INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo PHARMAPRESS CO

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

PHARMAPRESS CO
[tablet]

COMPOSITION:
Each tablet contains:
Enalapril maleate 20,0 mg
Hydrochlorothiazide 12,5 mg

PHARMACOLOGICAL CLASSIFICATION:
A : 7.13 - Other hypotensives.

PHARMACOLOGICAL ACTION:
PHARMAPRESS CO (enalapril maleate/hydrochlorothiazide) is a combination of an angiotensin-converting enzyme inhibitor (enalapril maleate) and a diuretic (hydrochlorothiazide), resulting in an additive anti-hypertensive effect. Enalapril is hydrolysed to enalaprilat, which is the active metabolite.

INDICATIONS:
PHARMAPRESS CO is indicated for the treatment of hypertension where fixed combination therapy is more appropriate than monotherapy.

CONTRA-INDICATIONS:
Hypersensitivity to any ingredient of PHARMAPRESS CO. A history of angioneurotic oedema in patients relating to previous treatment with an angiotensin-converting enzyme inhibitor. Hypersensitivity to other sulphonamide-derived medicines.
Pregnant and lactating mothers.
Anuria.

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.
Symptomatic hypotension may occur after the first dose of PHARMAPRESS CO; this is more likely in patients who have received prior diuretic therapy. Prior to initial therapy with PHARMAPRESS CO, diuretic therapy should be discontinued for 2-3 days. When therapy is administered to patients with ischaemic heart or cerebrovascular disease, particular consideration should be given, because an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
When enalapril has been given concomitantly with a diuretic, some hypertensive patients with no apparent pre-existing renal disease have developed minor increases in blood urea and serum creatinine. The combination should be discontinued, if this occurs during therapy with PHARMAPRESS CO.
PHARMAPRESS CO should be used with caution in patients with progressive liver disease or impaired hepatic function, since minor alterations of fluid and electrolyte balance may precipitate coma and hepatic encephalopathy.
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 new-borns 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. These adverse effects to the embryo and foetus do not appear to have resulted from intra-uterine ACE-inhibitor exposure limited in the first trimester.
The routine use of diuretics in otherwise healthy pregnant women is not indicated and exposes mother and foetus to unnecessary hazard. Diuretics do not prevent development of toxaemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxaemia. Thiazides cross the Placental barrier and appear in cord blood. Hazards include foetal and neonatal jaundice, thrombocytopenia and possibly other adverse reactions which occur in the adult.
Infants whose mothers have taken PHARMAPRESS CO should be closely observed for hypotension, oliguria and hyperkalemia. There is no experience with the removal of the combination product, PHARMAPRESS CO from the neonatal circulation. Enalapril, which crosses the placenta, has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit. There is no experience with the removal of hydrochlorothiazide, which also crosses the placenta, from the neonatal circulation.
Both enalapril and thiazides appear in human milk. If use of the medicine is deemed essential, the patient should stop nursing.

