SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Captopril 12.5mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 12.5 mg captopril

Excipients with known effect: Each tablet contains 25 mg lactose (as lactose monohydrate)

For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Tablet

Round, white tablets of diameter 6.0 -6.2mm with a break mark on one side, convex on the other side.

The score line is only to facilitate breaking for the ease of swallowing and not to divide into equal doses

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Hypertension: Captopril 12.5 mg tablets are indicated for the first line treatment of mild to moderate hypertension. In severe hypertension it should be used where standard therapy is ineffective or inappropriate.

Congestive heart failure: Captopril 12.5 mg tablets are indicated for the treatment of congestive heart failure. The drug should be used together with diuretics, and where appropriate, digitalis.

Myocardial infarction:

- short-term (4 weeks) treatment: Captopril 12.5 tablet is indicated in any clinically stable patient within the first 24 hours of an infarction.

- long-term prevention of symptomatic heart failure: Captopril 12.5mg tablets are indicated in clinically stable patients with asymptomatic and symptomatic left ventricular dysfunction to improve survival, delay the onset of symptomatic heart failure, reduce hospitalisations for heart failure, and reduce recurrent myocardial infarction and coronary revascularisation procedures. Determination of cardiac function by radionuclide ventriculography or echocardiography should be undertaken prior to initiation of preventive treatment with Captopril in post myocardial infarction patients.

4.2 Posology and method of administration

Posology

Dose should be individualised according to patient’s profile (see section 4.4) and blood pressure response. The recommended maximum daily dose is 150 mg.

Mild to moderate hypertension:

Initial dose 12.5mg twice daily. The usual maintenance dose is 25mg twice daily which can be increased incrementally, at 2-4 week intervals, until a satisfactory response is achieved, to a maximum of 50mg twice daily.

A thiazide diuretic may be added to Captopril tablets if satisfactory response has not been achieved. The dose of diuretic may be increased at a 1-2 week interval to the level of optimum response or until the maximum dose is reached.

Severe Hypertension:

In severe hypertension where standard therapy is ineffective or inappropriate because of adverse effects, the starting dose is 12.5mg b.d. The dosage may be increased incrementally to a maximum of 50mg t.i.d. Captopril tablets should be used together with other anti-hypertensive agents but the dose of these should be individually titrated. A daily dose of 150mg of Captopril should not normally be exceeded. heart failure:

Captopril therapy must be started under close medical supervision. Captopril should be introduced when diuretic therapy (such as frusemide 40-80 mg or equivalent) is insufficient to control symptoms. A starting dose of 6.25 mg or 12.5 mg BID or TID may minimise a transient hypotensive effect. The possibility of this occurring can be reduced by discontinuing or reducing diuretic therapy if possible, prior to initiating captopril. Titration to the maintenance dose (75 - 150 mg per day) should be carried out based on patient's response, clinical status and tolerability, up to a maximum of 150 mg per day in divided doses. The dose should be increased incrementally, with intervals of at least 2 weeks to evaluate patient’s response.

Myocardial infarction:

-    short-term treatment: Captopril treatment should begin in hospital as soon as possible following the appearance of the signs and/or symptoms in patients with stable haemodynamics. A 6.25 mg test dose should be administered, with a 12.5 mg dose being administered 2 hours afterwards and a 25 mg dose

12 hours later. From the following day, captopril should be administered in a 100 mg/day dose, in two daily administrations, for 4 weeks, if warranted by the absence of adverse haemodynamic reactions. At the end of the 4 weeks of treatment, the patient’s state should be reassessed before a decision is taken concerning treatment for the post-myocardial infarction stage.

