CAPTOPRIL BIOGARAN 50 mg Cpr séc Plq/3x10 (30)

Scored tablet.

The tablet can be divided into equal doses.

Captopril....................................................................................................................................................50,00 mg

For a scored tablet.

Excipients with known effect: castor oil, lactose.

Each scored tablet contains 2,80 mg of castor oil and 105,00 mg of lactose monohydrate.

Excipients:

• Arterial hypertension.

• Congestive heart failure.

• Myocardial infarction within the first 24 hours in patients with stable haemodynamic status.

• Post-myocardial infarction in patients with left ventricular dysfunction (ejection fraction ≤ 40 %), and otherwise in the absence of clinical signs of heart failure.

Long-term treatment with captopril improves long-term survival, reduces the risk of recurrent infarction as well as the risk of developing heart failure.

• Macroproteinuric diabetic nephropathy of insulin-dependent diabetes.

Long-term treatment slows the progression of renal damage.

Dosage

Captopril, in tablet form, is administered before, during or after meals; possible changes in absorption by food do not modify the therapeutic effect (see section Pharmacokinetics).

Arterial hypertension

• In the absence of prior hydrosaline depletion or renal insufficiency (i.e. in current practice): 
The effective dose is 50 mg per day in 2 doses of 25 mg at twelve-hour intervals.
Depending on the response to treatment, the dose must be adjusted, in steps of 3 to 4 weeks, up to 100 mg/day in 2 doses.

• Certain severe hypertensions may require higher doses (maximum of 150 mg/day in 2 or 3 doses), at least at the start of treatment. These doses may then be reduced.
Exceptionally, doses above 150 mg/day are used. They warrant haematological and renal monitoring (see section Warnings and precautions).

• In hypertension previously treated with a diuretic: 

• either stop the diuretic 3 days beforehand to reintroduce it later if necessary,
• or administer the initial dose of captopril of 12,50 mg (1/2 tablet of 25 mg) and adjust according to the blood pressure response obtained and tolerability (see section Warnings and precautions).

It is also recommended to measure plasma creatinine and potassium before treatment and within 15 days after starting treatment.

• In elderly patients (see section Warnings and precautions), possibly initiate treatment with a lower dose of 25 mg/day adapted to the patient's renal function, assessed before starting treatment, if the latter is less than 40 ml/min. (see table below).
The value of creatinine clearance (Clcr) calculated from serum creatinine and adjusted for age, weight and sex, according to the Cockcroft* formula for example, correctly reflects the state of renal function in this type of patient.

*Clcr = (140 - age) x weight/0.814 x serum creatinine with: 

-          age in years,

-          weight in kg,

-          creatinine level in micromol/l.

This formula is valid for male subjects, and must be corrected for women by multiplying the result by 0,85.

• In renovascular hypertension, it is recommended to start treatment at a dose of 6,25 mg per day (1/4 of tablet of 25 mg) and then adjust it to the patient's blood pressure response.

Serum creatinine and potassium will be monitored in order to detect the onset of possible functional renal insufficiency (see section Warnings and precautions).

• In case of renal impairment, the captopril dose is adjusted to the degree of this insufficiency: 

The doses given in the following table must not be exceeded in order to avoid an excessive increase in drug concentrations.

Creatinine clearance ml/min/1,73 m2	Maximum total daily dose (mg)	Initial doses (mg)
> 41	in principle 150	25 - 50
40 - 21	100	25
20 - 11	75	12,5
< 10	37,5	6,25

The diuretics to be combined in this case are so-called loop diuretics (see sections Contraindications, Warnings and precautions, Interactions and Pharmacodynamics).

In these patients, normal medical practice includes periodic monitoring of potassium and creatinine, for example every two months during periods of therapeutic stability (see section Warnings and precautions).

• In the hypertensive hemodialysis patient
Captopril is dialysable (see section Warnings and precautions).

 

Congestive heart failure

The initial dose must be low, particularly in cases of: 

• normal or low blood pressure at the start,

• renal failure,

• iatrogenic hyponatraemia (diuretic) or not.

Captopril may be used in combination with diuretic treatment, accompanied where appropriate by digitalis treatment.