DOSAGE AND DIRECTIONS FOR USE:
Hypertension
One tablet, administered once daily is the usual dosage. The dosage may be increased to a maximum of two tablets, administered once daily, if appropriate.
Dosage in Renal Insufficiency
For patients with renal impairment, thiazides may not be the appropriate diuretic for use and are ineffective at creatinine clearance values of 30 mL/min or below (i.e. moderate or severe renal insufficiency).
In any patient with renal insufficiency, PHARMAPRESS CO must not be used as initial therapy. PHARMAPRESS CO may be used in patients with creatinine clearance of >30 and <80 mL/min, but only after titration of the individual components.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects:
The most common clinical side-effects are fatigue and dizziness, which generally respond to dosage reduction.
Other side-effects are impotence, muscle cramps, nausea, orthostatic effects including hypotension, aesthenia, cough and headaches.
Less common side-effects that have occurred include:
Cardiovascular effects such as non-orthostatic hypotension, tachycardia, palpitations, syncope and chest pain.
Gastro-intestinal effects for example diarrhoea, dyspepsia, abdominal pain, constipation, vomiting and flatulence and pancreatitis.
Nervous System/Psychiatric effects such as vertigo, nervousness, insomnia, paraesthesia and somnolence.
Respiratory effects such as dyspnoea.
Skin conditions for example Stevens-Johnson Syndrome, pruritus, diaphoresis and rash.
Other effects include decreased libido, renal dysfunction, dry mouth, renal failure, tinnitus, gout and arthralgia.
A symptom complex has been reported which may include: vasculitis, myalgia, fever, arthralgia/arthritis, a positive anti-nuclear antibody, serositis, elevated erythrocyte sedimentation rate, eosinophilia and leukocytosis. Rash or other dermatological manifestations or photosensitivity may occur.
Hypersensitivity/Angioneurotic Oedema
Angioneurotic oedema of the extremities, face, tongue, lips, glottis and/or larynx have been reported (see "Special Precautions").
Side-effects that have occurred with one of the individual active ingredients may also contribute to the side-effects encountered with PHARMAPRESS CO and include:
Side-effects with Enalapril: confusion, jaundice, hepatic failure, hepatitis (either hepatocellular or cholestatic), pancreatitis, ileus, sore throat and hoarseness, rhinorrhoea, myocardial infarction or cerebrovascular accident (possibly secondary to excessive hypotension in high risk patients), angina pectoris, cardiac rhythm disturbances, depression, flushing, alopecia, photosensitivity, pulmonary infiltrates, bronchospasm/asthma, glossitis, stomatitis, anorexia, taste alteration, blurred vision, urticaria, oliguria, toxic epidermal necrolysis, exfoliative dermatitis, pemphigus and erythema multiforme.
Side-effects with Hydrochlorothiazide: anorexia, gastric irritation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, leukopenia, aplastic anaemia, haemolytic anaemia, agranulocytosis, purpura, photosensitivity, sialoadenitis, xanthopsia, fever, respiratory distress (including pneumonitis and pulmonary oedema), necrotizing angitis (vasculitis), urticaria, interstitial nephritis, glycosuria, electrolyte imbalance, (including hyponatraemia), anaphylactic reaction, restlessness, muscle spasm and transient blurred vision.
Increases in serum creatinine and blood urea and elevations of liver enzymes and/or serum bilirubin have been seen. These are usually reversible upon discontinuation of PHARMAPRESS CO. Hyperuricaemia, hypokalaemia and hyperglycaemia, have been noted. Hyponatremia and hyperkalaemia have occurred. Decreases in haematocrit haemoglobin, white cell count and platelets have occurred. Thrombocytopenia, neutropenia, and bone marrow depression have been reported, but a direct causal relationship to PHARMAPRESS CO has not been established.
SPECIAL PRECAUTIONS:
Hypotension and Electrolyte Fluid Imbalance
In some patients, symptomatic hypotension may occur. Patients should be observed for clinical signs of fluid or electrolyte imbalance, eg. hyponatremia, hypochloraemic alkalosis, volume depletion, hypokalaemia or hypomagnesaemia. This may occur during intercurrent diarrhoea or vomiting. At appropriate intervals, periodic determination of serum electrolytes should be performed in such patients.
The patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of normal saline if hypotension occurs. A transient hypotensive response is not a contra-indication to further doses. Following the restoration of effective blood volume and pressure, reinstitution of therapy at reduced dosage may be possible; or either of the components may be used appropriately alone.
Renal Function Impairment
See "Dosage in Renal Insufficiency" under "Dosage and directions for Use".
In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, increases in serum creatinine and blood urea, reversible upon discontinuation of therapy, have been seen with angiotensin-converting enzyme (ACE) inhibitors.
Hepatic disease
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Surgery/Anaesthesia
In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, enalapril may block angiotensin II formation secondary to compensatory release of renin. Volume expansion can correct hypotension considered to be due to this mechanism.
Metabolic and Endocrine effects.
Glucose tolerance may be impaired by thiazide therapy. It may be required that dosage of antidiabetic agents, including insulin is adjusted. Urinary calcium excretion may be decreased by thiazides. Intermittent and slight elevation of serum calcium may be caused by thiazides. Marked hypercalcinaemia may be evidence of hidden hyperparathyroidism. Before carrying out tests for parathyroid function, thiazides should be discontinued.
Increases in triglyceride and cholesterol levels may be associated with thiazide diuretic therapy.
Thiazide therapy may precipitate gout and/or hyperuricaemia in certain patients. Urinary uric acid may be increased by enalapril and the hyperuricaemic effect of hydrochlorothiazide may thus be attenuated.
Hypersensitivity/Angioneurotic Oedema
Angioneurotic oedema of the extremities, face, lips, glottis and/or larynx and tongue has been reported. PHARMAPRESS CO should be discontinued promptly in such cases and appropriate monitoring should be instituted to ensure complete resolution of symptoms. The condition may resolve without treatment, in those instances where swelling has been confined to the face and lips, although antihistamines have been useful in relieving symptoms. Angioneurotic oedema associated with laryngeal oedema may be fatal. Where there is involvement of the glottis, larynx or the tongue, likely to cause airway obstruction, appropriate therapy, such as subcutaneous epinephrine solution 1:1000 (0,3 mL to 0,5 mL) should be administered promptly. Patients with a history of angio-oedema unrelated to ACE - inhibitor therapy, may be at increased risk of angio-oedema, while taking an ACE - inhibitor. (Also see "Contra-Indications"). In patients receiving thiazides, sensitivity reactions may occur with or without a history of bronchial asthma or allergy. The use of thiazides has been reported to activate or exacerbate systemic lupus erythematosis.
Cough
Cough has been reported. Characteristically, the cough is persistent and non-productive and resolves after discontinuation of therapy. ACE-inhibitor induced cough should be considered as part of the differential diagnosis of cough.
Anaphylactoid reactions during hymenoptera desensitisation:
Less frequently, 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.
Paediatric Use
The safety and efficacy in children have not been established.
Use in the Elderly
The tolerability and efficacy of enalapril maleate and hydrochlorothiazide, administered concomitantly, were similar in both elderly and younger hypertensive patients.