-    chronic treatment: if captopril treatment has not begun during the first 24 hours of the acute myocardial infarction stage, it is suggested that treatment be instigated between the 3^rd and 16^th day post-infarction once the necessary treatment conditions have been attained (stable haemodynamics and management of any residual ischaemia). Treatment should be started in hospital under strict surveillance (particularly of blood pressure) until the 75 mg dose is reached. The initial dose must be low (see section 4.4), particularly if the patient exhibits normal or low blood pressure at the initiation of therapy. Treatment should be initiated with a dose of 6.25 mg followed by 12.5 mg 3 times daily for 2 days and then 25 mg 3 times daily if warranted by the absence of adverse haemodynamic reactions. The recommended dose for effective cardioprotection during long-term treatment is 75 to 150 mg daily in two or three doses. In cases of symptomatic hypotension, as in heart failure, the dosage of diuretics and/or other concomitant vasodilators may be reduced in order to attain the steady state dose of captopril. Where necessary, the dose of captopril should be adjusted in accordance with the patient’s clinical reactions. Captopril may be used in combination with other treatments for myocardial infarction such as thrombolytic agents, beta-blockers and acetylsalicylic acid.

Older people:

The dose should be titrated against the blood pressure response and kept as low as possible to achieve adequate control. Since elderly patients may have reduced renal function and other organ dysfunctions, it is suggested that a low dose of captopril (6.25 mg BID) be used initially.

Children:

The efficacy and safety of captopril have not been fully established. Captopril is not recommended for the treatment of mild to moderate hypertension in children.

Experience in neonates, particularly premature infants, is limited. Because renal function in infants is not equivalent to that of older children and adults, lower doses of captopril should be used with the patients under close medical supervision.

The starting dose should be 0.3 mg per kg bodyweight up to a maximum of 6 mg per kg bodyweight daily, in divided doses. The dose should be individualised according to the response and may be given two or three times daily.

For patients requiring special precautions (children with renal dysfunction, premature infants, new-borns and infants, because their renal function is not the same with older children and adults) the starting dose should be only 0.15 mg captopril/kg weight.

Patients with renal impairment:

Since captopril is excreted primarily via the kidneys, dosage should be reduced or the dosage interval should be increased in patients with impaired renal function.

In patients with impaired renal function, the following daily dose may be recommended to avoid accumulation of captopril.

Creatinine clearance (mL/min/1.73 m2)	Daily starting dose (mg)	Daily maximum dose (mg)
> 40	25-50	150
21-40	25	100
10-20	12.5	75
<10	6.25	37.5

Patients with severely impaired renal function will take longer to reach steady-state captopril levels and will reach higher steady-state levels for a given daily dose than patients with normal renal function. These patients may therefore respond to smaller or less frequent doses.

Therefore in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73m²), the initial daily dose should be 12.5 mg b.d. The dose can then be titrated against the response but adequate time should be allowed between dosage adjustments. When concomitant diuretic therapy is required, a loop diuretic (e.g. furosemide), rather than a thiazide should be the diuretic of choice.

Captopril is readily eliminated by haemodialysis.

Method of administration For Oral Administration.

Captopril may be taken before, during and after meals.

4.3 Contraindications

•    Hypersensitivity to the active substance or to any of excipients listed in section 6.1 or any other ACE inhibitor.

•    Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

•    History of angioedema associated with previous ACE inhibitor therapy

•    Hereditary / idiopathic angioneurotic oedema

Lactation (see section 4.6).

The concomitant use of captopril with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m ) (see sections 4.5 and 5.1)

4.4 Special warnings and precautions for use

Precautions:

Evaluation of the patient should include assessment of renal function prior to initiation of therapy and at appropriate times thereafter (see recommended dose and dosage schedule section).

Warnings:

The incidence of adverse reactions to captopril is principally associated with renal function since the drug is excreted primarily by the kidney. The dose should not exceed that necessary for adequate control and should be reduced in patients with impaired renal function.

Aortic and mitral valve stenosis/Obstructive hypertropic

cardiomyopathy: Captopril should be used with caution in patients with aortic stenosis/ left ventricular valvular and outflow tract obstruction and avoided in cases of cardiogenic shock and haemodynamically significant obstruction. As limited experience has been obtained in the treatment of acute hypertensive crises, the use of captopril should be avoided in these patients.

Hypotension:

With the first one or two doses some patients with uncomplicated hypertension may experience symptomatic hypotension. In most instances, symptoms are relieved simply by the patient lying down.

