prodrug), following oral absorption, is hydrolysedto enalaprilat (active form), which is an angiotensin-converting enzyme (ACE) inhibitor.
Clinical Pharmacology
Heart failure, Mortality trials
In a multicentre, placebo-controlled clinical trial, 2569 patients with all degrees of symptomatic heart failure and ejection fraction = 35 percent were randomized to placebo or enalapril and followed up for up to 55 months (SOLVD-Treatment). Use of enalapril was associated with an 11 percent reduction in all - cause mortality and a 30% reduction in hospitalization for heart failure. Diseases that excluded all patients from enrollment in the study included severe stable angina (>2 attacks/day), haemodynamically significant valvular or outflow tract obstruction, renal failure (creatinine >2,5 mg/dL), cerebral vascular disease (e.g. significant carotid artery disease), advanced pulmonary disease, malignancies, active myocarditis and constrictive pericarditis. The mortality benefit associated with enalapril does not appear to depend upon digitalis being present.
A second multicentre trial used the SOLVD protocol for study of asymptomatic or minimally symptomatic patients. 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 up for 5 years. The majority of patients in the SOLVD-Prevention trial had a history of ischaemic heart disease. A history of myocardial infarction was present in 80 percent of the patients, current angina pectoris in 34 percent and a history of hypertension in 37 percent. No statistically significant mortality effect was demonstrated in this population. Enalapril treated subjects had 32% fewer first hospitalizations for heart failure, and 32% fewer total heart failure hospitalizations.
Compared to placebo, 32 percent fewer patients receiving enalapril developed symptoms of overt heart failure. Hospitalizations for cardiovascular reasons were also reduced. There was an insignificant reduction in hospitalizations for any cause in the enalapril treatment group (for enalapril vs. placebo, respectively, 1166 vs. 1201 first hospitalizations, 2649 vs. 2840 total hospitalizations), although the study was not powered to look for such an effect.
The SOLVD-Prevention trial was not designed to determine whether treatment of asymptomatic patients with low ejection fraction would be superior, with respect to preventing hospitalization, to closer follow-up and use of enalapril at the earliest sign of heart failure. However, under the conditions of follow-up in the SOLVD-Prevention trial (every 4 months at the study clinic; personal physician as needed), 68% of patients on placebo who were hospitalized for heart failure had no prior symptoms recorded which would have signaled initiation of treatment.
The SOLVD-Prevention trial was also not designed to show whether enalapril modified the progression of underlying heart disease.
In another multicentre, placebo-controlled trial (CONSENSUS) limited to patients with NYHA Class IV congestive heart failure and radiographic evidence of cardiomegaly, use of enalapril was associated with improved survival. The results are shown in the following table.

	Survival (%)
	Six months	One year
Enalapril (n = 127)	74	64
Placebo (n = 126)	56	48

In both CONSENSUS and SOLVD-Treatment trials, patients were also usually receiving digitalis, diuretics or both.

INDICATIONS
HR-Enalapril maleate is indicated in
- Hypertension
all grades of essential hypertension
renovascular hypertension
- Heart failure
HR-Enalapril maleate is indicated for the treatment of symptomatic congestive cardiac failure, usually in combination with digitalis and diuretics. In these patients enalapril improves symptoms, increases survival and decreases the frequency of hospitalization. (see Clinical Pharmacology, Heart failure, Mortality, under Pharmacological Action, for details)
- Asymptomatic Left Ventricular dysfunction
In clinically stable asymptomatic patients with left ventricular dysfunction (ejection function = 35 percent), enalapril decreases the rate of development of overt heart failure and decreases the incidence of hospitalization for heart failure. (see Clinical Pharmacology, Heart failure, Mortality, under Pharmacological Action, for details)

CONTRA-INDICATIONS

-	Hypersensitivity to enalapril maleate or any of the components of this formulation.
-	Aortic stenosis and hypertrophic cardiomyopathy.
-	Patients with a history of angioneurotic oedema relating to previous treatment with an ACE inhibitor.
-	Lactation - enalapril and enalaprilat are secreted into the breast milk. Exercise caution when administering to nursing mothers.
-	Porphyria

WARNINGS

Should a woman become pregnant while receiving an ACE-inhibitor, the treatment must be stopped promptly and the patient switched to a different medicine. Should a woman contemplate pregnancy, the doctor should consider alternative medication.

