COMPOSITION: Each ENAP-CO tablet contains 20 mg enalapril maleate and 12,5 mg hydrochlorothiazide.
PHARMACOLOGICAL CLASSIFICATION: A 7.1.3 Vascular medicines - other hypotensives.
ENAP-CO (enalapril maleate and hydrochlorothiazide) is a combination of an angiotensin-converting enzyme (ACE) inhibitor (enalapril maleate) and a diuretic (hydrochlorothiazide), which produces an additive anti-hypertensive effect. The active metabolite, enalaprilat, is formed by hydrolysation of enalapril.
ENAP-CO is indicated for the treatment of hypertension in patients stabilised on the individual components administered at the same dosages.
CONTRA-INDICATIONS: Anuria. Hypersensitivity to any ingredient of this product. In patients with a history of angioneurotic oedema relating to previous treatment with an ACE-inhibitor. Hypersensitivity to other sulphonamide-derived medicines. Pregnant and breast-feeding mothers (see Warnings).
Concomitant use with lithium (see Interactions).
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. 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.
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 ENAP-CO should be closely observed for hypotension, oliguria and hyperkalaemia. There is no experience with the removal of the combination product, ENAP-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.
After administration of the initial dose, symptomatic hypotension may occur. Hypotension is more likely in patients who have received prior diuretic therapy. Discontinue diuretic therapy for 2-3 days before therapy with ENAP-CO is initiated. In patients with ischaemic heart or cerebrovascular disease, therapy should be administered with extreme caution because an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
Minor increases in blood urea and serum creatinine have developed in some hypertensive patients with no apparent pre-existing renal disease when enalapril has been given concomitantly with a diuretic. Should this occur during therapy with ENAP-CO, the combination should be discontinued.
Minor alterations of fluid and electrolyte balance may precipitate hepatic encephalopathy and coma, therefore, ENAP-CO should be used with caution in patients with impaired hepatic function or progressive liver disease.
DOSAGE AND DIRECTIONS FOR USE: Hypertension The usual dosage is one tablet, once a day. The dosage may be increased to a maximum of two tablets, administered once daily, if necessary. Dosage in Renal Insufficiency The use of thiazides may not be appropriate in patients with renal impairment. Thiazides are ineffective at creatinine clearance values of 30 mL/min or below (i.e. moderate or severe renal insufficiency).
Do not use ENAP-CO as initial therapy in any patient with renal insufficiency. ENAP-CO may however be used in patients with creatinine clearance greater than 30 and less than 80 mL/minute, but only after the individual components have been successfully titrated.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects Dizziness and fatigue, the most common clinical side-effects, generally respond to dosage reduction. Other side-effects include: Muscle cramps, nausea, aesthenia, orthostatic effects including hypotention, headaches, cough and impotence.
Less common side-effects which have been reported include: Nervous System/Psychiatric Insomnia, somnolence, paraesthesia, vertigo, nervousness. Cardiovascular Syncope, non-orthostatic hypotension, palpitations, tachycardia, chest pain. Respiratory Dyspnoea Gastro-intestinal Diarrhoea, vomiting, dyspepsia, abdominal pain, flatulence, constipation. Hypersensitivity/Angioneurotic Oedema Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported (see Special Precautions). Other Renal dysfunction, renal failure, decreased libido, dry mouth, gout, tinnitus, arthralgia.
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, including skin rash and photosensitivity may occur. Skin Stevens-Johnson syndrome, rash, pruritus, diaphoresis. Laboratory Test Findings Cases of hyperglycaemia, hyperuricemia and hypokalemia have been recorded. In some patients, increases in blood urea and serum creatinine, and elevations of liver enzymes and/or serum bilirubin have occurred. These are usually reversible upon discontinuation of the combination medication. Hyperkalemia and hyponatremia have been noted. Decreases in haemoglobin, haematocrit, platelets and white cell count have been noted.
Reports of neutropenia, thrombocytopenia and bone marrow depression have been received, but no direct casual relationship to the combination medication could be established.
Side-effects reported for one of the individual components that may also contribute to side-effects encountered with this combination medication, include the following: Hydrochlorothiazide Anorexia, gastric irritation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, sialoadenitis, xanthopsia, leukopenia, agranulocytosis, aplastic anaemia, haemolytic anaemia, purpura, photosensitivity, fever, urticaria, necrotising angiitis (vasculitis), respiratory distress (including pneumonitis and pulmonary oedema), interstitial nephritis, anaphylactic reaction, glycosuria, electrolyte imbalance, including hyponatraemia, restlessness, muscle spasm, transient blurred vision. Enalapril Ileus, pancreatitis, hepatitis, either hepatocellular or cholestatic, jaundice, depression, confusion, bronchospasm/asthma, sore throat and hoarseness, cardiac rhythm disturbances, angina pectoris, myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients, rhinorrhoea, photosensitivity, alopecia, flushing, taste alteration, anorexia, blurred vision, urticaria, stomatitis, glossitis, oliguria, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, pulmonary infiltrates, hepatic failure, pemphigus.