In patients with severe renin dependent hypertension (e.g. renovascular hypertension) or severe congestive heart failure, who are receiving large doses of diuretic, exaggerated hypotensive responses have occurred, usually within one hour of the initial dose of captopril. In these patients, by discontinuing diuretic therapy or significantly reducing the diuretic dose for four to seven days prior to initiating captopril the possibility of this occurrence is reduced. By commencing captopril therapy with small doses (6.25 mg or 12.5 mg) the duration of any hypotensive effect is lessened. Some patients may benefit from an infusion of saline.

The occurrence of first dose hypotension does not preclude subsequent dose titration with captopril.

Patients with heart failure are at higher risk of hypotension and a lower starting dose is recommended when initiating therapy with an ACE inhibitor. Caution should be used whenever the dose of captopril or diuretic is increased in patients with heart failure.

Hypotension has been occasionally reported in patients on Captopril due to causes of acute volume depletion such as vomiting or diarrhoea. Symptomatic hypotension is more likely to occur in hypertensive patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea, vomiting or haemodialysis. Volume and/or sodium depletion should be corrected before the administration of an ACE inhibitor and a lower starting dose should be considered.

As with any antihypertensive agent, excessive blood pressure lowering in patients with ischaemic cardiovascular or cerebrovascular disease may increase the risk of myocardial infarction or stroke. If hypotension develops, the patient should be placed in a supine position. Volume repletion with intravenous normal saline may be required.

Renal impairment: in cases of renal impairment (creatinine clearance <40 mL/min), the initial dosage of captopril must be adjusted according to the patient's creatinine clearance (see section 4.2), and then as a function of the patient's response to treatment. Routine monitoring of potassium and creatinine are part of normal medical practice for these patients.

Angioedema: angioedema of the extremities, face, lips, mucous membranes, tongue, glottis or larynx may occur in patients treated with ACE inhibitors including captopril, particularly during the first weeks of treatment. This may occur anytime during treatment. However, in rare cases, severe angioedema may develop after long-term treatment with an ACE inhibitor. Treatment should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. In those instances where swelling has been confined to the face and lips the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema involving the tongue, glottis or larynx may be fatal. Emergency therapy should be instituted. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, which may include subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures to ensure a patent airway, should be administered promptly. The patient should be hospitalised and observed for at least 12 to 24 hours and should not be discharged until complete resolution of symptoms has occurred.

Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see section 4.3).

Intestinal angioedema has also been reported rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan, or ultrasound or at surgery and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain (see section 4.8).

Cough: cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy.

Hepatic failure: rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis 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 the ACE inhibitor and receive appropriate medical follow-up.

Serum potassium (Hyperkalaemia): elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including captopril. Since captopril decreases aldosterone production, serum potassium is usually maintained in patients on diuretics. Potassium sparing diuretics or potassium supplements should not therefore be used routinely. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, diabetes mellitus, or those using concomitant or potassium-containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (e.g. heparin). If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended. In patients with marked renal impairment a significant elevation of serum potassium may occur.

Combination with lithium: the combination of lithium and captopril is not recommended due to the potentiation of lithium toxicity (see section 4.5)

Proteinuria: Proteinuria may occur particularly in patients with existing renal function impairment or on relatively high doses of ACE inhibitors. Proteinuria in patients with prior normal renal function is rare. Where proteinuria has occurred it has usually been in patients with severe hypertension and evidence of prior renal disease. Nephrotic syndrome occurred in some of these patients (one-fifth of proteinuric patients).

Total urinary proteins greater than 1 g per day were seen in about 0.7% of patients receiving captopril. The majority of patients had evidence of prior renal disease or had received relatively high doses of captopril (in excess of 150 mg/day), or both. In most cases, proteinuria subsided or cleared within six months whether or not captopril was continued. Parameters of renal function, such as BUN and creatinine, were seldom altered in the patients with proteinuria.

Patients with prior renal disease should have urinary protein estimations (dipstick on first morning urine) prior to treatment, and periodically thereafter.

Although membraneous glomerulopathy was found in biopsies taken from some proteinuric patients, a causal relationship to captopril has not been established.

