CAPOTEN

Captopril

Tablets 12.5, 25 and 50mg

Oral Solution 5mg/mL

Presentation

Capoten is available as 12.5mg, 25mg, and 50mg captopril tablets, and as a 5mg/mL oral solution. The 12.5mg tablet is a flat faced, bevelled-edged, capsule-shaped, scored white tablet with dimensions of 10.2 x 5.1mm. The 25mg tablet is a biconvex square double-scored white tablet 6.5mm square. The 50mg tablet is a biconvex oval scored white tablet and 6 x 11 mm dimensions. Inactive ingredients: microcrystalline cellulose, corn starch, lactose and stearic acid. The oral solution is a clear, colourless, unsweetened, solution. Inactive ingredients: citric acid, sodium citrate, disodium edetate, sodium benzoate,and water.

Uses

Actions

Capoten (captopril) is an inhibitor of angiotensin converting enzyme (ACE), which converts angiotensin I to angiotensin II, a potent endogenous vasoconstrictor substance.

Its beneficial effects in hypertension and heart failure 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 medicine.

Capoten 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 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. The reduction of angiotensin II leads to decreased aldosterone secretion, and as a result, small increases in serum potassium may occur along with sodium and fluid loss. Capoten may also interfere with the degradation of the vasodilator peptide, bradykinin. Increased concentrations of bradykinin or prostaglandin E₂ may also have a role in the therapeutic effect of Capoten.

Administration of Capoten results in a reduction of peripheral arterial resistance in hypertensive patients with either no change or an increase in cardiac output. There is an increase in renal blood flow following administration of Capoten and glomerular filtration rate is usually unchanged.

Reductions in blood pressure are usually maximal 60 to 90 minutes after oral administration. The blood pressure lowering effects of Capoten and thiazide-type diuretics are additive. Abrupt withdrawal of Capoten has not been associated with rapid increase in blood pressure.

In patients with heart failure, significantly decreased systemic vascular resistance and blood pressure (afterload), reduced pulmonary capillary wedge pressure (preload) and pulmonary vascular resistance, increased cardiac output, and increased exercise tolerance time have been demonstrated. These haemodynamic and clinical effects occur after the first dose and appear to persist for the duration of therapy.

Following myocardial infarction the loss of functioning myocardium results in hypertrophy of the residual myocardium and dilatation of the ventricle (remodelling). In the long term this may lead to the onset of clinically evident cardiac failure. In the Survival and Ventricular Enlargement (SAVE) study of patients (age 21-79 years) who survived the acute stage of an MI and had left ventricular dysfunction (ejection fraction <40%) without overt heart failure, therapy with Capoten at a maintenance dose of 150mg/day improved survival and clinical outcome compared to placebo. Capoten reduced the following :- all cause mortality (risk reduction = 19%, p=0.022); cardiovascular death (risk reduction = 21%, p=0.017); clinically reported recurrent myocardial infarction (risk reduction = 25%, p=0.011); manifestations of heart failure requiring initiation or augmentation of digitalis and diuretics (risk reduction = 19%, p = 0.008) or requiring the use of ACE inhibitor therapy (risk reduction = 35%, p < 0.001) and hospitalisation for heart failure (risk reduction = 20%, p=0.034).

In a multicenter, double-blind, placebo-controlled trial among 409 patients with insulin-dependent diabetes mellitus and proteinuria with or without hypertension (conventional antihypertensive agents were allowed to achieve blood pressure control), captopril treatment provided a 51% risk reduction in doubling of serum creatinine (p≤0.01), and a 51% risk reduction for the combined morbidity/mortality endpoint of end-stage renal disease (dialysis or renal transplantation) or death (p≤0.01).

The effects of treatment with captopril on the preservation of renal function are in addition to any benefit that may have been derived from the reduction in blood pressure.

In patients with diabetes mellitus and microalbuminuria, captopril reduced albumin excretion rate and attenuated the decline in glomerular filtration rate during two years of treatment.

