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

Logo APO-CAPTOPRIL 25 MG (tablets)
APO-CAPTOPRIL 50 MG (tablets)

SCHEDULING STATUS
S3

PROPRIETARY NAME
(and dosage form):

APO-CAPTOPRIL 25 MG (tablets)
APO-CAPTOPRIL 50 MG (tablets)

COMPOSITION
APO-CAPTOPRIL 25 MG (tablets): Each tablet contains 25 mg of
captopril.
APO-CAPTOPRIL 50 MG (tablets): Each tablet contains 50 mg of captopril.

PHARMACOLOGICAL CLASSIFICATION
A.7.1 Vasodilators, hypotensive medicines.

PHARMACOLOGICAL ACTION
Captopril is a sulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitor that primarily suppresses the renin-angiotensin-aldosterone system. Renin an enzyme synthesised by the kidneys, is released into the circulation where it acts on a plasma globulin substrate to produce angiotensin I, a relative inactive decapeptide. Angiotensin I is then converted enzymatically by angiotensin-converting enzyme (ACE) to the octapeptide angiotensin II, one of the most potent endogenous vasoconstrictor substances.
Angiotensin II also stimulates aldosterone secretion from the adrenal cortex, thereby contributing to sodium and fluid retention and potassium loss.
Captopril prevents the conversion of angiotensin I to angiotensin II by inhibition of ACE and this is reflected by a decrease in the pressor substance, angiotensin II, and an increase in plasma renin activity (PRA). The latter is due to the relative lack of negative feedback on renin release caused by reduction in angiotensin II. Decreased concentrations of aldosterone are found in blood and urine, and as a result, small increases in serum potassium may occur along with sodium and fluid loss.
Captopril produces a reduction in peripheral arterial resistance in hypertensive patients with either no change or an increase in cardiac output.
The effects of Captopril and of thiazide diuretics on the renin-angiotensin-aldosterone are complementary.
Pharmacokinetics
Following oral administration of Captopril, rapid absorption occurs with peak blood levels at about one hour. The average minimal absorption is approximately 75%. The presence of food in the gastro-intestinal tract reduces absorption by about 30 to 40%. Only 25 to 30% of the drug is bound to plasma proteins. The apparent elimination half-life in blood is about 4 hours for the 4 to 12 hour time intervals. The half-life of unchanged medicine is approximately 2 hours.
About 75% of a dose of Captopril is excreted in the urine (of which 50% is unchanged drug and the remainder conjugates with endogenous thiol compounds, e.g. captopril-cysteine and the disulphide dimmer of the parent compound).
The Survival and Ventricular Enlargement (SAVE) study was a multicentre randomised double blind, placebo-controlled trial conducted in 2 231 patients (age 21-79 years) who survived the acute phase of a myocardial infarction and did not have active ischaemia. Patients had left ventricular dysfunction (LVD), defined as a resting left ventricular ejection fraction 40%, but at the time of randomisation were not sufficiently symptomatic to require ACE inhibitor therapy for heart failure. About half the patients had had symptoms of heart failure in the past. Patients were given a test dose of 6,25 mg oral captopril and were randomised within 3 -16 days post-infarction to receive either captopril or placebo in addition to conventional therapy. Captopril was initiated at 6,25 mg or 12,5 mg three times daily and after two weeks titillated to a target maintenance dose of 50 mg three times daily. About 80% of patients were receiving the target doses at the end of the study. Patients were followed for a minimum of two years and for up to five years with an average follow up of up to 3,5 years.
Baseline blood pressure was 113/70 mm Hg and 112/70 mm Hg for the placebo and captopril groups, respectively.
Blood pressure increased slightly in both treatment groups during the study and was somewhat lower in the captopril group (119/74 vs. 125/77 mm Hg at 1 year). Therapy with captopril improved long-term survival and clinical outcomes compared to placebo. The risk reduction for all cause mortality was 19% (P=0,02) and for cardiovascular death was 21% (P=0,014). Captopril treated subjects had 22% (P=0,034) fewer first hospitalisations for heart failure. Compared to placebo, 22% fewer patients receiving captopril developed symptoms of overt heart failure. There was no significant difference between groups in total hospitalisations for all cause (2 056 placebo; 2 306 captopril).

INDICATIONS
Mild to Moderate Hypertension
APO-CAPTOPRIL is indicated for the treatment of mild to moderate hypertension in adult patients. It may be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of APO-CAPTOPRIL and thiazide diuretics are additive.
Congestive Heart Failure
APO-CAPTOPRIL is indicated for the treatment of patients with congestive heart failure who have not responded adequately to or cannot be controlled by conventional therapy with diuretics and/or digitalis and in whom vasodilatation is indicated APO-CAPTOPRIL has been used with diuretics and digitalis.
Left Ventricular Dysfunction after Myocardial Infarction
APO-CAPTOPRIL is indicated to improve survival following myocardial infarction in clinically stable patients with left ventricular dysfunction manifested as an ejection fraction <40%.