Renovascular hypertension:

There is an increased risk of hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors. Loss of renal function may occur with only mild changes in serum creatinine. In these patients, therapy should be initiated under close medical supervision with low doses, careful titration and monitoring of renal function.

Anaphylactoid reactions during desensitisation:

Sustained life-threatening anaphylactoid reactions have been rarely reported for patients undergoing desensitising treatment with hymenoptera venom while receiving another ACE inhibitor. 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 desensitisation procedures.

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

Recent clinical observations have shown a high incidence of anaphylactoidlike reactions during haemodialysis with high flux dialysis membranes (e.g. AN69) /lipoprotein apheresis membrane or undergoing low-density lipoprotein apheresis with dextran sulphate absorption in patients receiving ACE inhibitors. Therefore, this combination should be avoided. In these patients, consideration should be given to using a different type of dialysis, membrane or a different class of medication.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS):

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Haematological:

Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving captopril. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Captopril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol, or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections which in a few instances did not respond to intensive antibiotic therapy.

If captopril is used in such patients, it is advised that white blood cell count and differential counts should be performed prior to therapy, every 2 weeks during the first three months of captopril therapy, and periodically thereafter. During treatment all patients should be instructed to report any sign of infection (e.g. sore throat, fever), when a differential white blood cell count should be performed. Captopril and other concomitant medication (see section 4.5) should be withdrawn if neutropenia (neutrophils < 1000/mm³) is detected or suspected.

In most patients neutrophil count rapidly returned to normal upon discontinuing captopril.

Surgery/anaesthesia:

In patients undergoing major surgery, or during anaesthesia with agents which produce hypotension, captopril will block angiotensin II formation secondary to compensatory renin release. This may lead to hypotension which can be corrected by volume expansion.

Diabetic patients:

The glycaemia levels should be closely monitored in diabetic patients previously treated with oral antidiabetic drugs or insulin, namely during the first month of treatment with an ACE inhibitor.

Risk of hypokalaemia: the combination of an ACE inhibitor with a thiazide diuretic does not rule out the occurrence of hypokalaemia. Regular monitoring of kalaemia should be performed.

Lactose:

This product contains lactose, therefore it should not be used in cases of congenital galactosaemia, glucose and galactose malabsorption or lactase deficiency syndromes (rare metabolic diseases).

Ethnic differences:

As with other angiotensin converting enzyme inhibitors, captopril is apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.

Pregnancy:

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

4.5 Interaction with other medicinal products and other forms of interaction

Diuretics:

Potassium sparing diuretics or potassium supplements: Diuretics potentiate the antihypertensive effectiveness of captopril. ACE inhibitors attenuate diuretic induced potassium loss.Potassium sparing diuretics (triamterene, amiloride and spironolactone), or potassium supplements, or potassium-containing salt substitutes may cause significant increase in serum potassium. If concomitant use is indicated because of demonstrated hypokalaemia they should be used with caution and with frequent monitoring of serum potassium (see section 4.4).

Thiazide or loop diuretics: Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with captopril (see section 4.4). The hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake or by initiating therapy with a low dose of captopril. However, no clinically significant drug interactions have been found in specific studies with hydrochlorothiazide or furosemide.

Other antihypertensive agents: Captopril has been safely co-administered with other commonly used anti-hypertensive agents (e.g. beta-blockers and long-acting calcium channel blockers). Concomitant use of these agents may increase the hypotensive effects of captopril. Treatment with nitroglycerine and other nitrates, or other vasodilators, should be used with caution.

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Alpha blocking agents: concomitant use of alpha blocking agents may increase the antihypertensive effects of captopril and increase the risk of orthostatic hypotension.

Treatments of acute myocardial infarction: Captopril may be used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics, beta-blockers and/or nitrates in patients with myocardial infarction.

Tricyclic antidepressants / Antipsychotics: ACE inhibitors may enhance the hypotensive effects of certain tricyclic antidepressants and antipsychotics (see section 4.4). Postural hypotension may occur.

