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

Logo CAPACE 25 mg Tablets

SCHEDULING STATUS:
S3

PROPRIETARY NAME:
(and dosage form)

CAPACE 25 mg Tablets

COMPOSITION:
CAPACE 25 mg tablets contain 25 mg D-3-mercapto-2-methylpropanoyl-L-proline (
Captopril).

PHARMACOLOGICAL CLASSIFICATION:
Category A 7 1 Vasodilator, hypotensive medicine.

PHARMACOLOGICAL ACTION:
Although the mechanism of action of CAPACE has not yet been fully elucidated, its effects appear to result primarily from suppression of the renin-angiotensin-aldosterone system. However, there is no consistent correlation between renin levels and response to the drug. Renin, an enzyme synthesised by the kidney into the circulation where it acts on a plasma globulin substrate to produce angiotensin I, a relatively 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.
CAPACE 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 the 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.
Following oral administration of CAPACE, rapid absorption occurs with peak blood levels at about one hour. The average minimal absorption is approximately 75 percent. The presence of food in the gastro-intestinal tract reduces absorption by about 30 to 40 percent. Only 25 to 30 percent 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 interval. The half-life of unchanged drug is approximately 2 hours.
About 75 percent of a dose of CAPACE is excreted in the urine (of which 50 percent is unchanged drug and the remainder conjugates with endogenous thiol compounds, e.g. captopril-cysteine and the disulfide dimer of the parent compound).
CAPACE produces a reduction in peripheral arterial resistance in hypertensive patients with either no change or an increase in cardiac output.
The effects of CAPACE and of thiazide diuretics on the renin-angiotensin-aldosterone system are complementary.

INDICATIONS:
CAPACE 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 CAPACE and thiazides are additive.
CAPACE 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.
CAPACE has been used with diuretics and digitalis.

CONTRAINDICATIONS:
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.)

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 disturbances in foetal blood pressure regulatory mechanisms. Oligohydramnios 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.
Angioedema involving the extremities, face, eyes, lips, mucous membranes, tongue, glottis or larynx has been in patients treated with CAPACE. 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 CAPACE, some cases required medical therapy. (See SIDE-EFFECTS AND SPECIAL PRECAUTIONS).
Proteinuria has been seen in patients receiving CAPACE, 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. Nephritic syndrome (hypoalbuminemia, edema 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 CAPACE was continued.
Membranous glomerulopthy was found in biopsies taken from some proteinuric patients. A causal relationship to CAPACE has not been established.
For patients with prior renal disease or those receiving CAPACE at doses greater than 150 mg per day, urinary 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. It this exceeds one gram per day, the benefits and risks of continuing CAPACE should be evaluated.
Neutropenia has occurred in some patients receiving CAPACE especially in those who had pre-existing impaired renal function, collagen vascular disease, immunosuppressant therapy, concomitant allopurinol or a combination of these complicating factors.
All patients receiving CAPACE should be told 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, CAPACE should be discontinued until the results of the blood count are known.
Neutropenia was noted 2½ to 13 weeks after CAPACE had been started. Thus, for patients with impaired renal function, collagen vascular disease, or who are receiving immunosuppressant drugs, white blood cell and differential counts should be performed prior to therapy, every 2 weeks during the first three months of CAPACE therapy and periodically thereafter. If the neutrophil count falls below 1 000/mm3 CAPACE 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 CAPACE 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 drugs 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 captopril. The possibility of this occurrence can be lessened in these patients by discontinuing diuretic therapy or significantly reducing the diuretic dose for 4 to 7 days prior to initiating captopril. By commencing 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 CAPACE 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 percent were recorded in about half 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 CAPACE 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 CAPACE, usually along with a diuretic. CAPACE 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 experienced a reduction in renal function during long term treatment.