CONTRA-INDICATIONS
Hypersensitivity to the product or its components, or other angiotensin-converting enzyme inhibitors.
Safety and effectiveness in individuals less than 18 years of age have not been established.
Patients with a history of angioneurotic oedema relating to previous treatment with an ACE-inhibitor. (See SPECIAL PRECAUTIONS)
Patients with aortic stenosis or outflow tract obstruction.

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 pass through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios as well as hypotension, 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.
Angioedema involving the extremities, face, eyes, lips, mucous membranes, tongue, glottis or larynx has been seen in patients treated with APO-CAPTOPRIL. Patients should be advised to immediately report to their physician any signs or symptoms suggesting angioedema (e.g. swelling of face, eyes, lips, tongue, larynx and extremities; difficulty in swallowing or breathing; hoarseness) and to discontinue therapy. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Emergency therapy including but not necessarily limited to, subcutaneous administration of a 1:1000 solution of adrenaline should be promptly instituted. Swelling confined to the face, mucous membranes of the mouth, lips and extremities has usually resolved with discontinuation of APO-CAPTOPRIL, some cases required medical therapy (see SIDE-EFFECTS AND SPECIAL PRECAUTIONS).
Proteinuria has been seen in patients receiving APO-CAPTOPRIL, but this has been predominantly in those who had prior renal disease or in those receiving relatively high doses (in excess of 150 mg per day) or both. Alterations in renal function (as assessed by blood urea and serum creatinine) were infrequent in these patients and did not occur in those who had prior renal disease.
Nephrotic syndrome (hypoalbuminemia, oedema and protein excretion greater than 3 grams per day) has also occurred. In most cases, proteinuria subsided or cleared within 6 months whether or not APO-CAPTOPRIL was continued.
Membranous glomerulopathy was found in biopsies taken from some proteinuric patients. A causal relationship has not been established.
For patients with prior renal diseases or those receiving APO-CAPTOPRIL at doses greater than 150 mg per day, urinary protein estimations (dipstick) should be done prior to treatment and monthly during the first 9 months of therapy. If these show increasing amounts of urinary protein a 24-hour quantitative determination of urinary protein should be done. If this exceeds one gram per day, the benefits and risks of continuing APO-CAPTOPRIL should be evaluated.
Neutropenia has occurred in some patients receiving APO-CAPTOPRIL especially in those who had pre-existing impaired renal function, collagen vascular disease, immunosuppressant therapy, and concomitant allopurinol or a combination of these complicating factors. All patients receiving APO-CAPTOPRIL should be informed to report any signs of infection (e.g. sore throat, fever).
Serious infections resulting from the neutropenia and which proved fatal occurred only in patients with impaired renal function. A complete white blood cell count should be done immediately when infection is present. If the infection occurs during the first three months of therapy. APO-CAPTOPRIL should be discontinued until results of the blood count are known.
Neutropenia was noted 2 to 3 weeks after APO-CAPTOPRIL had been started. Thus for patients with impaired renal function, collagen vascular disease, or who are receiving immuno-suppressant drugs, white blood cell and differential counts should be performed prior to therapy, every 2 weeks during the first three months of APO-CAPTOPRIL therapy and periodically thereafter. If the neutrophil count falls below 1000/mm³ APO-CAPTOPRIL should be discontinued and the patient's course should be followed.
Bone marrow examinations in patients with neutropenia consistently showed myeloid hypoplasia and decreased numbers of megakaryocytes. Neutropenia was associated with significant alterations of peripheral red blood cell or platelet counts in some patients.
Since APO-CAPTOPRIL decreases aldosterone production, elevation of serum potassium may occur especially in patients with renal failure, or diabetes mellitus. Potassium sparing diuretics (spironolactone, triamterene and amiloride) or potassium supplements or other medicines associated with increases in serum potassium (e.g. heparin), if needed, should be used with caution since they may lead to a significant increase of serum potassium.
Patients already on diuretic therapy may occasionally experience dizziness or light-headedness, indicative of hypotension that may occur within one hour of the first dose.
In patients who are receiving aggressive diuretic therapy, particularly those with either severe renin dependent hypertension (e.g. renovascular hypertension) or severe congestive heart failure, exaggerated hypotensive responses have occurred, again usually within one hour of the initial dose of APO-CAPTOPRIL. By commencing APO-CAPTOPRIL therapy with small doses (6,25 or 12,5 mg) the duration of any hypotensive effect is reduced.
An exaggerated hypotensive response can be anticipated by medical supervision during the first hour after initial dosing; it can be rapidly reversed by intravenous infusion of normal saline if necessary.
A hypotensive episode following the initial dose of APO-CAPTOPRIL does not preclude further episodes.
In heart failure, where the blood pressure was either normal or low, decreases in mean blood pressure greater than 20% were recorded in about half of the patients. This transient fall in blood pressure may occur after any of the first several doses and may be associated with arrhythmia or conduction defects Patients should be followed closely for the first 2 weeks of treatment and whenever the dose of APO-CAPTOPRIL or diuretic or both is increased.
Some patients with renal disease, particularly those with bilateral renal artery stenosis, have developed increases in blood urea and serum creatinine, after reduction of blood pressure with APO-CAPTOPRIL usually along with a diuretic. APO-CAPTOPRIL dosage reduction or discontinuation of a diuretic, or both may be required. For some of these patients, it may not be possible to normalise blood pressure and maintain adequate renal perfusion. Some patients with heart failure have experienced a reduction in renal function during long term treatment.