Pharmacokinetics

Following oral administration of captopril, rapid absorption occurs with peak blood levels at about one hour. The presence of food in the gastrointestinal tract reduces the absorption of captopril. After administration of a radiolabelled oral dose, the apparent elimination half life for total radioactivity in blood is about 12 hours for the 12 to 48 hour time interval. The half life of unchanged captopril is approximately 2 hours. In a 24 hour period, over 95 per cent of the absorbed dose of captopril is excreted in the urine; 50 per cent as the unchanged compound, and the remainder as the disulphide dimer of captopril and captopril -cysteine disulphide. Approximately 25 to 30 per cent of the circulating compound is protein bound. Excretion of captopril is reduced in patients with renal impairment and hence drug accumulation is a possibility.

Capoten does not cross the blood-brain barrier to any significant extent.

Indications

Hypertension:

Capoten is indicated for the treatment of hypertension in adult and paediatric patients. It may be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of Capoten and thiazides are additive.

Heart Failure:

Capoten is indicated for the treatment of patients with heart failure. In such patients it is recommended that Capoten be administered with a diuretic.

Myocardial Infarction:

Capoten is indicated in clinically stable patients with asymptomatic and symptomatic left ventricular dysfunction following myocardial infarction to improve survival and reduce the risk of recurrent myocardial infarction or hospitalisation for heart failure.

Diabetic Nephropathy:

Capoten is indicated for the treatment of diabetic nephropathy in Type 1 diabetes with or without hypertension. In these patients Capoten prevents the progression of renal disease and reduces associated clinical sequelae (dialysis, renal transplantation and death).

Dosage And Administration

Dosage must be individualised. See Warnings regarding hypotension in salt and volume depleted patients.

Adults

Hypertension:

Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction (the antihypertensive effect of Capoten may be exaggerated), and other clinical circumstances.

The initial dose of Capoten is 50mg once daily or 25mg twice daily. If a satisfactory reduction of blood pressure has not been achieved the dose of Capoten may be increased and the total dosage should then be given in divided doses. Alternatively, a small dose of thiazide diuretic may be added prior to increasing the dose of Capoten. The usual maintenance dose is 50-100mg daily. For patients already receiving a diuretic, the initial dose of Capoten should be administered with care (see Warnings And Precautions ).

The usual effective dose of Capoten in mild to moderate hypertension does not exceed 100mg per day. However, in severe hypertension where further blood pressure reduction is required, the dose may be increased incrementally (while continuing the diuretic) and a t.i.d. dosage schedule may be considered. A maximum daily dose of 450mg Capoten should not be exceeded.

For patients with severe hypertension who are on multiple antihypertensive therapy it may be impractical to discontinue all therapy prior to starting Capoten. In such patients Capoten would usually be used in combination with a thiazide diuretic, therefore, the diuretic should be continued and other currently administered antihypertensive agents should be discontinued according to the instructions of the manufacturer. Capoten 25mg b.i.d. or t.i.d. should be initiated under close medical supervision.

For patients with accelerated or malignant hypertension, particularly those unresponsive to conventional therapy, the dosage may be increased at 24 hour intervals or less under continuous medical supervision, until a satisfactory blood pressure response is obtained or the maximum dose of Capoten is reached. In this regimen, addition of a more potent diuretic, e.g. frusemide may also be indicated. When Capoten is used alone, concomitant sodium restriction may be beneficial. Capoten may be used advantageously in conjunction with other antihypertensive agents.

Heart Failure:

Capoten therapy must be started under close medical supervision. It should be added to conventional treatment with diuretic (and digitalis where indicated). Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion. In patients with either normal or low blood pressure, who have been vigorously treated with diuretics and who may be hyponatremic and/or hypovolemic a starting dose of 6.25 or 12.5mg b.i.d. may minimise the duration of any transient hypotensive effect (see Warnings And Precautions - Hypotension); for these patients, titration to the usual daily dosage can then occur within the next several days. For most patients the usual initial daily dose is 25mg b.i.d.. The usual maintenance dose is 25-50mg b.i.d. After a dose of 50mg t.i.d. is reached, further increases in dosage should not normally be given. The usual maximum daily dose is 150mg but this may be increased at the discretion of the physician.

