CAPTOPRIL 5 MG / 5 ML ORAL SOLUTION - Summary of medicine characteristics

Captopril 5 mg/5 ml Oral Solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of 5 mg/5 ml oral solution contains 1 mg captopril

Excipients with known effects:

This medicinal product contains 93.81 mg sodium per maximum daily dose.

This medicinal product contains 0.625 mg sodium per ml.

This medicinal product contains 0.5 mg sodium benzoate per ml.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral solution

Clear, colourless solution

4.1 Therapeutic indications

Hypertension

Captopril is indicated for the treatment of essential hypertension

Heart failure

Captopril is indicated for the treatment of chronic heart failure

Myocardial Infarction:

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

Long-term prevention of symptomatic heart failure: Captopril is indicated in clinically stable patients with asymptomatic left ventricular dysfunction.

Type I Diabetic Nephropathy

Captopril is indicated for the treatment of macroproteinuric diabetic nephropathy in patients with type I diabetes.

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 150mg.

Captopril may be taken before, during and after meals.

Hypertension

The recommended starting dose is 25–50mg daily in two divided doses. The dose may be increased incrementally, with intervals of at least 2 weeks, to 100–150mg/day in two divided doses as needed to reach target blood pressure. Captopril may be used alone or with other antihypertensive agents, especially thiazide diuretics (see sections 4.3, 4.4, 4.5 and 5.1). A once-daily dosing regimen may be appropriate when concomitant antihypertensive medication such as thiazide diuretics is added.

In patients with a strongly active renin-angiotensin-aldosterone system (hypovolaemia, renovascular hypertension, cardiac decompensation) it is preferable to commence with a single dose of 6.25mg or 12.5mg. The inauguration of this treatment should preferably take place under close medical supervision. These doses will then be administered at a rate of two per day. The dosage can be gradually increased to 50mg per day in one or two doses and if necessary to 100mg per day in one or two doses.

Heart failure

Treatment with captopril for heart failure should be initiated under close medical supervision. The usual starting dose is 6.25mg – 12.5mg BID or TID. Titration to the maintenance dose (75 – 150mg per day) should be carried out based on patient's response, clinical status and tolerability, up to a maximum of 150mg 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 6.25mg test dose should be administered, with a 12.5mg dose being administered 2 hours afterwards and a 25mg dose 12 hours later. From the following day, captopril should be administered in a 100mg/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 3rd and 16th 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 75mg 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 6.25mg followed by 12.5mg 3 times daily for 2 days and then 25mg 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 150mg 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.

Type I Diabetic nephropathy

In patients with type I diabetic nephropathy, the recommended daily dose of captopril is 75–100mg in divided doses. If additional lowering of blood pressure is desired, additional antihypertensive medications may be added.

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. When concomitant diuretic therapy is required, a loop diuretic (e.g. furosemide), rather than a thiazide diuretic, is preferred in patients with severe renal impairment.

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

Elderly patients

As with other antihypertensive agents, consideration should be given to initiating therapy with a lower starting dose (6.25mg BID) in elderly patients who may have reduced renal function and other organ dysfunctions.

Dosage should be titrated against the blood pressure response and kept as low as possible to achieve adequate control.

Paediatric population

The efficacy and safety of captopril have not been fully established. The use of captopril in children and adolescents should be initiated under close medical supervision. The initial dose of captopril is about 0.3mg/kg body weight to be divided in 3 equal doses 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 0.15mg captopril/kg weight per day. Generally, captopril is administered to children 3 times a day, but dose and interval of dose should be adapted individually according to patient's response.

Method of administration

For oral use only.

Open the bottle and insert the syringe firmly into the adaptor opening.

Turn the bottle upside down with the syringe still in place.

Pull the plunger down and fill the syringe with a small amount of solution. Push the piston upward in order to remove any possible air bubbles.

Pull the piston down to the graduation mark corresponding to the quantity in millilitres (ml) prescribed by your doctor.

Turn the bottle the right way up. Remove the syringe from the adaptor. Administer the contents of the syringe into the mouth by pushing the piston to the bottom of the syringe and ensure the medicine is swallowed.

Close the bottle with the plastic screw cap. Wash the syringe and the cup with warm water after use. Dry the syringe and the cup with a clean paper towel and replace into the box with your medicine.

Once titrated to an effective dose of Captopril, patients should remain on their treatment and extreme caution should be exercised when changing between different formulations.