DOSAGE AND DIRECTIONS FOR USE
Dosage must be individualised.
See WARNINGS regarding hypotension in salt and volume depleted patients.
APO-CAPTOPRIL should be taken one hour before food intake.
Hypertension: The initial dose of APO-CAPTOPRIL is 25 mg two or three times a day. If a satisfactory reduction of blood pressure has not been achieved after two weeks the dose of APO-CAPTOPRIL may be increased to 50 mg two to three times a day. If after an additional two weeks a further reduction in blood pressure is desirable, a diuretic may be added. For patients already receiving a diuretic, the initial dose of APO-CAPTOPRIL should be lower and administered with care.
The dose of APO-CAPTOPRIL in mild to moderate hypertension must not exceed 150 mg per day.
When APO-CAPTOPRIL is used alone, concomitant sodium restriction may be beneficial.
APO-CAPTOPRIL may be used advantageously in conjunction with other anti-hypertensive agents.
Congestive Heart Failure: APO-CAPTOPRIL therapy must be started under close medical supervision. It should be added to conventional treatment with diuretic (and digitalis where indicated). A starting dose of 6,25 mg to 12,5 mg three times a day minimises the duration of any transient hypotensive effect. (See WARNINGS). This dosage may be increased over a period of one to two weeks to 75 - 300 mg per day.
Left Ventricular Dysfunction After Myocardial Infarction: Therapy may be initiated as early as three days following a myocardial infarction. After an initial dose of 6,25 mg APO-CAPTOPRIL therapy should be increased to 12,5 mg three times a day as tolerated. APO-CAPTOPRIL should then be increased as tolerated to 75 mg a day divided doses during the next several days and to a final target dose of 150 mg daily in divided doses over the next several weeks.
If symptomatic hypotension occurs, a dosage reduction may be required. Subsequent attempts at achieving the target dose of 150 mg should be based on the patient's tolerance to APO-CAPTOPRIL.
APO-CAPTOPRIL may be used in patients with other postmyocardial infarction therapies, e.g. thrombolytics, aspirin and beta blockers.
Patients with renal impairment: APO-CAPTOPRIL excretion is reduced in the presence of impaired renal function. After the desired therapeutic effect has been achieved the total daily dose should be reduced or the dose intervals increased.
The following maximum daily doses are suggested as a guide to minimise drug accumulation.
Creatinine Clearance
(mL/min/1,75 m³)
Maximal Total Daily
Dose (mg)
More than 80         More than 450
80-41         300
40-21         150
20-11         75
Less than 10         Less than 37,5
APO-CAPTOPRIL is removed by haemodialysis.
When concomitant diuretic therapy is required, a loop diuretic (e.g. furosemide), rather than a thiazide diuretic, is preferred in these patients with impaired renal function.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Skin
A rash may occur which is dose related. The rash is usually pruritic and maculopapular, but less frequently urticarial and generally occurs during the first 4 weeks of treatment.
It usually is self-limiting and reversible and may respond to antihistamine therapy.
Pruritis, erythema multiforme and toxic epidermal necrolysis, flushing, a reversible pemphigoid-like lesion, photo-sensitivity and angioedema have also been reported.
Gastro-Intestinal
A reversible taste impairment has occurred. Loss of mass may be associated with loss of taste. Stomatitis, resembling aphthous ulcers, has been reported. Elevation of liver enzymes has been noted in patients receiving the medicine although no causal relationship has been found. Cases of hepatocellular injury with secondary cholestasis have been reported in association with APO-CAPTOPRIL administration. Gastric irritation and abdominal pain may occur.
Renal
Proteinuria (See WARNINGS).
Transient elevations of blood urea and cretainine (See PRECAUTIONS). Hyperkalaemia, hyponatraemia and acidosis (See WARNINGS).
Haematological
Neutropenia, anaemia, thrombocytopenia and agranulocytosis especially in patients with renal failure and those with collagen vascular disorders such as systemic lupus erythematosus and scleroderma (see WARNINGS).
Cardiovascular
Hypertension may occur after initiation of APO-CAPTOPRIL therapy in patients with heart failure, renin-dependent hypertension or who are significantly volume depleted (see WARNINGS) Tachycardia and palpitations has been observed in volume-depleted patients.
Anaphylactoid Reactions
Recent clinical observations have shown an association of hypersensitivity-like (anaphylactoid) reactions during haemodialysis with high-flux dialysis membranes (eg. AN69) in patients receiving ACE-inhibitors as medication. Therefore, special attention should be given to these patients; and in particular to those having already shown similar reactions.
Other
Dizziness, fatigue, presistent dry cough and other respiratory tract symptoms, chest pain, pancreatitis hepatocellular injury or cholestatic jaundice, alopecia, and muscle cramps.
Paraesthesias of the hands, mood and sleep disturbances, impotence, serum sickness, bronchospasm and lymphadenopathy have been reported.
Angioedema of the face, eyes, lips, mucous membranes, tongue, glottis or larynx and the extremities may occur.
APO-CAPTROPRIL should be used only with extreme caution in patients with aortic stenosis because of the potentially harmful consequences of reduced coronary perfusion secondary to the reduced blood pressure.
APO-CAPTOPRIL may cause false-positive urine test for acetone.
Nursing Mothers: Concentrations of unchanged captorpril appear in human breast milk. Caution should be exercised when APO-CAPTOPRIL is administered to a nursing woman.
Surgery/Anaesthesia: In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, APO-CAPTOPRIL will block angiotensin II formation secondary to compensatory renin release. This may lead to hypotension that can be corrected by volume expansion.