Post-Myocardial Infarction:

The recommended dose for long-term prophylactic use in patients who have survived a myocardial infarction is a target dose of 150mg daily. Therapy may be initiated as early as 3 days following a myocardial infarction. The initial recommended dosage is 6.25 or 12.5 mg of Capoten. If the dose is well tolerated, Capoten may be increased to 37.5 mg daily then 75mg daily in divided doses during the next several days and then over the next several weeks to a recommended daily dose of 150 mg daily given b.i.d. or t.i.d.

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 captopril.

Capoten may be used in patients treated with other post-myocardial infarction therapies, e.g., thrombolytics, aspirin and beta-blockers.

Diabetic Nephropathy:

In patients with diabetic nephropathy, the recommended daily dose of Capoten is 75 to 100 mg in divided doses. If further blood pressure reduction is required, other antihypertensive agents such as diuretics, beta adrenoceptor blockers, centrally acting agents or vasodilators may be used in conjunction with Capoten.

Dosage Adjustment in Renal Impairment:

Captopril in divided doses of 75 to 100 mg/day was well tolerated in patients with diabetic nephropathy and mild to moderate renal impairment. (See Warnings And Precautions - Hyperkalemia). Because Capoten is excreted primarily by the kidneys, excretion rates are reduced in patients with impaired renal function. These patients will take longer to reach steady-state captopril levels and will reach higher levels for a given daily dose than patients with normal renal function. Therefore, these patients may respond to smaller or less frequent doses. Accordingly, for patients with significant renal impairment, initial daily dosage of Capoten should be reduced. Smaller increments should be used for titration, which should be quite slow (one-to two-week intervals). After the desired therapeutic effect has been achieved, the dose should be slowly back-titrated to determine the minimal effective dose. When concomitant diuretic therapy is required, a loop diuretic (e.g., frusemide), rather than a thiazide diuretic, is preferred in patients with severe renal impairment.

Children

The initial dose of Capoten is 0.3mg/kg administered under close medical supervision. Infants and older children more likely to develop hypotension, such as those on diuretic therapy may be started on 0.15mg/kg. Generally the dose of Capoten is administered 3 times a day. However, the frequency of dosing must be individualised according to the response of each patient. If a satisfactory reduction of blood pressure has not been achieved, each single dose may be increased at weekly intervals to 0.6, 1.2 and 2.0mg/kg. For those patients not receiving a diuretic, concomitant diuretic therapy may be instituted. For patients with accelerated hypertension, dosage may be increased at 24 hour intervals or less. A maximum total daily dose of 6.0mg/kg should not be exceeded. Dosage in infants and patients with renal dysfunction should be reduced appropriately (see Warnings And Precautions ).

Contraindications

A history of previous hypersensitivity to Capoten ( captopril or the inactive ingredients).

Pregnancy (see Use In Pregnancy ).

Patients with a history of hereditary and/or idiopathic angioedema or angioedema associated with previous treatment with an angiotensin converting enzyme inhibitor.

Warnings And Precautions

Anaphylactoid and Possibly Related Reactions

Possibly because angiotensin-converting enzyme is essential for degradation of endogenous bradykinin, patients receiving ACE inhibitors are subject to a variety of adverse reactions producing effects ranging from relatively mild, such as cough (see Precautions ), to serious such as the following:

Angioedema:

Severe life-threatening angioedema has been reported rarely with most of the angiotensin converting enzyme (ACE) inhibitors. The overall incidence is approximately 0.1% to 0.2%. There seems to be no sex difference in the incidence of angiodema or in the predisposition to angioedema in patients with heart failure or hypertension. In the majority of reported cases, the symptoms occurred during the first week of therapy. The aetiology is thought to be non-immunogenic and may be related to accentuated bradykinin activity. Usually the angioedema involves non-pitting oedema of the skin and oedema of the subcutaneous tissues and mucous membranes.

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with ACE inhibitors. In such cases, the product should be discontinued promptly and appropriate monitoring instituted to ensure complete resolution of symptoms. In instances when swelling has been confined to the face and lips, the angioedema has generally resolved either without treatment or with antihistamines. Angioedema associated with laryngeal oedema is potentially life threatening. Where involvement of the tongue, glottis, or larynx is likely to cause airway obstruction appropriate therapy, including adrenalin and oxygen administration, should be carried out promptly or the patient hospitalised. Patients who respond to medical treatment should be observed carefully for a possible re-emergence of symptoms of angioedema.