Non-steroidal anti-inflammatory medicinal products: it has been described that non-steroidal anti-inflammatory medicinal products (NSAIDs) and ACE inhibitors exert an additive effect on the increase in serum potassium whereas renal function may decrease. These effects are, in principle, reversible. Rarely, acute renal failure may occur, particularly in patients with compromised renal function such as the elderly or dehydrated. Chronic administration of NSAIDs may reduce the antihypertensive effect of an ACE inhibitor.

Indomethacin: A reduction of antihypertensive effectiveness may occur. This is probably also the case with chronic administration of other non-steroidal anti-inflammatory drugs.

Vasodilators: Captopril has been reported to act synergistically with peripheral vasodilators such as minoxidil. Awareness of this interaction may avert an initial hypotensive response.

Sympathomimetics (Clonidine):It has been suggested that the antihypertensive effect of captopril can be delayed/reduced when patients treated with clonidine are changed to captopril. Patients should be carefully monitored.

Allopurinol, procainamide: There have been reports of neutropenia, an increased risk for leucopenia and/or Stevens-Johnson syndrome in patients on captopril plus either allopurinol or procainamide. Although a causal relationship has not been established, these combinations should only be used with caution, especially in patients with impaired renal function.

Cytostatic agents: Concomitant administration with ACE inhibitors may lead to an increased risk for leucopenia especially when used at higher than currently recommended doses.

Immunosuppressants: Azathioprine and cyclophosphamide have been associated with blood dyscrasias in patients with renal failure who were also taking captopril. Concomitant administration with ACE inhibitors may lead to an increased risk for leucopenia especially when used at higher than currently recommended doses.

Probenecid: The renal clearance of captopril is reduced in the presence of probenecid.

Lithium: Concomitant use of lithium and ACE-inhibitors may result in reversible increases in serum lithium concentration and toxicity. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased risk of lithium toxicity with ACE inhibitors. Use of captopril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see section 4.4)

Antidiabetics: Pharmacological studies have shown that ACE inhibitors, including captopril, can potentiate the blood glucose-reducing effects of insulin and oral antidiabetics such as sulphonylurea in diabetics. Should this very rare interaction occur, it may be necessary to reduce the dose of the antidiabetic during simultaneous treatment with ACE inhibitors.

Clinical chemistry: Captopril may cause false-positive urine test for acetone.

4.6 Fertility, pregnancy and lactation

Pregnancy:

Controlled studies with ACE inhibitors have not been done in humans, but limited number of cases of first trimester exposures have not shown malformations.

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. Controlled studies with ACE inhibitors have not been done in humans, but limited number of cases of first trimester exposures have not shown malformations.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) [see section 5.3]. Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).

Breast-feeding: Captopril is contraindicated in the lactation period. Limited pharmacokinetic data demonstrate very low concentrations in breast milk (see section 5.2). Although these concentrations seem to be clinically irrelevant, the use of captopril tablets in breastfeeding is not recommended for preterm infants and for the first few weeks after delivery, because of the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience.

In the case of an older infant, the use of captopril tablets in a breast-feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect

4.7 Effects on ability to drive and use machines

The treatment of high blood pressure with this medication requires regular medical monitoring.

As with other antihypertensives, the ability to drive and use machines may be reduced, namely at the start of the treatment, or when posology is modified, and also when used in combination with alcohol, but these effects depend on the individual’s susceptibility.

4.8 Undesirable effects

The following side effects were observed during therapy with captopril and other ACE inhibitors:

Adverse reactions are ranked according to frequency using the following convention: Very common (>1/10), Common (>1/100 to <1/10), Uncommon (>1/1,000 to <1/100), Rare (>1/10,000 to <1/1,000), Very rare (<1/10,000), not known (cannot be estimated from the available data).

Undesirable effects reported for captopril and/or ACE inhibitor therapy include:

Blood and lymphatic disorders:

Very rare: neutropenia/agranulocytosis (see section 4.4), pancytopenia particularly in patients with renal dysfunction (see section 4.4), anaemia (including aplastic and haemolytic), thrombocytopenia (see section 4.4), lymphadenopathy eosinophilia, auto-immune diseases and/or a positive ANA-titres.