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 The use of ACE-inhibitors has been associated with cough. The cough is of a non-productive and persistent nature, which resolves after therapy is discontinued. ACE-inhibitor-induced cough should be considered as part of the differential diagnosis of cough. Elderly Use No significant differences in efficacy and tolerability, were identified in elderly or younger hypertensive patients when enalapril maleate and hydrochlorothiazide were administered concominantly. Haemodialysis patients The use of this combination medication is not indicated in patients requiring dialysis for renal failure (see Dosage and Directions for Use). Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g. AN69®), receiving concomitant ACE-inhibitor treatment. A different type of dialysis membrane or a different class of antihypertensive agent, should be considered when treating such patients. Hepatic Disease Thiazide 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. Hypersensitivity/Angioneurotic Oedema In some patients, angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported. Discontinue treatment in such cases and monitor patients to ensure complete resolution of symptoms. Where swelling is confined to the face and lips, the condition may resolve without treatment. Antihistamine treatment has proved useful in relieving these symptoms. Angioneurotic oedema associated with laryngeal oedema may be fatal. If involvement of the tongue, glottis or larynx, which is likely to cause airway obstruction should occur, appropriate therapy such as subcutaneous adrenaline solution 1:1 000 (0,3 mL to 0,5 mL) should be administered immediately.
A history of angioedema unrelated to ACE-inhibitor therapy may expose patients to increased risk of developing angioedema while receiving an ACE-inhibitor. (See Contra-indications).
Thiazide therapy may cause sensitivity reactions in certain patients, with or without, a history of allergy or bronchial asthma. Reports of exacerbation or activation of systemic lupus erythematosus have been associated with the use of thiazides. Hypotension and Electrolyte/Fluid imbalance Some patients may develop symptomatic hypotension. Such patients should be monitored for clinical signs of fluid or electrolyte imbalance, e.g. volume depletion, hyponatremia, hypochloremic alkalosis, hypomagnesaemia or hypokalemia which may occur during intercurrent diarrhoea or vomiting. Serum electrolytes should be periodically determined at appropriate intervals when treating these patients.
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. Provided blood volume and pressure have been restored effectively, reintroduction of therapy using reduced doses can be considered; as an alternative, either of the components may be administered as monotherapy. Metabolic and Endocrine Effects Glucose tolerance may be impaired by thiazide therapy. Dosage of antidiabetic agents including insulin, may need to be adjusted. Thiazides may decrease urinary calcium excretion and cause intermittent and slight elevation of serum calcium. It should be kept in mind, that marked hypercalcinemia may be evidence of hidden hyperparathyroidism. Discontinue thiazides before carrying out tests of parathyroid function.
In some cases, thiazide diuretic therapy may be associated with increases in cholesterol and triglyceride levels.
In certain patients thiazide therapy may precipitate hyperuricemia and/or gout, enalapril may, however, increase urinary acid and thus attenuate the hyperuricemic effect of hydrochlorothiazide. Paediatric use The safety and efficacy of the combination medication in children have not been established. Renal Function Impairment See Dosage in Renal Insufficiency under Dosage and Directions for Use.
Increases in blood urea and serum creatinine have been seen in some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, who were receiving treatment with ACE-inhibitors; these symptoms are reversible upon discontinuation of therapy. 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.
Interactions: Concurrent use of the following drugs may cause interactions with thiazide diuretics: Anti-diabetic medicine (oral agents and insulin) - the dosage of the anti-diabetic medication may have to be adjusted. Alcohol, Barbiturates or Narcotics - may potentiate orthostatic hypotension. Corticosteroids, ACTH - increased electrolyte depletion, particularly hypokalemia, may occur. Non-steroidal Anti-inflammatory Agents - reduction of the diuretic, natriuretic and anti-hypertensive effects of diuretics in certain patients. Pressor Amines (e.g. adrenalin) - a decreased response to pressor amines may occur, but this is generally not sufficient to preclude their use. Other interactions: Lithium The combination of lithium and diuretics should be avoided. Renal clearance of lithium is reduced by diuretic agents and ACE-inhibitors, exposing patients to a high risk of lithium toxicity. Refer to lithium preparation package inserts before use of such preparations. Non-depolarising Muscle Relaxants Responsiveness to tubocurarine may be increased during thiazide therapy. Other Antihypertensive Therapy The combination of enalapril with ganglionic blocking agents or adrenergic blocking agents, should only be considered if the patient can be kept under careful observation. Serum Potassium The effect of enalapril usually attenuates the depletion of potassium by thiazide diuretics.
Serum potassium levels may be significantly increased, particularly in patients with impaired renal function if potassium supplements, potassium-sparing agents or potassium-containing salt substitutes, are used.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT: No specific information for the treatment of overdosage with the combination medication is available at present. Treatment is symptomatic and supportive. The following measures have been suggested: Induction of emesis and/or gastric lavage, correction of dehydration, electrolyte imbalance and hypotension using established procedures which should be introduced within 2 hours after ingestion. Hydrochlorothiazide Overdosage with thiazides is commonly associated with signs and symptoms caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. Hypokalemia may accentuate cardiac arrhythmias if digitalis has also been administered. Enalapril Maleate Overdosage is primarily characterised by hypotension, which commences approximately six hours after ingestion of tablets, resulting from blockade of the renin-angiotensin system, and stupor. Haemodialysis can be used to remove enalaprilat from the general circulation.
IDENTIFICATION: A round, white, flat tablet with a bevelled edge, scored on one side.
PRESENTATION: Available in blisters of 28 tablets.
STORAGE INSTRUCTIONS: Store in a cool (below 25°C), dry place. Protect from light and moisture.
KEEP OUT OF REACH OF CHILDREN.
REGISTRATION NUMBER: 34/7.1.3/0088
NAME AND BUSINESS ADDRESS OF APPLICANT: MC Pharma (Pty) Ltd
4th Floor, Argo Building
184 Erasmus Street
DATE OF PUBLICATION OF THIS PACKAGE INSERT: 7 February 2000