ACE-inhibitors can cause neonatal and foetal morbidity and mortality when administered to pregnant women during the 2nd and 3rd trimesters.
Since ACE-inhibitors pass through the placenta they can be presumed to cause disturbances in foetal blood pressure regulatory mechanisms.
The following have been reported in newborns, following administration of ACE-inhibitors to pregnant women during the 2nd and 3rd trimesters. Oligohydramnios, which may result in limb contractures, cranofacial deformities and hypoplastic lung development, as well as hypotension, hyperkalaemia, oliguria, anuria, cases of defective skull ossification have been observed and prematurity and low birth mass can occur.
Infants whose mothers have taken enalapril should be closely observed for hypotension, oliguria and hyperkalaemia.
These adverse effects of the embryo and foetus do not appear to have resulted from intra-uterine ACE-inhibitor exposure limited to the first trimester.
Enalapril has been removed from the neonatal circulation by peritoneal dialysis, with some clinical benefit.

DOSAGE AND DIRECTIONS FOR USE
The absorption of enalapril is not influenced by food, thus it may be administered before, during or after meals.
- Essential Hypertension
The initial dose is 10 mg to 20 mg administered once daily.
Mild hypertension - recommended initial dose is 10 mg daily.
Other degrees of hypertension - recommended initial dose 20 mg daily.
Usual maintenance dose 20 mg once daily.
The dose may be adjusted according to the needs and response of the individual patient.
- Renovascular Hypertension
Blood pressure and renal function, in such patients, may be particularly sensitive to ACE-inhibition. It is therefore recommended that initiation of therapy should be at a lower dose. (5 mg or less)
The dose may then be adjusted according to the needs and response of the individual patient.
Most patients may be expected to respond to one 20 mg tablet taken once daily
Caution is recommended in patients with hypertension who have recently been treated with diuretics.
- Concomitant Diuretic Therapy in Hypertension
Symptomatic hypotension may occur following the initial dose of enalapril.
This is more likely to occur in patients who are currently being treated with diuretics. Caution is recommended because these patients may be volume or salt depleted. It is recommended that diuretic therapy be discontinued 2-3 days prior to initiation of therapy with enalapril. If this is not possible the initial dose of enalapril should be low (5 mg or less) in order to determine the initial effect on the blood pressure. Dosage should then be adjusted according to the response of the individual patient.
Dosage in Renal Insufficiency
It is generally recommended that the intervals between the administration of enalapril should be prolonged and/or the dosage reduced.

Renal Status	Creatinine Clearance         mL/min	Initial Dose         mg/day
Mild Impairment	<80 >30	5
Moderate Impairment	= 30 >10	2,5
Severe Impairment Normally on dialysis *	= 10	2,5 mg on dialysis days**

* see Special precautions - heamodialysis patients.
** Enalaprilat is dialysable. Dosage on non-dialysis days should be adjusted depending on the blood pressure response.
- Heart Failure/Asymptomatic Left Ventricular Dysfunction
The initial dose of enalapril administered to these patients should be 2,5 mg. This should be done under close medical supervision to determine the initial effect on the blood pressure. In the absence of symptomatic hypotension or following effective management thereof, the dosage of HR-Enalapril maleate may be carefully titrated upwards, towards the usual maintenance dose of 20 mg per day, given as a single dose or two divided doses, as best tolerated by the patient.
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 patients with symptomatic heart failure, this dosage was effective in reducing mortality.
Blood pressure and renal function should be closely monitored, before and after starting treatment with enalapril (see Special Precautions) , because hypotension and consequent renal failure have occurred.
In patients taking diuretics, the dosage should be reduced, if possible, before initiation of therapy with enalapril.
The appearance of hypotension following the initial dose of enalapril does not imply that hypotension will recur during chronic therapy with enalapril and does not preclude continued use of enalapril.
Serum potassium should also be monitored. (see Interactions)