Immune system disorders

Unknown: serum sickness

Metabolism and nutrition disorder:

Rare: anorexia

Very rare: hyperkalaemia, hypoglycaemia (see section 4.4)

Unknown: acidosis (see section 4.4).

Psychiatric disorders:

Common: sleep disorders Very rare: confusion, depression.

Nervous system disorders:

Common: reversible and self-limiting taste impairment (weight loss may be associated with the loss of taste) and dizziness.

Rare: drowsiness, headache and paraesthesia (paraesthesias of the hands).

Very rare: cerebrovascular incidents, including stroke, and syncope.

Eye disorders:

Very rare: blurred vision

Cardiac disorders:

Uncommon: tachycardia or tachyarrhythmia, angina pectoris, palpitations.

Very rare: cardiac arrest, cardiogenic shock.

Vascular disorders:

Uncommon: hypotension (see section 4.4), Raynaud syndrome, flush, pallor. Respiratory, thoracic and mediastinal disorders:

Common: dry, irritating (non-productive) cough (see section 4.4) and dyspnoea,

Very rare: bronchospasm, rhinitis, allergic alveolitis / eosinophilic pneumonia. Gastrointestinal disorders:

Common: nausea, vomiting, gastric irritation, diarrhoea, constipation, dry mouth and abdominal pain.

Rare: intestinal angioedema, stomatitis, resembling aphthous ulcers. Pancreatitis has been reported rarely in patients treated with ACE inhibitors; in some cases this has proved fatal

Very rare: glossitis, peptic ulcer

Hepato-biliary disorders:

Rare: cases of hepatocellular injury and cholestatic jaundice.

Very rare: impaired hepatic function, hepatitis including necrosis. Elevation of liver enzymes and elevated bilirubin has been noted in a few patients.

Skin and subcutaneous tissue disorders:

Common: rashes, pruritus with or without a rash, and alopecia may occur. They are usually mild, transient and maculopapular, rarely urticarial and disappear within a few days of dosage reduction, short-term treatment with an antihistamine and/or discontinuing therapy. In a few cases the rash has been associated with fever.

Uncommon: angioedema (see section 4.4)

Very rare: urticaria, Stevens Johnson syndrome, erythema multiforme, photosensitivity, erythroderma, pemphigoid reactions and exfoliative dermatitis.

Unknown: vesicular or bullous rash, have been reported.

Musculoskeletal, connective tissue and bone disorders:

Very rare: myalgia, arthralgia.

Renal and Urinary Disorders:

Rare: renal function disorders including renal failure, polyuria, oliguria, increased urine frequency.

Very rare: nephrotic syndrome.

Reproductive system and breast disorders:

Very rare: impotence, gynaecomastia.

General disorders and administration site conditions:

Uncommon: chest pain, fatigue, malaise Very rare: fever

Investigations:

Very rare: proteinuria, decrease of serum sodium, elevation of BUN, elevated blood urea and creatinine, elevated serum potassium and serum bilirubin, decreases in haemoglobin, haematocrit, leucocytes, thrombocytes, elevated ESR, eosinophilia, and positive ANA-titre.

Idiosyncratic:

Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis, or larynx has been seen in patients treated with ACE inhibitors, including captopril. In this, situation, the ACE inhibitors should be discontinued. Where swelling is confined to the face, lips and mouth, the condition will usually resolve without further treatment, although antihistamines may be useful in relieving the symptoms. These patients should be followed carefully until the swelling has resolved. However, where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, subcutaneous adrenaline (0.5 mL, 1:1,000) should be administered promptly where indicated.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov .uk/yellowcard.

4.9 Overdose

Symptoms

Depending on the degree of overdosage, the following symptoms are possible: bradycardia, electrolyte disturbances, severe hypotension, circulatory shock, renal failure and stupor.