4.3 Contraindications

– History of hypersensitivity to captopril, to any of the excipients or any other ACE inhibitor.

– History of angioedema associated with previous ACE inhibitor therapy.

– Hereditary / idiopathic angioneurotic oedema.

– Second and third trimester of pregnancy (see sections 4.4 and 4.6)

– 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 m2) (see sections 4.5 and 5.1).

Concomitant use with sacubitril/val­sartan therapy. This medicinal product must not be initiated earlier than 36 hours after the last dose of sacubitril/val­sartan (see also sections 4.4 and 4.5).

4.4 Special warnings and precautions for use

Hypotension

Rarely hypotension is observed in uncomplicated hypertensive patients. 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.

Patients with heart failure are at higher risk of hypotension and a lower starting dose is recommended when initiating therapy with an ACE inhibitor. The magnitude of the decrease is greatest early in the course of treatment; this effect stabilises within a week or two, and generally returns to pre-treatment levels, without a decrease in therapeutic efficacy, within two months. Caution should be used whenever the dose of captopril or diuretic is increased in patients with heart failure.

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.

Infants, especially new-borns, 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.

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.

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.

AngioedemaAngi­oedema of the extremities, face, lips, mucous membranes, tongue, glottis or larynx may occur in patients treated with ACE inhibitors including Captopril. This may occur anytime during treatment. However, in rare cases, severe angioedema may develop after long-term treatment with an ACE inhibitor. In such cases, Captopril 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. 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).

Hypersensitivi­ty/Angioedema

Concomitant use of ACE inhibitors with sacubitril/val­sartan is contraindicated due to the increased risk of angioedema. Treatment with sacubitril/val­sartan must not be initiated earlier than 36 hours after the last dose of this medicinal product. Treatment with this medicinal product must not be initiated earlier than 36 hours after the last dose of sacubitril/val­sartan (see sections 4.3 and 4.5).

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5). Caution should be used when starting racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin in a patient already taking an ACE inhibitor.

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

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including captopril.

ACE inhibitors can cause hyperkalemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. However, in patients with impaired renal function, diabetes mellitus and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, or those patients taking other drugs associated with increases in serum potassium (e.g. heparin, trimethoprim or co-trimoxazole also known as trimethoprim/sul­famethoxazole) and especially aldosterone antagonists or angiotensin-receptor blockers, hyperkalaemia can occur. If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended.

Potassium-sparing diuretics and angiotensin-receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored (see section 4.5).

Combination with lithium

Captopril is not recommended in association with lithium due to the potentiation of lithium toxicity (see section 4.5).

Aortic and mitral valve stenosis/Obstruc­tive hypertropic cardiomyopathy ACE inhibitors should be used with caution in patients with left ventricular valvular and outflow tract obstruction and avoided in cases of cardiogenic shock and haemodynamically significant obstruction.

Neutropenia/A­granulocytosis

Neutropenia/a­granulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors, including 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 3 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 less than 1000/mm3) is detected or suspected. In most patients neutrophil counts rapidly return to normal upon discontinuing captopril.

Proteinuria

Proteinuria may occur particularly in patients with existing renal function impairment or on relatively high doses of ACE inhibitors.

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 150mg/day), or both. Nephrotic syndrome occurred in about one-fifth of proteinuric patients. 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 (dip-stick on first morning urine) prior to treatment, and periodically thereafter.

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

Anaphylactoid reactions have been reported in patients haemodialysed with high-flux dialysis membranes or undergoing low-density lipoprotein apheresis with dextran sulphate absorption. In these patients, consideration should be given to using a different type of dialysis, membrane or a different class of medication.

Surgery/Anaesthesia

Hypotension may occur in patients undergoing major surgery or during treatment with anaesthetic agents that are known to lower blood pressure. If hypotension occurs, it may 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.

Renal function in patients with heart failure

Some patients may develop stable elevations of BUN and serum creatinine >20% above normal or baseline upon long-term treatment with captopril. A few patients, generally those with severe pre-existing renal disease, required discontinuation of treatment due to progressively increasing creatinine.

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.

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).

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.

Paediatric population

Neonates

The neonatal response to treatment with ACE inhibitors is very variable, and some neonates develop profound hypotension with even small doses. Adverse effects such as apnoea, seizures, renal failure, and severe unpredictable hypotension are very common in the first month of life and it is therefore recommended that ACE inhibitors are used with caution, particularly in preterm neonates.

