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ENAP 5mg (Tablet); ENAP 10mg (Tablet); ENAP 20mg (Tablet)
ENAP 5mg (Tablet)
ENAP 10mg (Tablet)
ENAP 20mg (Tablet)
SCHEDULING STATUS:
S3
PROPRIETARY NAME
(and dosage form):
ENAP 5mg (Tablet)
ENAP 10mg (Tablet)
ENAP 20mg (Tablet)
COMPOSITION:
Each ENAP 5mg tablet contains 5mg enalapril maleate.
Each ENAP 10mg tablet contains 10mg enalapril maleate.
Each ENAP 20mg tablet contains 20mg enalapril maleate.
PHARMACOLOGICAL CLASSIFICATION:
A 7.1.3 Vascular medicines - other hypotensives.
PHARMACOLOGICAL ACTION:
Enalapril maleate is the maleate salt of enalapril, which is a derivative from the amino acids, L-alanine and L-proline. After oral absorption, enalaprilat is formed by hydrolysation of enalapril maleate. Enalaprilat is a specific, long-acting, non-sulphydryl angiotensin-converting enzyme (ACE) inhibitor.
In a multicenter, placebo-controlled clinical trial, 2,569 patients with all degrees of symptomatic heart failure and ejection fraction <35% were randomised to either receive placebo or enalapril and followed for up to 55months (SOLVD-Treatment). Patients receiving enalapril exhibited an 11% reduction in all-cause mortality and a 30% reduction in hospitalisation for heart failure. Patients were excluded from enrolment in the study if they suffered from severe stable angina (>2 attacks/day), haemodynamically significant valvular or outflow tract obstruction, renal failure (creatinine >2,5mg/dL), cerebral vascular disease (e.g. significant carotid artery disease), advanced pulmonary disease, malignancies, active myocarditis and constrictive pericarditis. Mortality benefits associated with enalapril do not appear to depend upon concomitant use of digitalis.
The SOLVD protocol was used in a second multicenter trial to study asymptomatic or minimally symptomatic patients. SOLVD-Prevention patients, with left ventricular ejection fraction <35% and no history of symptomatic heart failure, were randomised to either receive placebo (n = 2117) or enalapril (n = 2111), and followed for up to 5years. The majority of patients in the SOLVD-Prevention trial had a history of ischaemic heart disease. 80% of patients had a history of myocardial infarction, 34% had current angina pectoris, and 37% had a history of hypertension. In this population, no statistically significant mortality effect could be demonstrated. The incidence of first hospitalisations for heart failure in enalapril-treated subjects was 32% lower, and also 32% lower for total heart failure hospitalisations. Compared to placebo, 32% fewer patients receiving enalapril developed symptoms of overt heart failure. Hospitalisations for cardiovascular reasons were also reduced. An insignificant reduction in hospitalisations for any cause in the enalapril treatment group (for enalapril versus placebo, respectively, 1166 versus 1201 first hospitalisations, 2649 versus 2840 total hospitalisations) was noted, although the study was not powered to look for such an effect.
The design of the SOLVD-Prevention trial was not designed to determine whether treatment of asymptomatic patients with low ejection fraction would be superior, regarding prevention of hospitalisation, closer follow-up and use of enalapril at the earlier sign of heart failure. During follow-up in the SOLVD-Prevention trial (every 4 months at the study clinic; personal physician as required), no prior symptoms which would have signalled initiation of treatment were recorded in 68% of patients receiving placebo who were hospitalised for heart failure.
The SOLVD-Prevention trial was also not designed to show whether enalapril had an effect on the progression of underlying heart disease.
Another multicenter, placebo-controlled trial (CONSENSUS) which was limited to patients with NYHA Class IV congestive heart failure and radiographic evidence of cardiomegaly, showed that the use of enalapril was associated with improved survival. The results are summarised below:
|
|
SURVIVAL (%)
Six months |
Oneyear |
|
Enalapril (n = 127) |
74 |
64 |
|
Placebo (n = 126) |
56 |
48 |
In the SOLVD-Treatment and the CONSENSUS trials, patients were usually also receiving digitalis, diuretics or both.
INDICATIONS:
ENAP is indicated for:
Hypertension
Essential hypertension - all grades.
Renovascular hypertension.