There are reports where changing the patient over to another ACE inhibitor was followed by recurrence of oedema and others where is was not. Because of the potential severity of this rare event another ACE inhibitor should not be used in patients with a history of angioedema to a drug of this class.

Anaphylactoid reactions during desensitisation:

Two patients undergoing desensitising treatment with hymenoptera venom while receiving another ACE inhibitor, enalapril, sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when the ACE inhibitor was temporarily withheld, but they reappeared upon inadvertent rechallenge. Therefore, caution should be used in patients treated with ACE inhibitors undergoing such desensitisations procedures.

Anaphylactoid reactions during high-flux dialysis/lipoprotein apheresis membrane exposure:

Patients hemodialysed with high-flux polyacrylonitrile ("AN69") membranes are highly likely to experience anaphylactoid reactions if they are treated with ACE inhibitors. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. These combinations should therefore be avoided, either by use of a different class of medication or alternative membranes (eg. cuprophane or polysulphone PSF for haemodialysis).

Proteinuria

Total urinary proteins greater than 1g per day were seen in about 0.7 percent of patients receiving Capoten but, this has been predominantly (approximately 90%) in those who had evidence of prior renal disease, or in those receiving relatively high doses (in excess of 150mg per day), or both. Alterations in renal function (as assessed by blood urea nitrogen and serum creatinine) were infrequent in these patients and did not occur in those who had no prior renal disease. In patients without prior evidence of renal disease the incidence of proteinuria was 0.5 percent. In those patients without prior evidence of renal disease and receiving 150mg of Capoten or less per day the incidence was 0.2 percent.

Nephrotic syndrome (hypoalbuminaemia, oedema and protein excretion greater than 3 grams per day) occurred in about one-fifth of the proteinuric patients. In most cases, proteinuria subsided or cleared within 6 months whether or not Capoten was continued.

In a multicentre, double-blind, placebo-controlled trial in 207 patients with diabetic nephropathy and proteinuria (³ 500 mg per day) receiving captopril 75 mg/day for a median of 3 years, there was a consistent reduction in proteinuria. It is unknown whether long-term therapy in patients with other types of renal disease would have similar effects.

For patients with prior renal disease or those receiving Capoten at doses greater than 150mg per day, urinary protein estimations (dipstick) should be done prior to treatment and periodically thereafter. 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 Capoten should be evaluated.

Neutropenia/Agranulocytosis

Neutropenia has occurred in some patients receiving Capoten, but the risk of neutropenia is dependent on the clinical status of the patient especially pre-existing impaired renal function, collagen vascular disease, immunosuppressant therapy, or a combination of these complicating factors.

Neutropenia is very rare (<0.02%) in patients with hypertension who have normal renal function (Cr_s < 130 micromol/L and no collagen vascular disease).

In patients with some degree of renal impairment and no collagen vascular disease or coadministered immunosuppressant agents, neutropenia occurred in 0.3 percent of cases. Daily doses of Capoten were relatively high in these patients. In patients with renal failure, use of allopurinol concomitantly with Capoten has been associated with neutropenia.

In patients with collagen vascular disease (e.g. systemic lupus erythematosus, scleroderma), particularly those with coexisting renal impairment, Capoten should be prescribed only after an assessment of benefit and risk (and then with caution) since neutropenia has occurred in 3.7% of patients in clinical trials. Similar caution should be exercised in patients receiving immunosuppressant agents.

Neutropenia was noted 2½ to 13 weeks after Capoten has been started. For patients with impaired renal function, collagen vascular disease, or who are receiving immunosuppressant agents, white blood cell and differential counts should be performed prior to therapy, every 2 weeks during the first 3 months of Capoten therapy and periodically thereafter. Patients with complicating factors who are treated with captopril should be told to report any signs of infection (e.g. sore throat, fever). If infection is suspected white cell counts should be performed without delay.