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Dizziness and headache were the most commonly encountered side effects. Other side effects have occurred and include fatigue, asthenia, hypotension, orthostatic hypotension, syncope, nausea, diarrhoea, muscle cramps, rash, cough, renal dysfunction, renal failure and oliguria.
Hypersensitivity/Angioneurotic oedema
Angioneurotic oedema of the face, which may be fatal, extremities, lips, tongue, glottis and/or larynx have been reported.
Cardiovascular

-	Myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in risk patients (see special precautions)
-	chest pain
-	palpitations
-	rhythm disturbances
-	Angina pectoris

Gastrointestinal

-	Ileus, panreatitis, hepatic failure, hepatitis (either cholestatic or hepatocellular), jaundice, abdominal pain, vomiting, dyspepsia, constipation, anorexia, stomatitis.

Nervous system/Psychiatric
Depression, confusion, somnolence, insomnia, nervousness, paraesthesia, vertigo.
Respiratory
Pulmonary infiltrates, bronchospasm, asthma, dyspnoea, rhinorrhoea, sore throat and hoarseness.
Skin
Diaphoresis, erythema multiforme, exfoliative dermatitis, Stevens -Johnson syndrome, toxic epidermal necrolysis, pruritis, urticaria, alopecia, pemphigus.
Other
Impotence, flushing, taste alteration, tinnitis, glossitis, blurred vision.
A symptom complex has been reported which may include fever, serositis, vasculitis, myalgia, arthralgia/arthritis, a positive antinuclear antibody, elevated erythrocyte sedimentation rate, eosinophilia and leukocytosis. Rash, photosensitivity or other dermatologic manifestations may occur.
Clinical laboratory test findings
Increases in blood urea and serum creatinine, and elevations of liver enzymes and/or serum bilirubin have been seen. These are usually reversible upon discontinuation of enalapril. Hyperkalamaeia and hyponatraemia have occurred.
Decreases in haemoglobin and haematocrit have been reported.
SPECIAL PRECAUTIONS
Symptomatic Hypotension
This was seen in uncomplicated hypertensive patients. In hypertensive patients receiving enalapril, hypotension is more likely to occur if the patient has been volume depleted e.g. by diuretic therapy, dietary salt reduction, dialysis, diarrhoea or vomiting see interactions and side effects).
Heart failure patients with or without associated renal insufficiency have been known to suffer from symptomatic hypotension.
This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment.
In these patients therapy should be started under medical supervision and the patients should be followed closely whenever the dose of HR-Enalapril maleate and/or diuretic is adjusted. Similar considerations may apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in myocardial infraction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of normal saline. A transient hypotensive response is not a contra-indication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion.
In some patients with congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with HR-Enalapril maleate. This effect is anticipated, and usually is not a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of HR-Enalapril maleate may be necessary.
Renal Function Impairment
Patients with renal insufficiency may require reduced and/or less frequent doses of EnalaHexal. (See DOSAGE AND DIRECTIONS FOR USE.) In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, increases of blood urea and serum creatinine, reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal insufficiency.
Some patients with no apparent pre-existing renal disease have developed minor and usually transient increases in blood urea and serum creatinine when Enalapril has been given concomitantly with a diuretic. Dosage reduction of HR-Enalapril maleate and/or discontinuation of the diuretic may be required.
Hypersensitivity/Angioneurotic Oedema
Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including Enalapril . In such cases, HR-Enalapril maleate should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. In those instances where swelling has been confined to the face and lips the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms.
Angioneurotic oedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy such as subcutaneous epinephrine solution 1:1 000 (0,3 mL to 0,5 mL) should be administered promptly.
Patients with a history of angioedema unrelated to ACE-inhibitor therapy may be at increased risk of angioedema while receiving an ACE-inhibitor. (Also see CONTRA-INDICATIONS).
Anaphylactoid Reactions during Hymenoptera Desensitization
Rarely, patients receiving ACE-inhibitors during desensitization with hymenoptera venom have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitization.
Hemodialysis Patients
Anaphylactoid reactions have been reported in patients dialyzed 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.
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, enalapril blocks 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.
Serum Potassium - See INTERACTIONS
Paediatric Use - Enalapril has not been studied in children.