Oliguria is a risk in premature patients treated with captopril.

Routine monitoring of infants on ACE inhibitors should include renal function tests, blood pressure and transcutaneous oxygen saturation measurements.

Older Children

As with neonates, older children can experience severe hypotension on administration of captopril. Routine monitoring should include test for renal function. Dosages should be reduced in patients with impaired renal function.

As Captopril oral solution does not contain a taste masking agent, there is the possibility of patient non-compliance, and this should be monitored to ensure proper dosing.

Captopril oral solution is available in two strengths 5mg/5ml and 25mg/5ml; caution is advised in ensuring that the correct strength is given to the patient. The doctor should prescribe the most appropriate strength based upon the clinical requirements of the patient (see section 4.2).

Sodium

This medicinal product contains 93.8 mg sodium per maximum daily dose.

This medicinal product contains 0.625 mg sodium per ml equivalent to 0.031 % of the WHO recommended maximum daily intake of 2 g sodium for an adult

Sodium benzoate

Sodium benzoate may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).

This medicine contains 0.5 mg sodium benzoate in each ml.

4.5 Interaction with other medicinal products and other forms of interaction

Medicines increasing the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/val­sartan is contraindicated as this increases the risk of angioedema (see sections 4.3 and 4.4).

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors1 (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk for angioedema (see section 4.4).

Potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes

Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with captopril. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Care should also be taken when captopril is co-administered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sul­famethoxazole) as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Therefore, the combination of captopril with the above-mentioned drugs is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium.

Diuretics (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 antihypertensive 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.

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. 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).

Tricyclic antidepressan­ts/Antipsycho­tics

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

Allopurinol, procainamide, cytostatic or immunosuppres­sive agents

Concomitant administration with ACE inhibitors may lead to an increased risk for leucopenia especially when the latter are used at higher than currently recommended doses.

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.

Sympathomimetics

May reduce the antihypertensive effects of ACE inhibitors; patients should be carefully monitored.

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.

Ciclosporin

Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.

Heparin

Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.

Clinical Chemistry

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

4.6 Fertility, pregnancy and lactation

Pregnancy

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy (see section 4.3 and 4.4).

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. Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human fetotoxicity (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).

Breastfeeding

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 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 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.

Fertility

Very limited data are available on the effect on fertility.

4.7 Effects on ability to drive and use machines

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

Frequency is defined using the following convention: common (> 1/100, < 1/10), uncommon (> 1/1,000, < 1/100), rare (> 1/10,000, < 1/1,000) and very rare (< 1/10,000).

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, lymphadenopathy, eosinophilia, auto-immune diseases and/or positive ANA-titres.

Metabolism and nutrition disorders

Rare: anorexia

Very rare: hyperkalaemia, hypoglycaemia (see section 4.4)

Psychiatric disorders

Common: sleep disorders

Very rare: confusion, depression.

Nervous system disorders

Common: taste impairment, dizziness

Rare: drowsiness, headache and paraesthesia

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 irritations, abdominal pain, diarrhoea, constipation, dry mouth. Rare: stomatitis/aphthous ulcerations, intestinal angioedema (see section 4.4).

Very rare: glossitis, peptic ulcer, pancreatitis.

Hepato-biliary disorders

Very rare: impaired hepatic function and cholestasis (including jaundice), hepatitis including necrosis, elevated liver enzymes and bilirubin.

Skin and subcutaneous tissue disorders

Common: pruritus with or without a rash, rash, and alopecia.

Uncommon: angioedema (see section 4.4)

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

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, eosinophilia, increase of serum potassium, decrease of serum sodium, elevation of BUN, serum creatinine and serum bilirubin, decreases in haemoglobin, haematocrit, leucocytes, thrombocytes, positive ANA-titre, elevated ESR.

Paediatric population

Adverse effects such as apnoea, seizures, renal failure, and severe unpredictable hypotension are very common in the first month of life and it is therefore recommended that ACE inhibitors are used with caution; particularly in preterm neonates (see section 4.4).

Oliguria is a risk in premature patients treated with captopril (see section 4.4).

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 Website at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms of overdosage are severe hypotension, shock, stupor, bradycardia, electrolyte disturbances and renal failure.

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

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ACE inhibitors, plain, ATC code: C09AA01.

Captopril is a highly specific, competitive inhibitor of angiotensin-I converting enzyme (ACE inhibitors).