Management

Measures to prevent absorption (e.g. gastric lavage, administration of adsorbents and sodium sulphate within 30 minutes after intake) and hasten elimination should be applied if ingestion is recent. If hypotension occurs, the patient should be placed in the shock position and salt and volume supplementations should be given rapidly. Treatment with angiotensin-II should be considered. Bradycardia or extensive vagal reactions should be treated by administering atropine. The use of a pacemaker may be considered. Captopril may be removed from circulation by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: - Agents acting on the renin-angiotensin system, ACE Inhibitors, plain.

ATC Code: C09A A01.

Captopril inhibits angiotensin converting enzyme. The angiotensin converting enzyme (ACE) is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I into the vasoconstrictive drug angiotensin II. An inhibition of ACE causes a diminished formation of vasoconstrictive angiotensin II in tissue and plasma while a decrease in aldosterone secretion and an increase in the serum potassium concentration may occur. An enhanced activity of the plasma renin level results from the deficient negative feedback effect of angiotensin II on the renin secretion.

As ACE also degrades bradykinine, a vasodepressor peptide, an increased activity of circulating and local kallikrein-kinine-systems (and with that an activation of prostaglandin synthesis) are caused by the inhibition of ACE.

It is possible that this mechanism takes part in the blood-pressure-lowering action of ACE inhibitors and is jointly responsible for special side effects.

Reductions of blood pressure are usually maximal 60 to 90 minutes after oral administration of an individual dose of captopril. The duration of effect is dose related. The reduction in blood pressure may be progressive, so to achieve maximal therapeutic effects, several weeks of therapy may be required. The blood pressure lowering effects of captopril and thiazide-type diuretics are additive.

In patients with hypertension, captopril causes a reduction of the blood pressure in standing and lying without a compensatory increase in heart frequency, nor water and sodium retention.

Haemodynamically, captopril caused a significant reduction of the arterial peripheral resistance. Generally, no clinically relevant changes of the renal plasma flow and glomerular filtration rate occurred. In most patients, the antihypertensive effect started about 15-30 minutes after oral administration of captopril, the maximum efficacy was achieved within 60-90 minutes. The maximum blood-pressure-lowering effect is reached after 3-4 weeks.

With the recommended daily dosage, the antihypertensive effect continues even during long-term therapy. Short-term discontinuation of captopril does not cause a quick excessive increase in blood pressure (rebound effect). The treatment of hypertension with captopril leads also to a decrease in left ventricular hypertrophy.

In patients with cardiac insufficiency, haemodynamic investigations demonstrated a decrease in the systemic peripheral resistance and an increase in the venous capacity. The results of these effects are a reduction of the pre-and afterload of the heart (diminution of ventricular filling pressures). Furthermore, the cardiac output, the stroke work index and the exercise capacity were increased during therapy with captopril. In a large, placebo-controlled study in patients with left ventricular dysfunction (LVEF < 40%) following myocardial infarction, it was shown that captopril (initiated between the 3^rd to the 16^th day after infarction) prolonged the survival time and reduced cardiovascular mortality. The latter was manifested as a delay in the development of symptomatic heart failure and a reduction in the necessity for hospitalisation due to heart failure compared to placebo. There was also a reduction in re-infarction and in cardiac revascularisation procedures and/or in the need for additional medication with diuretics and/or digitalis or an increase in their dosage compared to placebo.

A retrospective analysis showed that captopril reduced recurrent infarcts and cardiac revascularisation procedures (neither were target criteria of the study).

Another large, placebo-controlled study in patients with myocardial infarction showed that captopril (given within 24 hours of the event and for duration of one month) significantly reduced overall mortality after 5 weeks compared to placebo. The favourable effect of captopril on total mortality was still detectable even after one year. No indication of a negative effect in relation to early mortality on the first day of treatment was found.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Captopril cardioprotection effects are observed regardless of the patient’s age or gender, location of the infarction and concomitant treatments with proven efficacy during the post-infarction period (thrombolytic agents, beta-blockers and acetylsalicylic acid).

5.2 Pharmacokinetic properties

Captopril is an orally active agent that does not require biotransformation for activity. The average minimal absorption is approximately 75%. Peak plasma concentrations are reached within 60-90 minutes. The presence of food in the gastrointestinal tract reduces absorption by about 30-40%. Plasma protein binding is 25-30%. In healthy probands, the average distribution volume in the steady state is approximately 0.7 L/kg. It may rise to 2.05 L/kg due to an enhanced captopril uptake into different types of tissue.