If the neutrophil count falls below 1000/mm³, Capoten should be discontinued and the patient's course should be followed. In clinical trials, neutrophil counts returned to normal in about 2 weeks in most cases upon discontinuing Capoten. About 13 percent of the cases of neutropenia have ended fatally, but almost all fatalities were in patients with serious illness, having collagen vascular disease, renal failure, heart failure or immunosuppressant therapy, or a combination of these complicating factors.

Bone marrow examination in patients with neutropenia consistently showed myeloid hypoplasia, frequently accompanied by erythroid hypoplasia and decreased numbers of megakaryocytes. Neutropenia was associated with significant alterations of peripheral red blood cell or platelet counts in 6 patients.

Hypotension

Although most patients tolerate the antihypertensive effects of Capoten well, those already on diuretic therapy may occasionally experience dizziness or light-headedness, usually mild, indicative of hypotension, that may occur within one hour of the first dose. In most instances, symptoms are relieved simply by instructing the patient to lie down. In patients who are salt/volume depleted (such as those 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 Capoten. 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 Capoten. By commencing Capoten therapy with small doses, (6.25 or 12.5mg), the duration of any hypotensive effect is reduced. The likelihood of an exaggerated hypotensive response can be predicted early if the patient is under medical supervision during the first hour after initial dosing; and if necessary, it can be rapidly reversed by intravenous infusion of normal saline. A hypotensive episode following the initial dose of Capoten does not preclude further doses which can be given without difficulty once the blood pressure has increased.

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 of the patients. This transient fall in blood pressure may occur after any of the first several doses and is usually well tolerated, producing either no symptoms or brief mild lightheadedness, although in rare instances it has been associated with arrhythmia or conduction defects. Hypotension was the reason for discontinuation of medication in 3.6 percent of patients with heart failure.

Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. A starting dose of 6.25 or 12.5 mg b.i.d. or t.i.d. may minimise the hypotensive effect. Patients should be followed closely for the first 2 weeks of treatment and whenever the dose of Capoten, or diuretic, or both is increased.

If associated symptoms are troublesome or, persist, they are usually relieved by a reduction of the dose of either Capoten or diuretic. Hypotension is not per se a reason to discontinue Capoten.

Impaired Renal Function

Hypertension:

Some patients with renal disease, particularly those with bilateral renal artery stenosis, have developed increases in BUN and serum creatinine after reduction of blood pressure with Capoten, usually along with a diuretic. Capoten dosage reduction or discontinuation of 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.

Heart Failure:

Some patients with heart failure have experienced a reduction in renal function during long-term treatment that usually stabilised at the reduced level. Less than 5% of patients, generally those with pre-existing renal disease, required discontinuation of treatment due to progressively increasing creatinine.

Hyperkalaemia

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including captopril. When treated with ACE inhibitors, patients at risk of developing hyperkalaemia include those with: renal impairment; diabetes mellitus; and those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes; or other drugs associated with increases in serum potassium (e.g. heparin).

Cough

ACE inhibitor induced cough should be considered as part of the differential diagnosis of cough.

Hepatic Failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic neurosis and (sometimes) death. The mechanism of this syndrome is not understood.

Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue ACE inhibitors and receive appropriate medical follow up.

Surgery/Anaesthesia

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, Capoten will block 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.

Aortic Stenosis

Capoten, as with any agent that reduces vascular resistance, 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.

Patients treated for severe congestive heart failure should be cautioned to increase their physical activity slowly.

Urine Acetone

Capoten may cause a false-positive urine test for acetone.

Use in Pregnancy

When used in pregnancy during the second and third trimester, ACE inhibitors can cause injury and even death to the developing foetus. When pregnancy is detected Capoten should be discontinued as soon as possible. In humans, exposure of the mother in the second and third trimesters of pregnancy has been associated with foetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible and irreversible renal failure and death. Oligohydramnios has been reported, presumably as a consequence of decreased renal function, in the foetus; in this setting oligohydramnios has been associated with foetal limb contractures, craniofacial deformation and hypoplastic lung development. Prematurity, intrauterine growth retardation and patent ductus arteriosus have been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure. Consequently women who become pregnant whilst taking Capoten should be switched to alternative, appropriate anti-hypertensive therapy.

Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to ACE inhibitors. Women should be instructed to notify their doctor immediately if pregnancy is suspected. Mothers whose embryos and foetuses are exposed to ACE inhibitors only during the first trimester should be told that the adverse effects do not appear to have resulted from intrauterine ACE inhibitor exposure that has been limited to the first trimester.

Use in Lactation

Following oral administration, concentrations of unchanged Capoten in human breast milk are one percent or less of those in maternal blood. The effect of this small amount of Capoten on the nursing infant has not been determined. Because of the potential for serious adverse reactions in breast fed infants given captopril, a decision should be made whether to discontinue breast feeding or to discontinue the drug, taking into account the importance of Capoten to the mother.

Paediatric Use

Safety and effectiveness in children have not been established. There is limited experience reported in the literature with the use of captopril in the paediatric population; dosage, on a weight basis, was generally reported to be comparable to or less than that used in adults. Infants, especially newborns, may be more susceptible to the adverse haemodynamic effects of captopril. Excessive, prolonged and unpredictable decreases in blood pressure and associated complications, including oliguria and seizures, have been reported. Because renal function in infants is not equivalent to that of older children and adults, lower doses of Capoten should be used with the patient under close medical supervision. Capoten should be used in children only if other measures for controlling blood pressure have not been effective.

Adverse Effects

Reported incidence are based on clinical trials involving approximately 7,000 patients treated with Capoten.

Skin:

A rash occurred in 8.5 percent of patients with normal renal function and 13 percent of patients with evidence of prior renal functional impairment. It was dose related, having occurred only in 7 percent of patients at doses of 150mg or less per day. 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. The rash is usually mild and disappears within a few days of dosage reduction, short-term treatment with an antihistamine and/or discontinuing therapy.

Pruritus, flushing, fever, arthralgia, eosinophilia, a reversible pemphigoid-like lesion and photosensitivity have also been reported.

Gastrointestinal:

Two percent of patients receiving 150mg or less per day of Capoten developed a diminution or loss of taste perception. At doses in excess of 150mg per day 7 percent of patients experienced this effect. Taste impairment is reversible and usually self-limited (2 to 3 months). In most patients the condition resolved with the continuation of therapy. Weight loss may be associated with the loss of taste.

Hepatic:

Elevation of liver enzymes have been noted in a few patients receiving the medication although no causal relationship has been found.

Renal:

Proteinuria (see Warnings And Precautions ).

Transient elevations of BUN and creatinine (see Warnings And Precautions ).

Increase in the serum potassium concentrations and acidosis (see Warnings And Precautions ). Renal insufficiency, renal failure, nephrotic syndrome, polyuria, oliguria and urinary frequency.

Haematologic:

Neutropenia/agranulocytosis, anaemia, thrombocytopenia and pancytopenia (see Warnings And Precautions ).

Cardiovascular:

Hypotension may occur after initiation of Capoten therapy in patients with heart failure, renin-dependent hypertension or who are significantly volume-depleted (see Warnings And Precautions ). Tachycardia, chest pain and palpitations have each been observed in approximately 1% of patients. Angina pectoris, myocardial infarction, Raynaud's syndrome and congestive heart failure have occurred in ≤ 0.3% of patients.

Immunologic:

Angioedema has been reported in approximately 0.1% of patients. Angioedema involving the upper airways has caused fatal airways obstruction.

Respiratory:

Cough has been reported in 0.5-2% of patients treated with captopril in clinical trials.

The following have been reported in about 0.5 to 2 percent of patients but did not appear at increased frequency compared to placebo or other treatments used in controlled trials: gastric irritation, abdominal pain, nausea, vomiting, diarrhoea, anorexia, constipation, aphthous ulcers, peptic ulcer, dizziness, headache, malaise, fatigue, insomnia, dry mouth, dyspnea, alopecia, paresthesias.

Other clinical adverse effects reported since the drug was marketed are listed below by body system. In this setting, an incidence or causal relationship cannot be accurately determined.

General: Asthenia, gynecomastia.