DOSAGE AND DIRECTIONS FOR USE:
Dosages must be individualised.
See WARNINGS regarding hypotension in salt and volume depleted patients.
CAPACE should be taken one hour before food intake.
Hypertension: The initial dose of CAPACE 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 CAPACE may be increased to 50 mg two or 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 CAPACE should be lower and administered with care.
The dose of CAPACE in mild to moderate hypertension must not exceed 150 mg per day.
When CAPACE is used alone, concomitant sodium restriction may be beneficial.
CAPACE may be used advantageously in conjunction with other antihypertensive agents.
Congestive Heart Failure: CAPACE 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 or 12,5 mg three times a day may minimise 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.
Patients with renal impairment: CAPACE 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)
MINIMUM TOTAL DAILY
        DOSE (mg)
more than         80         450
          80-41         300
          40-21         150
          20-11         75
less than         10         37,5
CAPACE 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 rarely urticarial and generally occurs during the first 4 weeks of treatment. It usually is self-limited and reversible and may respond to antihistamine therapy.
Pruritus, flushing, a reversible pemphigoid-like lesion, photosensitivity 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, have been reported.
Elevation of liver enzymes has been noted in patients receiving the drug although no causal relationship has been found. Cases of hepatocellular injury with secondary cholestasis have been reported in association with CAPACE administration.
Gastric irritation and abdominal pain may occur.
Renal: Proteinuria (see WARNINGS).
Transient elevations of blood urea and creatinine (See PRECAUTIONS).
Increase in the serum potassium concentrations and acidosis. (See WARNINGS).
Haematologic: Neutropenia, anemia and thrombocytopenia. (See WARNINGS).
Respiratory: Irritating cough.
Cardiovascular: Hypotension may occur after initiation of CAPACE therapy in patients with heart failure, renin-dependent hypertension or who are significantly volume depleted. (See WARNINGS).
Tachycardia has been observed in volume-depleted patients.
Anaphylactoid Reactions: Recent clinical observations have shown an association of hypersensitivity-like (anaphylactoid) reactions during hemodialysis with high-flux dialysis membranes (e.g., 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: Paraesthesias of the hands, 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.
CAPACE 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.
CAPACE may cause a false-positive urine test for acetone.
Nursing mothers: Concentrations of unchanged captopril appear in human breast milk. Caution should be exercised when CAPACE is administered for a nursing woman.
Surgery/Anaesthesia: In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, CAPACE will block angiotensin II formation secondary to compensatory renin release. This may lead to hypotension which can be corrected by volume expansion.
Agents Having Vasodilator Activity: Data on the effect of concomitant use of other vasodilators in patients receiving CAPACE for heart failure are not available; therefore, nitroglycerin or other nitrates (as used for management of angina) or other drugs having vasodilator activity should, if possible, be discontinued before starting CAPACE. If resumed during CAPACE therapy, such agents should be administered cautiously, and perhaps at low dosage.
Agents Affecting Sympathetic Activity: The sympathetic nervous system may be especially important in supporting blood pressure in patients receiving captopril alone or with diuretics. Therefore, agents affecting sympathetic activity (e.g., ganglionic 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 CAPACE, especially in cases of low renin hypertension. Other nonsteroidal 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 inhibitor therapy. These drugs should be coadministered 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:
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. Captopril is removed by haemodialysis. Treatment is symptomatic and supportive.

IDENTIFICATION:
CAPACE 25 mg: A slightly mottled, white 6,5 mm square tablet, biconvex, quadrisected on one face.

PRESENTATION:
CAPACE 25 mg is available in blister packs of 60 tablets.

STORAGE INSTRUCTIONS:
Store at room temperature not exceeding 25°C. Protect from excessive moisture, heat and light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:
CAPACE 25 mg - 27/7.1/0398

NAME AND BUSINESS ADDRESS OF APPLICANT:
GAREC (Pty) Ltd
PO Box 1123
Halfway House
1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
18 January 1993

SC182

Current: May 2004
Source: Community Pharmacy

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