4.1. Therapeutic indications

Hypertension: Captopril oral solution is indicated for the treatment of hypertension.

Heart Failure: Captopril oral solution is indicated for the treatment of chronic heart failure with reduction of systolic ventricular function, in combination with diuretics and, when appropriate, digitalis and beta-blockers.

Myocardial Infarction:

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

- long-term prevention of symptomatic heart failure: Captopril oral solution is indicated in clinically stable patients with asymptomatic left ventricular dysfunction (ejection fraction equal to or below 40%).

Type I Diabetic Nephropathy: Captopril oral solution is indicated for the treatment of macroproteinuric diabetic nephropathy in patients with type I diabetes. (See section 5.1).

4.2. Posology and method of administration

Captopril Oral Solution is available in two strengths 5mg/5ml and 25mg/5ml;

For lower doses that include fractions of a mg, the 5mg/5ml product should be used.

For higher doses the 25mg/5ml product is recommended.

The following table provides a guide for using Captopril 5mg/5ml or Captopril 25mg/5ml for most common dose.

Dose

Captopril 5mg/5ml

Captopril 25mg/5ml

Adult population

6.25 mg

6.25ml

12.5 mg

12.5 ml

25 mg

5ml

37.5 mg

7.5ml

50mg

10ml

75mg

15ml

100mg

20ml

150mg

30ml

Paediatric population

0.15mg/kg

0.15ml/kg

0.3mg/kg

0.3ml/kg

For further information on measuring the dose please see section 6.5

The 5mg/5ml product is supplied with the following administration devices:

• 1 mL syringe graduated with numbered increments of 0.1mL (= 0.1 mg captopril) and intermediate increments of 0.05mL (= 0.05mg captopril)

• 5mL syringe graduated with numbered increments of 1mL (= 1mg captopril) and intermediate increments of 0.2mL (= 0.2mg captopril).

The 25mg/5ml product is supplied with the following administration devices:

• 5mL syringe graduated with numbered increments of 1mL (= 5mg captopril) and intermediate increments of 0.2mL (= 1mg captopril).

• 30 mL measuring cup graduated in numbered increments of 5 mL (= 25mg captopril) and intermediate increments of 1mL (= 5mg captopril).

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.

Captopril oral solution may be taken before, during and after meals.

Hypertension: the recommended starting dose is 25-50 mg daily in two divided doses. The dose may be increased incrementally, with intervals of at least 2 weeks, to 100-150 mg/day in two divided doses as needed to reach target blood pressure. Captopril oral solution 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 6.25 mg or 12.5 mg. 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 50 mg per day in one or two doses and if necessary to 100 mg 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 6.25 mg - 12.5 mg BID or TID. 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 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 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.

Type I Diabetic nephropathy: in patients with type I diabetic nephropathy, the recommended daily dose of captopril is 50-100 mg in two or three divided doses. If additional lowering of blood pressure is desired, additional antihypertensive medications may be added (see sections 4.3, 4.4, 4.5 and 5.1).

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.

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

Elderly patients: as with other antihypertensive agents, consideration should be given to initiating therapy with a lower starting dose (6.25 mg BID) in elderly patients who may have reduced renal function and other organ dysfunctions (see above and section 4.4).

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 as older children and adults) the starting dose should be only 0.15mg captopril/kg weight. 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

Switching between Captopril and other captopril formulations:

Once titrated to an effective dose of Captopril Oral Solution, patients should remain on their treatment and re-titration should be performed when changing between Captopril and other captopril formulations.

4.3. Contraindications

- Hypersensitivity to captopril, to any other ACE inhibitor or to any of the excipients (see section 6.1)

- History of angioedema associated with previous ACE inhibitor therapy

- Hereditary/idiopathic angioneurotic oedema

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

- The concomitant use of Captopril oral solution 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. Captopril 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. 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.

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.

Hypersensitivity/angioedema:

Angioneurotic oedema of the extremities, face, lips, mucous membranes, tongue, glottis and/or larynx may occur in patients treated with ACE inhibitors particularly during the first week of treatment. However, in rare cases, severe angioedema may develop after long-term treatment with an ACE inhibitor. Treatment should be discontinued promptly. 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.

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 captopril. Treatment with captopril 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 gliptins (e.g. vildagliptin) in a patient already taking an ACE inhibitor.

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

Intestinal angioedema

Intestinal angioedema has also been reported very 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.

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, hyperkalemia 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.”

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:

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 and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim or co-trimoxazole also known as trimethoprim/sulfamethoxazole and especially aldosterone antagonists or angiotensin-receptor blockers, hyperkalemia can occur. 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:

The combination of lithium and captopril is not recommended (see section 4.5)

Aortic and mitral valve stenosis / Obstructive hypertrophic 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.

Anaemia:

Anaemia with reduced haemoglobin level was reported in renal transplant or haemodialysis patients. The reduction was grater in patients with higher baseline levels. Anaemia does not appear to be dose-dependent, however it is linked to ACE inhibitors mechanism of action. The reduction is moderate and occurs within 1 to 6 months, after it remains stable. It is reversible upon captopril discontinuation.