Cardiovascular: Cardiac arrest, cerebrovascular accident/insufficiency, rhythm disturbances, orthostatic hypotension, syncope.

Dermatologic: Bullous pemphigus, erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis.

Gastrointestinal: Pancreatitis, glossitis, dyspepsia.

Hematologic: Anaemia, including aplastic and haemolytic.

Hepatobiliary: Jaundice, hepatitis, including rare cases of hepatic necrosis, cholestasis.

Metabolic: Symptomatic hyponatremia.

Musculoskeletal: Myalgia, myasthenia.

Nervous/Psychiatric: Ataxia, confusion, depression, nervousness, somnolence.

Respiratory: Bronchospasm, eosinophilic pneumonitis, rhinitis.

Special Senses: Blurred vision.

Urogenital: Impotence.

As with other ACE inhibitors, a syndrome has been reported which may include: fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash or other dermatologic manifestations, eosinophilia and an elevated ESR.

Foetal/Neonatal Morbidity and Mortality:

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with foetal and neonatal injury, and death (see Warnings And Precautions ).

Altered Laboratory Findings

Serum Electrolytes:

Hyperkalemia, especially in patients with renal impairment.

Hyponatremia, particularly in patients receiving a low sodium diet or concomitant diuretics.

BUN/Serum Creatinine:

Transient elevations of BUN or serum creatinine, especially in volume or salt depleted patients or those with renovascular hypertension may occur. Rapid reduction of longstanding or markedly elevated blood pressure can result in decreases in the glomerular filtration rate and, in turn, lead to increases in BUN or serum creatinine.

Hematologic:

A positive ANA has been reported.

Liver Function Tests:

Elevations of liver transaminases, alkaline phosphatase, and serum bilirubin have occurred.

Interactions

Hypotension - Patients on Diuretic Therapy

Patients on diuretics and especially those in whom diuretic therapy was recently instituted, as well as those on severe dietary salt restriction or dialysis, may occasionally experience a precipitous reduction of blood pressure usually within the first hour after receiving the initial dose of captopril.

The possibility of hypotensive effects with captopril can be minimised by either discontinuing the diuretic or increasing the salt intake approximately one week prior to initiation of treatment with captopril or initiating therapy with small doses (6.5 or 12.5mg). Alternatively, provide medical supervision for at least one hour after the initial dose.

Agents Having Vasodilator Activity

Nitroglycerine or other nitrates (as used for management of angina) or other agents having vasodilator activity should be administered cautiously, and a lower dosage considered.

Agents Causing Renin Release

Captopril's effect will be augmented by antihypertensive agents that cause renin release. For example, diuretics (e.g. thiazides) may activate the renin angiotensin-aldosterone system.

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. Beta-adrenergic blocking agents add some further antihypertensive effect to captopril, but the overall response is less than additive.

Agents Increasing Serum Potassium

Since captopril decreases aldosterone production, elevation of serum potassium may occur. Potassium-sparing diuretics such as spironolactone, triamterene, or amiloride, or potassium supplements, should be given only for documented hypokalaemia, and then with caution, since they may lead to a significant increase in serum potassium. Salt substitutes containing potassium should also be used with caution.

Inhibitors of Endogenous Prostaglandin Synthesis

It has been reported that indomethacin may reduce the antihypertensive effect of captopril, especially in cases of low renin hypertension. Other nonsteroidal anti-inflammatory agents may also have this effect.

Lithium

Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These agents 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.

Overdosage

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 for normalisation of the blood pressure.

Capoten is removed from the adult circulation by haemodialysis; there is inadequate data as to the effectiveness of this method for neonates or children. Peritoneal dialysis is not effective for removing Capoten; there is no information concerning exchange transfusion for removing Capoten from the general circulation.

Pharmaceutical Precautions

Store Capoten tablets below 30°C. Protect from moisture.

Store Capoten oral solution below 25°C.

Medicine Classification

Prescription Medicine

Package Quantities

Tablets 12.5, 25 and 50mg in blister packs of 60.

Tablets 50mg in calendar pack of 30.

Oral solution contains 5mg/mL in 95mL bottles