It is recommended to initiate treatment with 1/4 of a 25 mg tablet (6,25 mg) under blood pressure monitoring and to increase it gradually in steps of 12,5 mg then 25 mg per day, always under blood pressure monitoring, up to the effective dose, which lies between 50 and 100 mg per day divided into 2 or 3 doses.

The dose selected should not lower systolic blood pressure on standing below 90 mmHg.

Symptomatic hypotension may occur in heart failure patients treated with high doses of diuretics: in this case the initial dose must be halved (see section Warnings and precautions) by starting treatment with a dose of 6,25 mg every other day.

Creatinine and potassium measurements must be performed at each dose increase, then every 3 to 6 months depending on the stage of heart failure, in order to monitor treatment tolerance.

Acute phase myocardial infarction

Captopril treatment will be initiated in a hospital setting as early as possible after the onset of signs and/or symptoms in haemodynamically stable patients.

A test dose of 6,25 mg is administered, then 2 hours after a dose of 12,5 mg and 12 hours after a dose of 25 mg. The following day, captopril will be administered at a dose of 100 mg/day in 2 daily doses for 4 weeks if the patient's haemodynamic tolerance allows it.

At the end of these 4 weeks of treatment, the patient's condition will be reassessed before a therapeutic decision is made for the post-myocardial infarction phase.

Post-myocardial infarction

If captopril treatment has not been started in the acute phase of myocardial infarction within the first 24 hours, it is suggested to begin treatment between day 3th and day 16th of the infarction as soon as the conditions for starting treatment are met (haemodynamic stability; management of any residual ischaemia).

Initiation of treatment, until a dose of 75 mg is reached, will be carried out in a hospital setting under strict monitoring, particularly of blood pressure.

The initial dose must be low (see section Warnings and precautions) especially if patients have normal or low blood pressure at the start. Treatment is initiated by taking one1/4 of a 25 mg tablet (6,25 mg) followed by 1/2 tablet of 25 mg (12,5 mg), 3 times a day for 2 days, then one 1 tablet of 25 mg, 3 times a day if the patient's haemodynamic tolerance allows it.

The recommended dose for effective cardioprotection in long-term treatment is 75 mg to 150 mg per day in two or three doses.

In case of symptomatic hypotension, as in heart failure, the dosage of concomitant diuretics and/or other vasodilators may be reduced to allow the maintenance dose of captopril to be reached. Where appropriate, the captopril dose will be adjusted according to the patient's clinical tolerance.

Captopril may be combined with other treatments for myocardial infarction such as thrombolytics, beta-blockers and aspirin.

Diabetic nephropathy

The daily dose of captopril is 50 to 100 mg, divided into two or three daily doses.

In cases of established chronic renal insufficiency, this dose will be adjusted to the degree of renal insufficiency (see the correspondence table and the formula for calculating creatinine clearance from serum creatinine).

This medicine MUST NOT BE used in the following cases: 

• hypersensitivity to the active substance, to any of the excipients listed in section Composition or to any other angiotensin-converting enzyme inhibitor,

• history of angioedema related to taking an angiotensin-converting enzyme inhibitor,

• hereditary / idiopathic angioedema,

• 2th and 3th trimesters of pregnancy (see sections Warnings and precautions and Fertility, pregnancy and breastfeeding),

• concomitant use with a treatment containing sacubitril/valsartan. Treatment with captopril must not be started less than 36 hours after the last dose of sacubitril/valsartan (see also sections Warnings and precautions and Interactions).

The combination of CAPTOPRIL BIOGARAN with medicines containing aliskiren is contraindicated in patients with diabetes or renal insufficiency (GFR [glomerular filtration rate] < 60 ml/min/1,73 m2) (see sections Interactions and Pharmacodynamics).

This medicine is GENERALLY NOT RECOMMENDED in the following situations: 

• combinations with potassium-sparing diuretics, potassium salts, estramustine and lithium (see section Interactions),

• bilateral renal artery stenosis or in a functionally single kidney,

• hyperkalaemia,

• pregnancy (1er trimester),

• breastfeeding.

Special warnings

Neutropenia/agranulocytosis

Neutropenia / agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving angiotensin-converting enzyme inhibitors, including captopril. Neutropenia occurs rarely in patients with normal renal function and without other risk factors. Captopril must be used with extreme caution in patients with collagen disease, in those receiving immunosuppressive treatment, in cases of treatment with allopurinol or procainamide, or when these risk factors are combined, particularly in the presence of pre-existing renal insufficiency. Some of these patients have developed serious infections which, in a small number of cases, did not respond to intensive antibiotic therapy.

