INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
PHARMAPRESS 10 mg TABLET
PHARMAPRESS 20 mg TABLET

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

PHARMAPRESS 10 mg TABLET
PHARMAPRESS 20 mg TABLET

COMPOSITION:
Each PHARMAPRESS 10 mg tablet contains 10 mg enalapril maleate.
Each PHARMAPRESS 20 mg tablet contains 20 mg enalapril maleate.

PHARMACOLOGICAL CLASSIFICATION:
A 7.1.3 Vascular medicines - other hypotensives

PHARMACOLOGICAL ACTION:
PHARMAPRESS (enalapril maleate, MSD) is the maleate salt of enalapril, a derivative of two amino acids, L-alanine and L-proline. Following oral absorption, PHARMAPRESS is hydrolysed to enalaprilat, which is a specific, long-acting, non-sulphydryl angiotensin converting enzyme inhibitor.

CLINICAL PHARMACOLOGY
Heart Failure Mortality Trials
In a multicenter, placebo-controlled clinical trial, 2 569 patients with all degrees of symptomatic heart failure and ejection fraction < 35 percent were randomized to placebo or enalapril and followed for up to 55 months (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 >2,5 mg/dL), cerebral vascular disease (e.g., significant carotid artery disease), advanced pulmonary disease, malignancies, active myocarditis and contrictive 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 asymtomatic 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 up 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 patients, current angina pectoris in 34%, and a history of hypertention 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. Hospitalization for cardiovascular reasons was 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 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.

	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:
PHARMAPRESS is indicated in:
• Hypertension
all grades of essential hypertension
renovascular hypertension
• Heart failure
PHARMAPRESS is indicated for the treatment of symptomatic congestive heart failure, usually in combination with diuretics and digitalis. In these patients PHARMAPRESS improves symptoms, increases survival, and decreases the frequency of hospitalization (see Clinical Pharmacology, Heart Failure, Mortality Trials under PHARMACOLOGICAL ACTION for details).
• Asymptomatic Left Ventricular Dysfunction
In clinically stable asymptomatic patients with left ventricular dysfunction (ejection fraction < 35 percent), PHARMAPRESS decreases the rate of development of overt heart failure and decreases the incidence of hospitalization for heart failure, (see Clinical Pharmacology, Heart Failure, Mortallity Trials under PHARMACOLOGICAL ACTION for details).

CONTRA-INDICATIONS:
• Enalapril and enalaprilat are secreted in human milk. Caution should be exercised if PHARMAPRESS is given to a nursing mother.
• Hypersensitivity to the product or any of its components, and in patients with a history of angioneurotic oedema relating to previous treatment with an angiotensin converting enzyme inhibitor.

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 consider alternative medication.
ACE-inhibitors can cause foetal and neonatal morbidity and mortality when administered to pregnant women during the second and third trimesters. ACE-inhibitors pass through the placenta and can be presumed to cause disturbances in foetal blood pressure regulatory mechanisms.
Oligohydramnios which may result in limb contractures, craniofacial deformities and hypoplastic lung development as well as hypotension, 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.
Infants whose mothers have taken PHARMAPRESS 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 ACE-inhibitor exposure limited to the first trimester.
Enalapril, which crosses the placenta, has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit.

DOSAGE AND DIRECTIONS FOR USE:
Since its absorption is not affected by food, PHARMAPRESS tablets may be administered before, during or after meals.
In the presence of renal insufficiency and in patients with congestive heart failure or patients who are currently being treated with a diuretic, a lower initial dose of PHARMAPRESS may be required (see below).
Essential Hypertension
The initial dose is 10 mg to 20 mg depending on the degree of hypertension and is given once daily. In mild hypertension the recommended initial dose is 10 mg daily. For other degrees of hypertension the initial dose is 20 mg daily. The usual maintenance dose is one 20 mg 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. 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 one 20 mg tablet, taken once daily. For patients with hypertension who have been treated with diuretics, caution is recommended. (See paragraph above) .
Concomitant Diuretic Therapy in Hypertension
Symptomatic hypotension may occur following the initial dose of PHARMAPRESS, 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 2-3 days prior to the initiation of therapy with PHARMAPRESS. If this is not possible, the initial dose of PHARMAPRESS should be low (5 mg or less) to determine the initial effect on the blood pressure. Dosage should then be adjusted according to the needs of the patient.
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	2,5 mg 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:
Blood pressure and renal function should be monitored closely before and after starting treatment with PHARMAPRESS (see SPECIAL PRECAUTIONS) because hypotension and consequent renal failure have been reported. The initial dose of PHARMAPRESS in patients with symptomatic heart failure or asymptomatic left ventricular dysfunction is 2,5 mg daily and it should be administered under close medical supervision to determine the initial effect on blood pressure. If possible the dose of diuretic should be reduced before beginning treatment with Pharmapress. In patients treated with diuretics, the dosage should be reduced it possible before beginning treatment with PHARMAPRESS. The appearance of hypotension after the initial dose of PHARMAPRESS does not imply that hypotension will recur during chronic therapy with PHARMAPRESS and does not preclude continued use of PHARMAPRESS.
In the absence of, or after effective management of symptomatic hypotension following initiation
of therapy with PHARMAPRESS in congestive heart failure, the dose should be gradually increased, depending on the patient's response to the usual maintenance dose (10 to 20 mg) in a single or divided dose. This dose titration may be performed over a 2-4 week period, or more rapidly if indicated by the presence of residual signs and symptoms of heart failure.