Heart failure
Treatment of symptomatic congestive heart failure, usually in combination with diuretics and digitalis. In these patients symptom improvement, survival increase and decrease frequency of hospitalisation were observed (see PHARMACOLOGICAL ACTION).
Asymptomatic Left Ventricular Dysfunction
In asymptomatic patients with left ventricular dysfunction (ejection fraction < 35%) who are clinically stable, the rate of development of overt heart failure and incidence of hospitalisation for heart failure are decreased (see PHARMACOLOGICAL ACTION).
CONTRA-INDICATIONS:
Hypersensitivity to the product or any of its components. In patients with a history of angioneurotic oedema relating to previous treatment with an ACE-inhibitor.
Lactation
Caution should be exercised during lactation as enalapril and enalaprilat are secreted in human milk.
WARNINGS:
Should a woman become pregnant while receiving an ACE-inhibitor, the treatment must be stopped promptly and switched to a different medicine.
Should a woman contemplate pregnancy, the doctor should institute alternative medication. |
ACE-inhibitors can cause foetal and neonatal morbidity and mortality when administered to pregnant women during the 2nd and 3rd trimesters. ACE-inhibitors pass through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms.
Oligohydramnios, which may result in limb contractures, craniofacial deformities and hypoplastic lung development, as well as hypotension, hyperkalemia, oliguria and anuria in newborns have been reported after administration of ACE-inhibitors in the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur.
Neonates born to mothers who have taken ACE-inhibitors should be closely monitored for hypotention, oliguria and hyperkalemia. Intra-uterine ACE-inhibitor exposure limited to the first trimester did not appear to have these adverse effects on the embryo and foetus.
Some clinical benefit has been obtained by using peritoneal dialysis to remove enalapril, which crosses the placenta, from the neonatal circulation.
DOSAGE AND DIRECTIONS FOR USE:
ENAP may be administered before, during or after meals as its absorption is not affected by food intake.
Essential Hypertension
Depending on the degree of hypertension, an initial dose of 10 to 20mg is given once daily. The recommended initial dose in mild hypertension is 10mg daily. An initial dose of 20mg daily should be used for other degrees of hypertension. The usual maintenance dose is one 20mg tablet taken once daily. Dosage should be adjusted to the patient’s needs.
Renovascular Hypertension
Blood pressure and renal function in patients with renovascular hypertension may be particularly sensitive to ACE-inhibition, therefore, a lower starting dose (e.g. 5mg or less) should be used to initiate therapy. Dosage adjustment should be made according to the needs of the patient. The majority of patients may be expected to respond to one 20mg tablet, taken once daily. Caution is recommended in patients with hypertension who have been treated recently with diuretics. (See paragraph below).
Concomitant Diuretic Therapy in Hypertension
Following the initial dose of ENAP, symptomatic hypotension may occur; such reactions are more likely to occur in patients receiving concomitant diuretic treatment.
As these patients may be volume or salt depleted, caution is recommended during administration of ENAP. Diuretic therapy should be discontinued for 2-3 days prior to initiation of therapy with ENAP. If this is not possible, a low initial dose (5mg or less) should be used to assess the initial effect on the patient’s blood pressure. Dosage should then be adjusted according to the patient’s needs.
Dosage in Renal Insufficiency
In general, the intervals between enalapril administration should be prolonged and/or a reduced dosage should be administered.
|
Renal Status |
Creatinine Clearance mL/min |
Initial Dosemg/day |
|
Mild impairment |
<80>30 |
5 |
|
Moderate impairment |
<30>10 |
2,5 |
Severe impairment
Normally these patients will be on dialysis* |
<10 |
2,5mg on dialysis days** |
* See SPECIAL PRECAUTIONS - Haemodialysis Patients
** Enalaprilat is dialysable. Dosage on non-dialysis days should be adjusted depending on the blood pressure response.
Heart Failure/Asymptomatic Left Ventricular Dysfunction
In patients with asymptomatic heart failure or asymptomatic left ventricular dysfunction, an initial dose of 2,5mg should be used. Close medical supervision is necessary to determine the initial effect on blood pressure. After initiation of therapy with ENAP in heart failure, provided symptomatic hypotension is absent, or has been effectively managed, the dose should be increased gradually to the usual maintenance dose of 20mg, given in a single dose or two divided doses, depending on patient tolerance.
This dose titration should be carried out over a 2 to 4 week period, or more rapidly if residual signs and symptoms of heart failure are present. This dosage regimen is effective in reducing mortality in patients with symptomatic heart failure.