If captopril is administered to these patients, it is advised to perform a white blood cell count and differential leukocyte count before starting treatment, then every two weeks during the first three months of treatment with captopril and periodically thereafter. During treatment, every patient must be instructed to report any sign of infection (for example: sore throat, fever) and a differential leukocyte count must be performed. Captopril and any concomitant treatment that may be responsible (see section Interactions) will be discontinued if neutropenia (neutrophil granulocytes < 1000/mm3) is detected or suspected. In most patients, the neutrophil count quickly returns to normal after stopping captopril.

Hypersensitivity/angioedema (Quincke's oedema)

Angioneurotic oedema of the extremities, face, lips, mucous membranes, tongue, glottis and/or larynx may occur in patients treated with angiotensin-converting enzyme inhibitors (ACEI), particularly during the first week of treatment. However, in rare cases, severe angioedema may develop after several months or years of long-term treatment with an ACEI. Treatment must be stopped immediately.

When the oedema involves only the face and lips, the course is generally regressive without treatment, although antihistamines have been used to relieve symptoms.

Angioedema of the tongue, glottis or larynx may be fatal. Emergency treatment must be initiated. When the tongue, glottis or larynx is involved, potentially causing airway obstruction, a subcutaneous adrenaline solution at 1/1000 (0,3 ml to 0,5 ml) must be administered promptly and other appropriate treatments must be applied.

Prescription of an ACE inhibitor should not be considered thereafter in these patients (see section Contraindications).

Concomitant use of ACE inhibitors with the sacubitril/valsartan combination is contraindicated due to the increased risk of angioedema. Treatment with sacubitril/valsartan must not be started less than 36 hours after the last dose of captopril. Treatment with captopril must not be started less than 36 hours after the last dose of sacubitril/valsartan (see sections Contraindications and Interactions).

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (for example sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk of angioedema (for example swelling of the airways or tongue, with or without respiratory impairment) (see section Interactions). Caution should be exercised when initiating treatment with racecadotril, mTOR inhibitors (for example sirolimus, everolimus, temsirolimus) and gliptins (for example vildagliptin) in a patient already taking an ACE inhibitor.

Intestinal angioedema

Rare cases of intestinal angioedema have been reported in patients treated with ACE inhibitors. These patients present with abdominal pain (with or without nausea or vomiting); in some cases intestinal angioedema was not preceded by facial angioedema and did not have abnormal C-1 esterase levels. Intestinal angioedema is diagnosed by abdominal CT scan, ultrasound or during surgical procedure.

Symptoms resolve after discontinuation of treatment. Intestinal angioedema should be included in the differential diagnosis of patients treated with ACE inhibitors presenting with abdominal pain.

Autoimmune hypoglycaemic syndrome:

Cases of autoimmune hypoglycaemic syndrome, including severe hypoglycaemic events, have been reported during treatment with captopril (see section Adverse effects). If autoimmune hypoglycaemic syndrome is suspected, treatment with captopril should be discontinued and an appropriate alternative treatment should be initiated.

Anaphylactoid reactions during high-flux dialysis/low-density lipoprotein (LDL) apheresis

Anaphylactoid reactions have been reported in haemodialysed patients with high-flux dialysis membranes or undergoing low-density lipoprotein apheresis with dextran sulphate adsorption. In these patients, a change of dialysis membrane type or drug class should be considered.

Anaphylactoid reactions during desensitisation

Prolonged, life-threatening anaphylactoid reactions have rarely been reported in patients undergoing hymenoptera venom desensitisation while receiving an angiotensin-converting enzyme inhibitor. In the same patients, temporary withdrawal of the angiotensin-converting enzyme inhibitor prevented these reactions, but they reappeared upon inadvertent re-administration. Therefore, particular caution should be exercised in patients treated with an angiotensin-converting enzyme inhibitor who undergo this type of desensitisation.