INTERACTIONS:
Other Antihypertensive Therapy
Adrenergic blocking agents or ganglionic blocking agents, combined with enalapril, should only be administered under careful observation of the patient.
Serum Potassium
The potassium losing effect of thiazide diuretics is normally diminished by the effect of enalapril. The use of potassium sparing agents, potassium containing salt substitutes or potassium supplements, may lead to a significant increase in serum potassium, particularly in patients with impaired renal function.
Lithium
Lithium should generally not be given with diuretics. The renal clearance of lithium is reduced by diuretic agents and ACE-inhibitors and add a high risk of lithium toxicity. Before the use of such preparations, refer to the package inserts of lithium preparations.
Non-depolarising Muscle Relaxants
The responsiveness to tubocurarine may be increased by the administration of thiazides. When administered concurrently the following drugs may interact with thiazide diuretics: Potentiation of orthostatic hypotension may occur with barbiturates, alcohol or narcotics.
The dosage of the anti-diabetic medication (insulin and oral agents) may be required to be adjusted.
ACTH and Corticosteroids may intensify the depletion of electrolytes, particularly hypokalaemia. The diuretic, anti-hypertensive and natriuretic effects of diuretics can be reduced by the administration of non-steroidal anti-inflammatory agents in some patients.
A possible decreased response to pressor amines (eg. adrenalin) occur but not sufficient to preclude their use.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
On the treatment of overdosage with PHARMAPRESS CO, no specific information is available. Treatment is symptomatic and supportive. Suggested measures include induction of emesis and/or gastric lavage, and correction of electrolyte imbalance, hypotension and dehydration, by established procedures introduced within 2 hours after ingestion.
Enalapril Maleate
Hypotension is the most prominent feature of overdosage, beginning some six hours after ingestion of tablets, concomitant with blockade of the renin-angiotensin system and stupor. Haemodialysis may be used to remove Enalapril from the general circulation.
Hydrochlorothiazide
The most common signs and symptoms observed are those caused by electrolyte depletion (hypochloraemia, hypokalaemia, hyponatraemia) and from excessive diuresis, dehydration will result.
Cardiac arrythmias may be accentuated by hypokalaemia, if digitalis has also been administered.

IDENTIFICATION:
A round, yellow biconvex tablet.

PRESENTATION:
PHARMAPRESS CO is packed in blister packs of 30 tablets.

STORAGE INSTRUCTIONS:
Store in a well closed container in a dry place.
Protect from light. Store below 25 C.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:
34/7.1.3/0190

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pharmacare Limited
7 Fairclough Road
Korsten
Port Elizabeth
6020

DATE OF PUBLICATION OF APPROVAL OF THIS PACKAGE INSERT:
08 May 2000

D854
A&S PRINTERS

New addition to this site: June 2004
Source: Community Pharmacy

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