The beneficial effects of ACE inhibitors appear to result primarily from the suppression of the plasma renin- angiotensin-aldosterone system. Renin is an endogenous enzyme synthesised by the kidneys and released into the circulation where it converts angiotensinogen to angiotensin-I a relatively inactive decapeptide. Angiotensin-I is then converted by angiotensin converting enzyme, a peptidyldipep­tidase, to angiotensin-II. Angiotensin-II is a potent vasoconstrictor responsible for arterial vasoconstriction and increased blood pressure, as well as for stimulation of the adrenal gland to secrete aldosterone. Inhibition of ACE results in decreased plasma angiotensin-II, which leads to decreased vasopressor activity and to reduce aldosterone secretion. Although the latter decrease is small, small increases in serum potassium concentrations may occur, along with sodium and fluid loss. The cessation of the negative feedback of angiotensin-II on the renin secretion results in an increase of the plasma renin activity.

Another function of the converting enzyme is to degrade the potent vasodepressive kinin peptide bradykinin to inactive metabolites. Therefore, inhibition of ACE results in an increased activity of circulating and local kallikrein-kinin-system which contributes to peripheral vasodilation by activating the prostaglandin system; it is possible that this mechanism is involved in the hypotensive effect of ACE inhibitors and is responsible for certain adverse reactions.

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 in supine and erect blood pressure, without inducing any compensatory increase in heart rate, nor water and sodium retention.

In haemodynamic investigations, captopril caused a marked reduction in peripheral arterial resistance. In general there were no clinically relevant changes in renal plasma flow or glomerular filtration rate. In most patients, the antihypertensive effect began about 15 to 30 minutes after oral administration of captopril; the peak effect was achieved after 60 to 90 minutes. The maximum reduction in blood pressure of a defined captopril dose was generally visible after three to four weeks.

In the recommended daily dose, the antihypertensive effect persists even during long-term treatment. Temporary withdrawal of captopril does not cause any rapid, excessive increase in blood pressure (rebound). The treatment of hypertension with captopril leads also to a decrease in left ventricular hypertrophy.

Haemodynamic investigations in patients with heart failure showed that captopril caused a reduction in peripheral systemic resistance and a rise in venous capacity. This resulted in a reduction in pre-load and after-load of the heart (reduction in ventricular filling pressure). In addition, rises in cardiac output, work index and exercise capacity have been observed during treatment 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 3rd to the 16th 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.

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).

Type I diabetic nephropathy

In a placebo-controlled, multicentre double blind clinical trial in insulindependent (Type I) diabetes with proteinuria, with or without hypertension (simultaneous administration of other antihypertensives to control blood pressure was allowed), captopril significantly reduced (by 51%) the time to doubling of the baseline creatinine concentration compared to placebo; the incidence of terminal renal failure (dialysis, transplantation) or death was also significantly less common under captopril than under placebo (51%). In patients with diabetes and microalbuminuria, treatment with captopril reduced albumin excretion within two years.

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.

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.

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%.

Approximately 25–30% of the circulating drug is bound to plasma proteins.The apparent elimination half-life of unchanged captopril in blood is about 2 hours. Greater than 95% of the absorbed dose is eliminated in the urine within 24 hours; 40–50% is unchanged drug and the remainder are inactive disulphide metabolites (captopril disulphide and captopril cysteine disulphide). Impaired renal function could result in drug accumulation. Therefore, in patients with impaired renal function the dose should be reduced and/or dosage interval prolonged (see section 4.2).

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

Lactation

In the report of twelve women taking oral captopril 100mg 3 times daily, the average peak milk level was 4.7pg/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

Animal studies performed during organogenesis with captopril have not shown any teratogenic effect but captopril has produced fetal toxicity in several species, including foetal mortality during late pregnancy, growth retardation and postnatal mortality in the rat. 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

Disodium edetate

Sodium benzoate (E211)

Sodium citrate (E331)

Citric acid monohydrate (E330) Water, purified

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

18 months

After first opening: 1 month

6.4 Special precautions for storage

Do not store above 30°C.

Do not freeze.

Store in the original package in order to protect from light.

6.5 Nature and contents of container

Amber glass bottle with child resistant screw cap with a polyethylene adaptor. The bottle is packed in a carton containing 1 ml and 5 ml oral syringes.

Pack size: 100 ml

6.6 Special precautions for disposal

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

TEVA UK Limited Brampton Road, Hampden Park, Eastbourne, East Sussex, BN22 9AG, United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 00289/2155