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

It is established that the combination of angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists (ARB II) or aliskiren increases the risk of hypotension, hyperkalaemia and impaired renal function (including the risk of acute renal failure). Consequently, dual blockade of the RAAS by the combination of ACE inhibitors, ARB II or aliskiren is not recommended (see sections Interactions and Pharmacodynamics).

Nevertheless, if such a combination is considered absolutely necessary, it should only be carried out under the supervision of a specialist and with close and frequent monitoring of renal function, blood electrolytes and blood pressure. ACE inhibitors and ARBs should not be combined in patients with diabetic nephropathy.

Proteinuria

Proteinuria may occur, particularly in patients with pre-existing renal impairment or receiving relatively high doses of angiotensin-converting enzyme inhibitors. Total proteinuria exceeding 1 g per day was observed in approximately 0,7 % of patients treated with captopril.

The majority of patients had pre-existing renal disease or had received relatively high doses of captopril (more than 150 mg/day) or both. One fifth of the proteinuric patients presented nephrotic syndrome. In most cases, proteinuria decreased or completely regressed within six months, whether or not treatment with captopril was continued.

Patients with proteinuria rarely showed alterations in renal function parameters, such as urea or creatinine.

An estimation of proteinuria (dipstick test on first-morning urine) should be performed before starting treatment and periodically thereafter, in patients with a history of renal disease.

Pregnancy

ACE inhibitors must not be started during pregnancy. Unless continuation of ACE inhibitor therapy is considered essential, it is recommended that antihypertensive treatment be changed to a medicinal product with a well-established safety profile for use during pregnancy in patients planning a pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately and, if appropriate, alternative treatment should be started (see sections Contraindications and Fertility, pregnancy and breastfeeding).

Precautions for use

Cough

A dry cough has been reported with the use of angiotensin-converting enzyme inhibitors. It is characterised by its persistence and by its disappearance upon discontinuation of treatment. In cases where prescription of an ACE inhibitor is essential, continuation of treatment may be considered. An iatrogenic aetiology should be considered in the presence of this symptom.

Risk of arterial hypotension and/or heart failure, sodium depletion

Significant stimulation of the renin-angiotensin-aldosterone system is observed particularly during significant fluid and sodium depletion (strict salt-free diet or prolonged diuretic treatment), in patients with initially low blood pressure, in cases of renal artery stenosis, congestive heart failure and oedematous-ascitic cirrhosis. Blockade of this system by an angiotensin-converting enzyme inhibitor may then cause, especially at the first dose and during the first two weeks of treatment, a sudden drop in blood pressure and/or, although rarely and over a more variable timeframe, an increase in plasma creatinine reflecting functional renal insufficiency that is sometimes acute. In all these situations, treatment should be initiated progressively.

As with all antihypertensive agents, an excessive drop in blood pressure may increase the risk of myocardial infarction or stroke in patients with ischaemic heart disease or cerebrovascular disease.

If hypotension develops, the patient should be placed in the supine position. Volume replacement with an intravenous saline solution may be necessary.

Paediatric population

The tolerability and efficacy of captopril in children have not been demonstrated in controlled studies. However, captopril has been administered in paediatric cardiology. Treatment is initiated in a hospital setting.

Elderly subject

Renal function (serum creatinine) and serum potassium should be assessed before starting treatment (see section Dosage and administration). The starting dose will subsequently be adjusted according to the blood pressure response, a fortiori in cases of sodium and water depletion, in order to avoid sudden-onset hypotension.

Renal impairment

In cases of renal impairment (creatinine clearance below 40 ml/min), the initial dose of captopril should be adjusted to the creatinine clearance, then adjusted according to the therapeutic response (see section Dosage and administration).

In these patients and in those with glomerular nephropathy, normal medical practice includes periodic monitoring of potassium and creatinine.

Subject with known atherosclerosis

Since the risk of hypotension exists in all these patients, particular caution should be exercised in those with ischaemic heart disease or cerebral circulatory insufficiency, starting treatment at a low dose.

Anaemia

Anemia with a decrease in hemoglobin levels has been observed in renal transplant or hemodialysis patients, the decrease being all the greater the higher the baseline values. This effect does not appear to be dose-dependent but would be related to the mechanism of action of angiotensin-converting enzyme inhibitors.

This decrease is moderate, occurs within 1 to 6 months and then remains stable. It is reversible upon discontinuation of treatment. Treatment may be continued in this type of patient, with regular hematological monitoring.

