ALAPREN2,5 Tablets
ALAPREN5 Tablets
ALAPREN10 Tablets
ALAPREN20 Tablets

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

ALAPREN2,5 Tablets
ALAPREN5 Tablets
ALAPREN10 Tablets
ALAPREN20 Tablets

COMPOSITION
Alapren 2,5 Tablets
Each tablet contains
Enalapril maleate 2,5mg
Alapren 5 Tablets
Each tablet contains
Enalapril maleate 5mg
Alapren 10 Tablets
Each tablet contains
Enalapril maleate 10mg
Alapren 20 Tablets
Each tablet contains
Enalapril maleate 20mg
Sugar free.

PHARMACOLOGICAL CLASSIFICATION
A7.1.3 Vascular medicines - Other hypotensives.

PHARMACOLOGICAL ACTION
Mechanism of Action
Following oral administration and absorption, enalapril is hydrolysed to enalaprilat which is a specific, long-acting, non-sulfhydryl Angiotensin converting enzyme (ACE) inhibitor. Enalapril is a derivative of two amino acids; L-alanine and L-proline. ACE is a peptidyl dipeptidase which catalyses the conversion of angiotensin I to the pressor substance angiotensinII. This results in reduced plasma renin activity and decreased aldosterone secretion. The blood pressure lowering effect of enalapril is primarily through suppression of the renin- angiotensin- aldosterone system.
Clinical Pharmacology
Heart Failure, Mortality trials
In a multicenter, placebo-controlled clinical trial, 2569patients with all degrees of symptomatic heart failure and ejection fraction <35% were randomized to placebo or enalapril and followed for up to 55months (SOLVD-Treatment). Use of enalapril was associated with an 11% reduction in all-cause mortality and a 30% reduction in hospitalization for heart failure. Diseases that excluded patients from enrollment in the study included severe stable angina (>2 attacks/day), hemodynamically 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. The mortality benefit associated with enalapril does not appear to depend upon digitalis being present.
A second multicenter 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 randomized to placebo (n = 2117) or enalapril (n = 2111) and followed for up to 5 years. The majority of patients in the SOLVD-Prevention trial had a history of ischemic heart disease. A history of myocardial infarction was present in 80% of the patients, current angina pectoris in 34 %, and a history of hypertension in 37%. 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% fewer patients receiving enalapril developed symptoms of overt heart failure. Hospitalizations for cardiovascular reasons were also reduced. There was an insignificant reduction in hospitalization 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 multicenter, 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.

Treatment	Surival (%)
	Six Months One Year	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
Treatment of hypertension: All grades of essential hypertension and renovascular hypertension.
Treatment of heart failure: Enalapril is indicated for the treatment of symptomatic congestive heart failure, usually in combination with diuretics and digitalis. In these patients enalapril improves symptoms, increases survival, and decreases the frequency of hospitalization (see Clinical Pharmacology, Heart Failure, Mortality trials under Pharmacological Actions for details).
Asymptomatic left ventricular dysfunction: In clinically stable asymptomatic patients with left ventricular dysfunction (ejection fraction <35%), 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 trials under Pharmacological Actions for details).

CONTRA-INDICATIONS
Hypersensitivity to the product or any of the components and in patients with a history of angioneurotic oedema relating to previous ACE inhibitor treatment.
Lactation - Enalapril and enalaprilat are secreted into the breast milk.

WARNINGS

Should a woman become pregnant while receiving Alapren, the treatment must be stopped promptly and switched to a different medicine. Should a woman contemplate pregnancy, the doctor should institute alternative medication.

Alapren can cause foetal and neonatal morbidity and mortality when administered to pregnant women during the 2nd and 3rd trimesters. Alapren 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 Alapren in the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur.
Infants whose mothers have taken enalapril should be closely observed for hypotension, oliguria and hyperkalemia. These adverse effects to the embryo and foetus do not appear to have resulted from intra-uterine Alapren exposure limited to the first trimester.
Alapren, which crosses the placenta, has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit.

INTERACTIONS
Antihypertensive Therapy
The combination of Alapren with other antihypertensive medicines may increase the antihypertensive effect, especially in combination with diuretics.
The combination of Alapren with beta-adrenergic blocking agents and methyldopa or calcium entry blockers potentiates the hypotensive effects of enalapril.
Ganglionic blocking agents or adrenergic blocking agents, combined with Alapren, should only be administered with careful observation of the patient.
Because of lack of experience, concomitant treatment of Alapren with calcium antagonists is not recommended.
Serum Lithium
Lithium elimination may be reduced. Therefore the lithium levels of serum should be carefully compared if lithium salts are to be administered.
Serum Potassium
Risk factors for the development of hyperkaleamia 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. Alapren may elevate serum potassium levels in patients with renal failure, especially when they are receiving potassium supplements, potassium sparing diuretics or potasssium containing salt substitutes. If concomitant use of the above mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.
Others
Narcotic drugs/antipsychotics may cause postural hypotension when used concomitantly with Alapren.
Concomitant administration of allopurinol, cytostatic or immuno- suppressive agents, systemic corticosteroids or procainamide with Alapren may increase the risk for leucopenia. Concomitantly administered cyclosporin increases the risk of hyperkalaemia with Alapren.
The antihypertensive effect of Alapren may be reduced or abolished by concomitant therapy with a nonsteroidal anti-inflammatory agent.
Since sympathomimetics may reduce the antihypertensive effects of Alapren, careful monitoring of the desired effects should be done.
Alcohol enhances the hypotensive effect of concomitantly administered Alapren.