SIDE EFFECTS AND SPECIAL PRECAUTIONS:
Side effects:
Dizziness and headache were the more commonly reported side effects. Other side effects occurred and included fatigue, asthenia, hypotension, orthostatic hypotension, syncope, nausea, diarrhoea, muscle cramps, rash, cough, renal dysfunction, renal failure and oliguria.
Hypersensitivity reactions including angioneurotic oedema of the face, (which may be fatal), extremities, lips, tongue, glottis and/or larynx have been reported (see SPECIAL PRECAUTIONS).
Cardiovascular side effects include myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see SPECIAL PRECAUTIONS); chest pain; palpitations; rhythm disturbances and Angina Pectoris.
Gastrointestinal side effects include ileus, pancreatitis, hepatocellular or cholestatic hepatitis; jaundice, abdominal pain, vomiting, dyspepsia, constipation, anorexia and stomatitis.
Nervous system and psychiatric effects include depression, confusion, somnolence, insomnia, nervousness, paraesthesia and vertigo.
Respiratory effects include pulmonary infiltrates, bronchospasm, asthma, dyspnoea, rhinorrhoea, sore throat and hoarseness.
Effects on the skin include diaphoresis, erythema multiforme, exfoliative dermatitis, Stevens Johnson syndrome, toxic epidermal necrolysis, pruritus, urticaria and alopecia.
Other side effects include impotence, flushing, taste alteration, tinnitus, glossitis and 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 Pharmapress. Hyperkalemia and hyponatremia have occurred. Decreases in haemoglobin and haematocrit have been reported.

SPECIAL PRECAUTIONS:
Symptomatic Hypotension
Symptomatic hypotension was seen in uncomplicated hypertensive patients. In hypertensive patients receiving PHARMAPRESS, hypotension is most likely to occur if the patient has been volume depleted, e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting (see INTERACTIONS and SIDE EFFECTS). In patients with congestive heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. 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, hyponatremia 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 PHARMAPRESS 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 infarction of 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 PHARMAPRESS. This effect is anticipated, and usually is not a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of PHARMAPRESS may be necessary.
Renal Function Impairment
Patients with renal insufficiency may require reduced and/or less frequent doses of PHARMAPRESS. (See DOSAGE AND DIRECTIONS FOR USE). In some patients with bilateral 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 PHARMAPRESS has been given concomitantly with a diuretic. Dosage reduction of PHARMAPRESS 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 PHARMAPRESS. In such cases, PHARMAPRESS 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 hymenotera venom have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapry prior to each desensitization.
Hemodialysis Patients
Anaphylactoid reactions have been reported in patiens 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
PHARMAPRESS has not been studied in children.

INTERACTIONS:
The combination of PHARMAPRESS with other antihypertensive medicines may increase the antihypertensive effect, especially in combination with diuretics.
The combination of PHARMAPRESS with beta-adrenergic blocking agents and methyldopa or calcium entry blockers potentiates the hypotensive effects of PHARMAPRESS.
Ganglionic blocking agents or adrenergic blocking agents, combined with PHARMAPRESS, should only he administered with careful observation of the patient.
Because of lack of experience, concomitant treatment of PHARMAPRESS with calcium antagonists is not recommended.
The 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 hyperkalemia 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 PHARMAPRESS 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.

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 saline solution. If ingestion is recent, induce emesis. Enalaprilat may be removed from the general circulation by haemodialysis.

IDENTIFICATION:
PHARMAPRESS 10 mg: A round, pink tablet with bevelled edges, bisected on one side PHARMAPRESS 20 mg: A round, peach tablet with bevelled edges, bisected on one side

PRESENTATION:
Blister packs of 30 tablets.

STORAGE INSTRUCTIONS:
Store at room temperature (below 25°C). Protect from moisture.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBERS:
PHARMAPRESS 10 mg: 33/7.1.3/0479
PHARMAPRESS 20 mg: 33/7.1.3/0480

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pharmacare Ltd
Building 12
Healthcare Park
Woodlands Drive
Woodmead
Sandton
2148

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
26 November 1999

        574996/050425
        UNIPRINT-L

Updated on this site: June 2006
Source: Community Pharmacy
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