Surgical intervention

In cases of anaesthesia, and even more so when anaesthesia is performed with agents with hypotensive potential, ACE inhibitors can cause hypotension. Treatment interruption, when possible, is therefore recommended the day before the procedure for captopril.

Hepatic impairment

Angiotensin-converting enzyme inhibitors have rarely been associated with a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis and, occasionally, a fatal outcome. The mechanism of this syndrome is unknown. Patients receiving an angiotensin-converting enzyme inhibitor who develop jaundice or a marked increase in liver enzymes should discontinue the angiotensin-converting enzyme inhibitor and receive appropriate medical follow-up.

Hyperkalaemia

ACE inhibitors can cause hyperkalaemia because they inhibit aldosterone release. This effect is generally not significant in patients with normal renal function. However, in patients with impaired renal function, diabetic patients and/or patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim or co-trimoxazole (trimethoprim/sulfamethoxazole combination), and in particular aldosterone antagonists or angiotensin II receptor antagonists, hyperkalaemia may occur. Potassium-sparing diuretics and angiotensin II receptor antagonists should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored (see section Interactions).

Renovascular hypertension

Treatment of renovascular hypertension is revascularisation. Nevertheless, captopril may be useful in patients with renovascular hypertension while awaiting corrective intervention or when such intervention is not possible. Treatment should then be initiated with caution, and renal function and serum potassium should be monitored, as some patients have developed functional renal insufficiency, reversible upon discontinuation of treatment (see section Dosage and administration).

In hypertension with unilateral renovascular disease, start treatment with low doses (¼ tablet to 25 mg) and continue treatment only if there is no decrease in ipsilateral glomerular filtration rate relative to the stenosis. Increased monitoring of glomerular filtration rate should be carried out.

Aortic and mitral stenosis / obstructive cardiomyopathy / cardiogenic shock

ACE inhibitors should be used with caution in patients with valvular stenosis or obstruction to left ventricular outflow, and avoided in cases of cardiogenic shock and significant haemodynamic obstruction.

Other at-risk populations

In patients with heart failure severe (stage IV), and in insulin-dependent diabetic patients (spontaneous tendency to hyperkalaemia), initiation of treatment should take place under medical supervision with a reduced initial dose.

In elderly diabetic patients, particularly those with nephropathy and neuropathy, the risk of hyperkalaemia under ACE inhibitors is increased due to frequent hypoaldosteronism, which should lead to increased monitoring of serum potassium.

Do not interrupt beta-blocker treatment in a hypertensive patient with coronary insufficiency: the ACE inhibitor will be added to the beta-blocker.

Ethnic specificity

As observed with other angiotensin-converting enzyme inhibitors, captopril is apparently less active on blood pressure in Black people than in other people, probably due to a higher prevalence of a low renin level in the hypertensive Black population.

Black patients receiving an angiotensin-converting enzyme inhibitor have a higher risk of developing angioedema compared with non-Black patients.

Laboratory tests

Captopril may lead to a false positive when testing urine for acetone.

Excipients

This medicine contains lactose. Patients with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases) must not take this medicine.

This medicine contains castor oil and may cause stomach upset and diarrhoea.

Hyperkalaemic medicines

Certain medicines or therapeutic classes may promote the occurrence of hyperkalaemia: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II antagonists, non-steroidal anti-inflammatory drugs, heparins (low molecular weight or unfractionated), immunosuppressants such as ciclosporin or tacrolimus, trimethoprim. The combination of these medicines increases the risk of hyperkalaemia. This risk is particularly significant with potassium-sparing diuretics, especially when they are combined with each other or with potassium salts, whereas the combination of an ACE inhibitor and an NSAID, for example, carries a lower risk provided the recommended precautions are implemented.

Data from clinical trials have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through concomitant use of angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and impaired renal function (including acute renal failure) compared with the use of a single agent acting on the RAAS (see sections Contraindications, Warnings and precautions and Pharmacodynamics).

Contraindicated combinations

+ Aliskiren in diabetic patients or patients with renal insufficiency (GFR < 60 ml/min/1,73 m²)

Risk of hyperkalaemia, renal insufficiency, increased cardiovascular morbidity and mortality.