PREGNANCY AND LACTATION
See Contra-indications and Warnings.

DOSAGE AND DIRECTIONS FOR USE
Since food does not interfere with the absorption of Alapren, the dose may be administered before, during or after meals.
Essential hypertension: The initial dose is 10 to 20mg depending on the degree of hypertension and is given once daily. In mild hypertension the recommended initial dose is 10mg daily. For other degrees of hypertension the initial dose is 20mg daily. The usual maintenance dose is one 20mg tablet taken once daily. The dosage should be adjusted according to the needs of the patient.
Renovascular hypertension: 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 (e.g. 5mg or less). The dosage should then be adjusted according to the needs of the patient. Most patients may be expected to respond to one 20mg tablet, taken once daily. For patients with hypertension who have been treated recently with diuretics, caution is recommended (See paragraph above).
Concomitant diuretic therapy in hypertension: Symptomatic hypotension may occur following the initial dose of Alapren; this is more likely in patients who are being treated currently with diuretics. Caution is recommended, therefore, since these patients may be volume or salt depleted. The diuretic therapy should be discontinued for 2-3days prior to initiation of therapy with Alapren. If this is not possible, the initial dose of enalapril should be low (5mg or less) to determine the initial effect on the blood pressure. Dosage should then be adjusted according to the needs of the patient.
Use in the elderly (over 65years): Therapy should be initiated with Alapren in a dose of 2,5mg. The hypotensive response to Alapren may be greater in some elderly patients than in younger patients.
Dose titration should be carried out according to the need for the control of blood pressure.
Heart failure/asymptomatic left ventricular dysfunction: In such patients the recommended starting dose of Alapren is 2,5mg once daily initiated under medical supervision to determine the initial effect on the blood pressure. It is important that therapy is initiated in hospital for patients with severe heart failure. In the absence of, or after effective management of, symptomatic hypotension following initiation of therapy with Alapren in heart failure, the dose of Alapren should be titrated gradually to the usual maintenance dose of 20mg daily given as a single dose or two divided doses, according to the tolerability of the patient.
The dose titration of enalapril should be performed over two to four weeks or more rapidly in the presence of residual signs and symptoms of heart failure. The patient’s blood pressure, renal function and serum potassium must be monitored closely both before and during treatment with Alapren because hypotension and consequent renal failure have been reported.
Patients who are treated with diuretics should have the diuretic dose reduced, if possible, before starting treatment with Alapren. In case hypotension develops following the initial dose of Alapren, this does not imply that hypotension will recur during chronic therapy with Alapren and does not preclude continued use of Alapren.
Use in impaired renal function: (See Special Precautions). Since enalapril is excreted by the kidney, it should be used with caution in patients with renal impairment. Therapy should begin with 2,5mg and the dose should be titrated against the response. It is important that the dose be kept as low as possible to adequately control the disease process.
Dosage in Renal Insufficiency:
Generally 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 these patients will be on dialysis*	<10	2,5mg on dialysis days**

* See Special Precautions, Hemodialysis patients.
** Enalaprilat is dialysable. Dosage on non-dialysis days should be adjusted depending on the blood pressure response.
Children: There are no studies on the pediatric use of enalapril.
Serum potassium also should be monitored (see Interactions).