Care must be taken to monitor blood pressure and renal function closely before and after starting treatment with ENAP (see SPECIAL PRECAUTIONS), because hypotension followed by renal failure, has been reported. In patients receiving treatment with diuretics, the dosage of the diuretic should if possible be reduced before treatment with ENAP is initiated. If hypotension should occur after the initial dose of ENAP, it does not imply that hypotension will recur during chronic ENAP therapy, nor preclude continued use of ENAP.
Serum potassium levels should also be monitored (see INTERACTIONS).
SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects
The most commonly reported side-effects were dizziness and headache. Fatigue, asthenia, hypotension, orthostatic hypotension, syncope, nausea, diarrhoea, muscle cramps, rash, cough, renal dysfunction, renal failure and oliguria, have also been reported.
Other
Impotence, flushing, taste alteration, tinnitus, glossitis, blurred vision.
Nervous System/Psychiatric
Depression, confusion, somnolence, insomnia, nervousness, paraesthesia, vertigo.
Cardiovascular
Myocardial infarction or cerebrovascular accident, these reactions may be secondary to excessive hypotension in high risk patients (see SPECIAL PRECAUTIONS), chest pain, palpitations, rhythm disturbances, angina pectoria.
Respiratory
Broncho spasm/asthma, dyspnoea, rhinorrhoea, pulmonary infiltrates, sore throat and hoarseness.
Gastro-intestinal
Ileus, pancreatitis, hepatitis - either hepatocellular or cholestatic, jaundice, abdominal pain, vomiting, dyspepsia, constipation, anorexia, stomatitis, hepatic failure.
Skin
Diaphoresis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, pruritus, urticaria, alopecia, pemphigus.
Hypersensitivity/Angioneurotic Oedema
Angioneurotic oedema of the face, which may be fatal, extremities, lips, tongue, glottis and/or larynx have been reported (see SPECIAL PRECAUTIONS).
A symptom complex, which may include fever, serositis, vasculitis, myalgia, arthralgia/arthritis, a positive anti-nuclear antibody, elevated erythrocyte sedimentation rate, eosinophilia and leukocytosis, has been reported. Dermatologic manifestations, such as rash or photosensitivity may occur.
Clinical Laboratory Test Findings
Blood urea and serum creatinine increases, and raised liver enzymes and/or serum bilirubin levels have been observed. These findings are usually reversible upon discontinuation of enalapril. Hyperkalemia and hyponatremia have occurred.
Decreases in haemoglobin and haematocrit have been reported.
Special Precautions:
Anaphylactoid Reactions during Hymenoptera Desensitisation
Less frequently, patients receiving ACE inhibitors during desensitisation with hymenoptera venom have experiences life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitisation.
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.
Haemodialysis patients
Anaphylactoid reactions have been observed in patients dialyzed with high-flux membranes (e.g. AN69®) concomitantly receiving an ACE-inhibitor. Consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent in these patients.
Hypersensitivity/Angioneurotic Oedema
In some patients treated with ACE-inhibitors, including enalapril, angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported. In such cases, enalapril should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms before patients are discharged. In cases where swelling has been confined to the face and lips the condition generally resolves without treatment although antihistamines have been useful in relieving symptoms.
Angioneurotic oedema associated with laryngeal oedema may be fatal. Where airway obstruction could occur due to involvement of the tongue, glottis or larynx, prompt administration of appropriate therapy such as subcutaneous adrenaline solution 1:1 000 (0,3 mL to 0,5 mL) is indicated.
Patients may be at increased risk of angioedema while receiving an ACE-inhibitor if they have a history of angioedema unrelated to ACE-inhibitor therapy (also see CONTRA-INDICATIONS).
Paediatric use
No studies with enalapril have been carried out with children.
Renal Function Impairment
Reduced and/or less frequent doses of enalapril may be required for patients with renal insufficiency (see DOSAGE AND DIRECTIONS FOR USE). Increases of blood urea and serum creatinine have been observed in some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney; these symptoms were reversible upon discontinuation of therapy. Patients with renal insufficiency are more likely to develop these symptoms.
Minor and usually transient increases in blood urea and serum creatinine have been observed in some patients with no apparent pre-existing renal disease when enalapril has been given concomitantly with a diuretic. Dosage reduction of enalapril and/or discontinuation of the diuretic may be required.