+ Sacubitril/valsartan

Concomitant use of ACE inhibitors with the combination sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see sections Contraindications and Warnings and precautions).

Combinations not recommended

+ Aliskiren

Risk of hyperkalaemia, renal insufficiency, increased cardiovascular morbidity and mortality.

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

Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with captopril. Potassium-sparing diuretics (for example spironolactone, triamterene or amiloride), potassium supplements or salt substitutes containing potassium may cause significant increases in serum potassium. Caution is also required when administering captopril with other hyperkalaemic medicines, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim acts as a potassium-sparing diuretic like amiloride. Therefore, the combination of captopril with the above-mentioned medicines is not recommended. If concomitant use is indicated, it should be undertaken with caution and accompanied by frequent monitoring of serum potassium.

+ Estramustine

Risk of increased adverse effects of the angioneurotic oedema type (angioedema).

+ Lithium

Increase in lithium levels that may reach toxic values (reduced renal excretion of lithium). If use of an ACE inhibitor is essential, strict monitoring of lithium levels and adjustment of the lithium dosage.

+ Potassium

Hyperkalaemia (potentially fatal), especially in renal insufficiency (additive hyperkalaemic effects). Unless hypokalaemia is present.

Associations requiring precautions for use

+ Acetylsalicylic acid

At anti-inflammatory doses of acetylsalicylic acid (≥ 1 g per dose and/or ≥ 3 g per day) or at analgesic or antipyretic doses (≥ 500 mg per dose and/or < 3 g per day): acute renal failure in dehydrated patients, due to reduced glomerular filtration secondary to decreased synthesis of renal prostaglandins. Furthermore, reduction of the antihypertensive effect.

Hydrate the patient and monitor renal function at the start of treatment.

+ Non-steroidal anti-inflammatory drugs

Acute renal failure in at-risk patients (elderly subjects and/or dehydrated) due to decreased glomerular filtration (inhibition of vasodilatory prostaglandins due to non-steroidal anti-inflammatory drugs). Furthermore, reduction of the antihypertensive effect.

+ Baclofen

Increased risk of hypotension, particularly orthostatic hypotension.

Monitoring of blood pressure and dose adjustment of the antihypertensive if necessary.

+ Potassium-depleting diuretics

Risk of abrupt arterial hypotension and/or acute renal failure upon initiation or dose increase of treatment with an angiotensin-converting enzyme inhibitor in the presence of pre-existing sodium and water depletion.

In arterial hypertension, when prior diuretic treatment may have caused sodium and water depletion, one must:

• either discontinue the diuretic before starting ACE inhibitor treatment, and reintroduce a potassium-depleting diuretic later if necessary;

• or administer reduced initial doses of ACE inhibitor and gradually increase the dose.

In congestive heart failure treated with diuretics, start with a very low dose of ACE inhibitor, possibly after reducing the dose of the associated potassium-depleting diuretic.

In all cases: monitor renal function (serum creatinine) during the first weeks of ACE inhibitor treatment.

+ Eplerenone

Increased risk of hyperkalaemia, particularly in elderly subjects. Strict monitoring of serum potassium and renal function during the combination.

+ Insulin, sulfonylurea hypoglycaemic agents

The use of ACE inhibitors may increase the hypoglycaemic effect in diabetic patients treated with insulin. The occurrence of hypoglycaemic episodes seems exceptional (improved glucose tolerance which would result in a reduced insulin requirement).

Reinforce blood glucose self-monitoring.

+ Spironolactone

With spironolactone at a dose of 12,5 to 50 mg per day, and with low doses of ACE inhibitor.

In the treatment of class III or IV heart failure (NYHA) with ejection fraction <35 % and previously treated with the combination of ACE inhibitor + loop diuretic: risk of potentially fatal hyperkalaemia if the prescribing conditions of this combination are not respected.

Beforehand, verify the absence of hyperkalaemia and renal failure.

Close biological monitoring of serum potassium and serum creatinine (1 times per week during the first month, then once a month thereafter).

+ Allopurinol, procainamide, cytostatics or immunosuppressive agents

Concomitant administration of an angiotensin-converting enzyme inhibitor may increase the risk of leukopenia, particularly when the latter is used at doses higher than those currently recommended.

+ 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.