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-Effects
Cases of severe hypotension and renal failure have been reported with therapy with Alapren (see Side-Effects and Special Precautions)
Commonly reported side-effects include dizziness and headache. Other side-effects occurred and include fatigue, asthenia, hypotension, orthostatic hypotension, syncope, nausea, diarrhoea, muscle cramps, rash, cough, renal dysfunction, renal failure, and oliguria.
Cardiovascular: Myocardial infarction or cerebro-vascular accident, possibly secondary to severe hypotension in high risk patients (See Special Precautions), chest pain, palpitations, rhythm disturbances, angina pectoris.
Gastrointestinal: Ileus, pancreatitis, hepatic failure, hepatitis –either hepatocellular or cholestatic 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, pemphigus, pruritus, urticaria, alopecia.
Others: Impotence, flushing, taste alteration, tinnitus, glossitis, blurred vision.
A symptom complex has been reported which may include fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive ANA (Anti-Nuclear Antibody), elevated ESR (Erythrocyte Sedimentation Rate), eosinophilia, and leucocytosis. Rash, photosensitivity or other dermatological manifestations may occur.
Special Precautions
Assessment of renal function prior to initiation of therapy and during treatment should be included in the eva luation of patient, where appropriate.
Symptomatic hypotension: Symptomatic hypotension was seen in uncomplicated hypertensive patients. Hypotension is more likely to occur in hypertensive patients who are volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting (see Interactions and Side-Effects). In patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension is most likely to occur in those with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment (SeeDosage and Directions for use for management of these patients). In these patients, therapy should be started under medical supervision and the patient should be followed closely whenever the dose of Alapren and/or diuretic is adjusted. Similarly, patients with ischaemic heart or cerebrovascular disease may develop an excessive fall in blood pressure which could result in a myocardial infarction or cerebrovascular accident.
If hypotension develops, suitable management including placing the patient in a supine position and, if necessary, an intravenous infusion of normal saline may be required. A transient hypotensive response is not a contra-indication to further doses, which can be given usually without difficulty once the blood pressure is increased after volume expansion.
Some patients with heart failure who have normal or low blood pressure could develop additional lowering of systemic blood pressure following Alapren administration. If hypotension becomes symptomatic, a reduction of dose of enalapril and/or discontinuation of the diuretic may be necessary.
Impaired Renal Function: Caution should be exercised when using Alapren in patients with renal insufficiency. Such patients may require reduced or less frequent doses (see Dosage and Directions for use). The renal function should be monitored before and during therapy in those with renal insufficiency. 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 hypertensive patients, with no apparent pre-existing renal disease have developed minor and usually transient increases in blood urea and serum creatinine when Alapren has been given concurrently with a diuretic. In such cases, dosage reduction of Alapren 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 seen to occur following treatment with Alapren. This may occur at any time during treatment. In such cases, Alapren should be discontinued immediately and appropriate monitoring should be taken to ensure complete resolution of symptoms prior to dismissing the patient. The condition is usually self-resolving in case the swelling is confined to the face, lips and mouth, although anti-histamines may be useful in relieving symptoms. Angioneurotic oedema associated with laryngeal oedema may be fatal. Involvement of the tongue, glottis or larynx, likely to cause airways obstruction, necessitates emergency measures such as prompt administration of subcutaneous adrenaline (0,3-0,5mL, 1: 1000).
Patients with a history of angioedema unrelated to Alapren should be considered to be at increased risk of angioedema while receiving Alapren (see also Contra-indications)
Other hypersensitivity reactions including urticaria have been reported.
Anaphylactic reactions during hymenoptera desensitisation: In less frequent situations, patients receiving Alapren during desensitisation with hymenoptera venom (e.g. bee or wasp venom) have been found to experience life threatening anaphylactoid reactions. Temporarily withholding Alapren therapy prior to each desensitisation can help avert such reactions.
Haemodialysis patients: In patients dialysed with high-flux membranes and treated concomitantly with Alapren a high incidence of anaphylactoid reactions have been reported. It is recommended that in such patients a different type of dialysis membrane or a different class of antihypertensive agent should be used.
Cough: Cough which is non-productive, persistent and resolves after discontinuation of therapy may occur with use of Alapren. Alapren-induced cough should be considered as part of the differential diagnosis of cough.
General: Patients with aortic stenosis or outflow tract obstruction should not be treated with Alapren.
Surgery/Anaesthesia: Alapren blocks the formation of angiotensin-II secondary to compensatory renin release in patients undergoing major surgery or during anaesthesia with agents that cause hypotension. 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
Alapren has not been studied in children; and safety and efficacy have not been demonstrated in children.
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 Alapren. Hyperkalaemia and hyponatraemia have occurred.
Decreases in haemoglobin and haematocrit have been reported.

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.
Alapren may be removed from the general circulation by haemodialysis.

IDENTIFICATION
Alapren 2,5 Tablets
White to off-white round, biconvex uncoated tablets debossed with ‘0025’on one side and ‘ENP’on the other.
Alapren 5 Tablets
White to off-white round, biconvex uncoated tablets debossed with ‘ENP005’and a break line one one side and ‘R’on the other.
Alapren 10 Tablets
Pink, round biconvex uncoated tablets debossed with ‘ENP010’on one side and ‘R’on the other.
Alapren 20 Tablets
Peach coloured round, biconvex, uncoated tablets debossed with ‘ENP020’on one side and ‘R’on the other.

PRESENTATION
Alapren 2,5 Tablets: Carton containing 2blister strips of 7tablets in each blister
Alapren 5 Tablets: Carton containing 4blister strips of 7tablets in each blister
Alapren 10 Tablets: Carton containing 4blister strips of 7tablets in each blister
Alapren 20 Tablets: Carton containing 4blister strips of 7tablets in each blister

STORAGE INSTRUCTIONS
Store below 25°C, protected from moisture.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATIONNUMBERS

Alapren 2,5 Tablets:	34/7.1.3/0013
Alapren 5 Tablets:	34/7.1.3/0014
Alapren 10 Tablets:	34/7.1.3/0015
Alapren 20 Tablets:	34/7.1.3/0016

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
RANBAXY (SA) (PTY) LTD
3^rd Floor
Outspan House
1006 Lenchen Avenue North
CENTURION

DATE OF PUBLICATION OF THE PACKAGE INSERT
September 2000

Updated on this site: June 2005
Source: Pharmaceutical Industry