Serum Potassium
See INTERACTIONS.
Surgery/Anaesthesia
Enalapril is known to block angiotensin II formation secondary to compensatory renin release in patients undergoing major surgery or during anaesthesia with agents that produce hypotension. Should hypotension occur and be considered to be due to this mechanism, volume expansion can be used to correct the fall in blood pressure.
Symptomatic Hypotension
Symptomatic hypotension has been observed in uncomplicated hypertensive patients. Hypotension is more likely to occur in hypertensive patients receiving enalapril, if the patient has been volume-depleted, e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting (see INTERACTIONS and SIDE-EFFECTS). Symptomatic hypotension has been recorded in patients with heart failure, with or without associated renal insufficiency. It is more likely to develop in patients with more severe degrees of heart failure, reflected by the use of high doses of loop diuretics, hyponatremia or functional renal impairment. In these patients, therapy should be initiated under medical supervision and whenever the dose of enalapril and/or diuretic is adjusted, these patients should be carefully monitored. In patients with ischaemic heart or cerebrovascular disease in whom an excessive decrease in blood pressure could cause myocardial infarction or cerebrovascular accident, similar precautions should be applied.
If hypotension occurs, the patient should be made to lie down and, if necessary, an intravenous infusion of normal saline should be administered. A transient hypotensive response is not a contra-indication to further doses which can be given usually without further problems, once the blood pressure has improved by volume expansion.
In some congestive heart failure patients who have normal or low blood pressure, use of enalapril may result in additional lowering of systemic blood pressure. This effect should be anticipated and is usually not a reason to discontinue treatment. In cases where hypotension becomes symptomatic, it may become necessary to reduce or discontinue treatment with enalapril.
Interactions:
Serum Lithium
Lithium elimination may be reduced. Therefore if lithium salts are to be administered, serum lithium levels should be carefully monitored.
Antihypertensive Therapy
The combination of enalapril with other antihypertensive medicines, particularly diuretics, may increase the antihypertensive effect.
The hypotensive effects of enalapril are potentiated by combination with beta-adrenergic blocking agents and methyldopa or calcium entry blockers.
If glanglionic blocking agents or adrenergic blocking agents are combined with enalapril, the patient should be carefully observed.
No experience of the concomitant use of enalapril with calcium antagonists is currently available; therefore, this combination is not recommended.
Serum Potassium
Hyperkalemia may develop in the presence of risk factors such as renal insufficiency, diabetes mellitus and concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements, or potassium-containing salt substitutes.
The administration of enalapril to patients with renal failure, may lead to elevation of serum potassium. A significant increase in serum potassium can occur with the use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, particularly in patients with impaired renal function. If concomitant use of the agents mentioned above is deemed necessary, they should be used with caution and serum potassium should be monitored frequently.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Data on overdosage in humans is limited. The major features of overdosage reported to date are marked hypotension, which commences approximately six hours after ingestion of enalapril, resulting from blockade of the renin-angiotensin system, and stupor.
Intravenous infusion of normal saline solution is the treatment of choice for overdosage. Emesis should be induced if ingestion is recent.
Haemodialysis can be used to remove enalapril from the general circulation.
Treatment is symptomatic and supportive.
IDENTIFICATION:
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ENAP 5mg: |
A round, white, bevelled edge tablet, scored on one side. |
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ENAP 10mg: |
A round, flat, red brown, spotted tablet, with a bevelled edge and scored on one side. |
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ENAP 20mg: |
A round, flat, light orange, spotted tablet, with a bevelled edge and scored on one side. |
PRESENTATION:
Available in blisters of 28 tablets.
STORAGE INSTRUCTIONS:
Store in a dry place below 25°C. Do not remove tablets from the outer carton until required for use. Protect from light.
KEEP OUT OF REACH OF CHILDREN.
REGISTRATION NUMBER:
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ENAP 5mg: |
34/7.1.3/0085 |
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ENAP 10mg: |
34/7.1.3/0086 |
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ENAP 20mg: |
34/7.1.3/0087 |
NAME AND BUSINESS ADDRESS OF APPLICANT:
MC Pharma (Pty) Ltd
4th Floor, Argo Building
184 Erasmus Street
Meyerspark
0184
DATE OF PUBLICATION OF THIS PACKAGE INSERT:
7 February 2000
Updated on this site: December 2001 |
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