Captopril is metabolised to inactive disulfides to an extent of approximately 50%. The elimination half-life of the unchanged captopril is approximately 2 hours, that of the S-bound captopril approx. 12 hours. 95% of captopril is excreted via the urine within 24 hours: 40-50% as unchanged substance, 50-60% as captopril disulfide and captopril cystein disulfide.

In cases of impaired renal function, the elimination rate of captopril is lowered. In these cases, the dosage is to be reduced or the dosage intervals are to be prolonged (see section 4.2).

Studies in animals indicate that captopril does not cross the blood-brain barrier to any significant extent.

Bioavailability

A bioavailability study which was conducted in 1995 with 24 male subjects revealed the following results in comparison to the reference preparation when using captopril tablets 50 mg as a single dose and administering 2 x 50 mg captopril.

The values are calculated as arithmetic means and range of scatter (standard deviation).

Lactation:

In the report of twelve women taking oral captopril 100 mg 3 times daily, the average peak milk level was 4.7 gg/L and occurred 3.8 hours after the dose. Based on these data, the maximum daily dosage that a nursing infant would receive is less than 0.002% of the maternal daily dosage.

5.3 Preclinical safety data

Acute Toxicity

LD50 values of captopril (in mg/kg body weight).

Animal	Mode of administration
	Oral	IP	IV
Rat	6000	450	1000
Mouse	6000	380	-

Mice with induced hepatic or renal disturbances are about doubly as sensitive as normal animals.

Oral single doses of 300 mg/kg body weight (dog) and 500 mg/kg body weight (monkey) caused vomiting and decreased blood pressure.

Chronic Toxicity

Acute and chronic toxicological studies have been performed with captopril.

Long term carcinogenicity studies in the rat and mouse gave no evidence for a tumorgenic potential.

Reproductive Toxicology (Teratogenicity)

Captopril passes the placental barrier and is excreted into the mother's milk. In experiments in animals, no evidence of teratogenic properties of captopril was shown. Toxic effects on the progeny occurred for instance in the second half of pregnancy due to an increase in fetolethality. Treatment during the peri- and postnatal period caused a delayed growth in rats and an enhanced rate of mortality in young animals. The parental fertility was not affected.

In humans, the experience of the safety of administration during pregnancy is insufficient based on conventional studies of safety pharmacology, repeated dose toxicology, genotoxicity and carcinogenicity. In the last years cases a foetal syndrome with the following symptoms was described in connection with ACE inhibitors:

severe hypoplasia of cranial bones, intrauterine growth retardation, oligohydramnios, neonatal anuria. This syndrome can even cause death in the newborns. The hypotensive effect on the foetuses during the second and third trimester of pregnancy is supposed to be the reason. These effects are not to be expected when therapy is switched to other blood-pressure-lowering drugs in time during the first trimester of pregnancy.

Preclinical data reveal no other specific hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicology, genotoxicity and carcinogenicity.

6    PHARMACEUTICAL PARTICULARS

6.1 List of excipients

maize starch

microcrystalline cellulose lactose monohydrate stearic acid

6.2. Incompatibilities

None known

6.3    Shelf life

3 years.

6.4. Special precautions for storage

Store below 25°C.

6.5 Nature and contents of container

Polypropylene blisters backed by hard temper aluminium foil.

Pack sizes: 28, 56 or 100 tablets.

Additional

or 250 micron pvdc coated pvc welded on a 20 micron internally film-coated aluminium semi-rigid support.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements

7. MARKETING AUTHORISATION HOLDER

Tillomed Laboratories Ltd 3 Howard Road Eaton Socon, St Neots Cambridgeshire PE19 8ET UK

8. MARKETING AUTHORISATION NUMBER

PL 11311/0062

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

Date of first authorisation:15/03/1997 Date of renewal: 13/03/2009

10 DATE OF REVISION OF THE TEXT

02/02/2015