INTERACTIONS
Antihypertensive Therapy
The combination of enalapril with other antihypertensive medicines may increase the antihypertensive effect, especially in combination with diuretics.
The combination of enalapril with beta-adrenergic blocking agents and methyldopa or calcium entry blockers potentiates the hypotensive effects enalapril.
Ganglionic blocking agents or adrenergic blocking agents, combined with EnalaHexal, should only be administered with careful observation of the patient.
Because of the lack of experience, concomitant treatment of enalapril with calcium antagonists is not recommended.
Serum Potassium
Risk factors for the development of hyperkalaemia include renal insufficiency, diabetes mellitus and concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements, or potassium-containing salt substitutes.
In patients with renal failure, the administration of enalapril may lead to elevation of serum potassium. 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. If concomitant use of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.
Serum Lithium
The lithium elimination may be reduced. Therefore the lithium levels of serum should be carefully compared if lithium salts are to be administered.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Limited data are available for overdosage in humans. The most prominent feature of overdosage reported to date is marked hypotension, beginning some six hours after ingestion of tablets, concomitant with blockade of the renin-angiotensin system, and stupor.
The recommended treatment of overdosage is intravenous infusion of normal saline solution. If ingestion is recent, induce emesis.
Enalaprilat may be removed from the general circulation by haemodialysis.

IDENTIFICATION
HR-Enalapril maleate 2,5 is a white, oval, convex, scored tablet, coded “GEA” above “G07”.
Size approx. 4,2 x 8,8mm.
HR-Enalapril maleate 5 : white, round, convex, scored tablet, coded “GK2.”above “GEA”.
Diameter: approx. 6,5mm
HR-Enalapril maleate 10 : white, round, convex, scored tablet, coded “GEA”above “GL3”.
Diameter: approx. 8mm
HR-Enalapril maleate 20 : white, round, convex, scored tablets, coded “GEA”above “GM4”.
Diameter: approx. 10mm

PRESENTATION
HR-Enalapril maleate 2,5 mg tablets are packed into a white, opaque HDPE containers, closed with a tamper evident plastic screw cap. 30 tablets per container
HR-Enalapril maleate 5 mg/10 mg/20 mg tablets are packed in aluminium/aluminium blisters. Blisters are placed into a cardboard carton.
10 tablets per blister strip.
3 blister strips per carton (30’s)
30 blister strips per carton (300’s)

STORAGE INSTRUCTIONS
Store in a dry place below 25°C. Protect from light.
Do not remove blisters from the carton until required for use.
Do not remove tablets from container until required for use.
KEEP OUT OF REACH FROM CHILDREN.

REGISTRATION NUMBERS
HR-Enalapril maleate 2,5 –34/7.1.3/0029
HR-Enalapril maleate 5 –33/7.1.3/0506
HR-Enalapril maleate 10 –33/7.1.3/0507
HR-Enalapril maleate 20 –33/7.1.3/0508

NAME AND BUSINESS OF ADDRESS OF APPLICANT
Hexal Pharma (SA) (PTY) Ltd
UNIT A, 10 Fangio Rd
Mahogany Ridge
Westmead
3610

Marketed by Rolab
A sector of Novartis South Africa (Pty) Ltd

DATE OF PUBLICATION OF THIS PACKAGE INSERT
28 June 2000

59143

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