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 150 mg/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 adsorption. 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. Captopril should be stopped a day before the surgery. 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.

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)

Sodium:

This medicine contains less than 1 mmol sodium (23 mg) per ml that is to say essentially 'sodium-free'.

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.

Paediatric Population:

Neonates:

The neonatal response to treatment with ACE inhibitors is very variable, and some neonates develop profound hypotension with even small doses; a test-dose should be used initially and increased cautiously. 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. A small initial test dose should be administered with the patient supine, in order to avoid severe hypotension and tachycardia. As with adults hyperkalaemia may occur in conjunction with potassium sparing diuretics. Routine monitoring should include test for renal function. Dosages should be reduced in patients with impaired renal function.

Leukopenia has been reported in children with renal impairment treated with captopril.

Compliance:

As Captopril Oral Solution does not contain a taste or smell masking agent, there is the possibility of patient non-compliance, and this should be monitored to ensure proper dosing. Patients should be informed that Captopril oral solution may have a slight sulphurous odour, which does not suggest product deterioration or that the product is unsuitable for use.

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).

4.5. Interaction with other medicinal products and other forms of interaction

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 (see section 4.4).

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.

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 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.

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 immuno-suppressive 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.

Tricyclic anti-depressants, neuroleptics, amifostine, baclofen:

Co-administration of these drugs with captopril may potentially increase antihypertensive effects and risk of postural hypotension.

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 a false-positive urine test for acetone.

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

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).

Gold

In rare cases, nitritoid reactions with symptoms such as flushing, dizziness, nausea, vomiting and drop in blood pressure up to circulatory collapse have been observed in patients treated with ACE inhibitors and injectable gold preparation preparations (sodium aurothiomalate) at the same time.

Medicines increasing the risk of angioedema

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

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

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 sections 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).

Lactation:

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 Oral Solution in breast-feeding 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 Oral Solution 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

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 table below lists adverse reactions reported with Captopril, ranked under the following frequency classification:

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).

Within each frequency, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions with Captopril in clinical trials and post-marketing experience

Frequency

Common

Uncommon

Rare

Very rare

System organ class

Blood and lymphatic system disorders

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

Anorexia

Hyperkalaemia, hyponatraemia, hypoglycemia (see section 4.4)

Psychiatric disorders

Sleep disorders

Confusion, depression

Nervous system disorders

Taste impairment, dizziness

Drowsiness, headache and paraesthesia

Cerebrovascular incidents, including stroke, and syncope

Eye disorders

Blurred vision

Cardiac disorders

Tachycardia or tachyarrhythmia, angina pectoris, palpitations

Cardiac arrest, cardiogenic shock

Vascular Disorders

Hypotension (see section 4.4), Raynaud syndrome, flush, pallor

Respiratory, thoracic and mediastinal disorders

Dry, irritating (non-productive) cough (see section 4.4) and dyspnoea

Bronchospasm, rhinitis, allergic alveolitis/ eosinophilic pneumonia

Gastrointestinal disorders

Nausea, vomiting, gastric irritations, abdominal pain, diarrhoea, constipation, dry mouth

Intestinal angioedema (see section 4.4), Stomatitis/ aphthous ulcerations

glossitis, peptic ulcer, pancreatitis

Hepatobiliary disorders

Impaired hepatic function and cholestasis (including jaundice), hepatitis including necrosis, elevated liver enzymes and bilirubin

Skin and subcutaneous tissue disorders

Pruritus with or without a rash, rash, and alopecia

Angioedema (see section 4.4)

Urticaria, Stevens Johnson syndrome, erythema multiforme, photosensitivity, erythroderma, pemphigoid reactions and exfoliative dermatitis, bullous pemphigoid

Musculoskeletal and connective tissue disorders

Myalgia, arthralgia

Renal and urinary disorders

Renal function disorders including renal failure, polyuria, oliguria, increased urine frequency

Nephrotic syndrome

Reproductive system and breast disorders

Impotence, gynaecomastia

General disorders and administration site conditions

Chest pain, fatigue, malaise

Fever

Investigations

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, red cell sedimentation rate increased

Paediatric Population:

The major adverse events seen in the paediatric population were persistent dry cough, hyperkalemia, angioedema, decreased GFR, hypotension, neutropenia, impaired hepatic function and renal disorders.

The reactions most frequently observed during captopril therapy were headache, tachycardia, vomiting, postural symptoms, anaemia, rash and anorexia.

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: https://yellowcard.mhra.gov.uk 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.

After ingestion of an overdose, the patient should be kept under close supervision, preferably in an intensive care unit. Serum electrolytes and creatinine should be monitored frequently, as well as blood pressure. Therapeutic measures depend on the nature and severity of the symptoms.

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. The use of high-flux polyacrylonitrile membranes should be avoided.