INTERACTIONS
Vasodilators
Data on the effect of concomitant use of other vasodilators in patients receiving APO-CAPTOPRIL for heart failure are not available; therefore, nitroglycerin or other nitrates (as used in management of angina) or other medicines having vasodilator activity should, if possible, be discontinued before starting APO-CAPTOPRIL. If resumed during APO-CAPTOPRIL therapy, such agents should be administered cautiously and perhaps at low dosage.
Agents Affecting Sympathetic Activity
The sympatic nervous system may be especially important in supporting blood pressure in patients receiving APO-CAPTOPRIL alone or with diuretics. Therefore, agents affecting sympathetic activity (e.g. ganglion blocking agents or adrenergic neuron blocking agents) should be used with caution. Inhibitors of endogenous prostaglandin synthesis. It has been reported that indomethacin may reduce the antihypertensive effect of APO-CAPTOPRIL, especially in cases of low renin hypertension. Other non-steroidal anti-inflammatory agents (e.g. aspirin) may also have this effect.
Lithium
Increased serum lithium levels and symptoms of lithium nephrotoxicity have been reported in patients receiving concomitant lithium and ACE-inhibitors therapy. These drugs should be co-administered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
See "Side-Effects and Special Precautions". In the event of overdosage, hypotension would be the most important problem. Volume expansion with an intravenous infusion of normal saline is the treatment of choice APO-CAPTOPRIL is removed by haemodialysis. Treatment is symptomatic and supportive.

IDENTIFICATION
APO-CAPTOPRIL 25 MG: Square, white, biconvex tablets, quadrisected on one side, engraved APO over 25 on the other side.
APO-CAPTOPRIL 50 MG: White, oval, biconvex tablets, partially bisected and engraved "APO-50" on one side, plain on the other side.

PRESENTATION
APO-CAPTOPRIL 25 MG: White HDPE bottles containing 60, 100, 500 or 1000 tablets.
APO-CAPTOPRIL 50 MG. White HDPE bottles containing 60, 100, 500 or 1000 tablets.

STORAGE INSTRUCTIONS
Store below 25°C.
Store in a well-closed container, protected from moisture and heat.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBER
APO-CAPTOPRIL 25 MG: 32/7.1/0004
APO-CAPTOPRIL 50 MG: 32/7.1/0005

NAME AND BUSINESS ADDRESS OF APPLICANT
APOTEX S.A.
PHARMACEUTICAL INNOVATION
Apotex S.A. (PTY) Ltd.
Corner Fleming and Watt Street
Meadowdale Ext. 1

DATE OF PUBLICATION OF THIS PACKAGE INSERT
22 May 1998

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