Associations to be taken into account

+ Alpha-blockers for urological use

Increase of the hypotensive effect. Increased risk of orthostatic hypotension.

+ Amifostine

Increased risk of hypotension, particularly orthostatic hypotension.

+ Tricyclic antidepressants

Increased risk of hypotension, particularly orthostatic hypotension.

+ Alpha-blocking antihypertensives

Increased hypotensive effect. Increased risk of orthostatic hypotension.

+ Nitro derivatives and related substances

Increased risk of hypotension, particularly orthostatic hypotension.

+ Racecadotril

Concomitant use of ACE inhibitors with racecadotril may lead to an increased risk of angioedema (see section Warnings and precautions).

+ mTOR inhibitors (for example sirolimus, everolimus, temsirolimus)

Concomitant use of ACE inhibitors with mTOR inhibitors (for example sirolimus, everolimus, temsirolimus) may lead to an increased risk of angioedema (see section Warnings and precautions).

+ Gliptins

Concomitant use of ACE inhibitors with gliptins (for example vildagliptin) may lead to an increased risk of angioedema due to reduction of dipeptidyl peptidase IV (DPP-IV) enzyme activity by the gliptin in patients treated with an angiotensin-converting enzyme inhibitor.

+ Neuroleptics

Increased risk of hypotension, particularly orthostatic hypotension.

+ Gold

With intravenous gold salts: risk of a "nitritoid" reaction upon initiation of ACE inhibitor therapy (nausea, vomiting, vasomotor effects such as flushing, hypotension, possibly collapse).

Pregnancy

The available epidemiological data concerning the risk of malformation after exposure to ACE inhibitors during the 1er trimester of pregnancy is inconclusive. However, a small increase in the risk of congenital malformations cannot be excluded. Unless continued ACE inhibitor treatment is considered essential, patients planning a pregnancy should be changed to an alternative antihypertensive treatment which has 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 inhibitors during the 2th and 3th trimesters of pregnancy is known to cause foetotoxicity (decreased renal function, oligohydramnios, delayed ossification of the skull bones) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section Preclinical safety). If exposure to an ACE inhibitor has occurred from the 2th trimester of pregnancy, ultrasound screening of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections Contraindications and Warnings and precautions).

Breast-feeding

Captopril is excreted in breast milk in very small amounts. The quantity ingested by the breastfed infant corresponds to 0,3 % of the neonatal therapeutic dose. Consequently, administration of this medicine is possible in breastfeeding women, except in premature infants and/or in cases of impaired renal function in the infant. If the infant is older, use of captopril in breastfeeding women may be considered if this treatment is necessary for her and the infant is monitored for the occurrence of adverse effects.

As with other antihypertensives, particular caution should be exercised when driving or operating machinery at the start of treatment or when the dose is changed, due to the risk of dizziness. This caution also applies to concomitant alcohol consumption. These effects depend on individual susceptibility.

Adverse effects reported with captopril and/or angiotensin-converting enzyme inhibitors include the following:

Blood and lymphatic system disorders

• Very rare: neutropenia/agranulocytosis (see section Warnings and precautions), pancytopenia, particularly in patients with impaired renal function (see section Warnings and precautions), anemia (including aplastic and hemolytic), thrombocytopenia, lymphadenopathy, eosinophilia, autoimmune diseases and/or positive antinuclear antibodies.

Immune system disorders

• Frequency not known: autoimmune hypoglycemic syndrome.

Metabolism and nutrition disorders

• Rare: anorexia.

• Very rare: hyperkalemia, hypoglycemia.

Psychiatric disorders

• Common: sleep disorders.

• Very rare: confusion, depression.

Nervous system disorders

• Common: taste disturbance, dizziness.

• Rare: somnolence, headache and paresthesia.

• Very rare: cerebrovascular events, including stroke and syncope.

Eye disorders

• Very rare: blurred vision.

Cardiac disorders

• Rare: tachycardia or tachyarrhythmia, angina, palpitations.

• Very rare: cardiac arrest, cardiogenic shock.

Vascular disorders

• Rare: hypotension (see section Warnings and precautions), Raynaud's syndrome, flushing, pallor.

Respiratory, thoracic and mediastinal disorders

• Common: dry and irritating (non-productive) cough (see section Warnings and precautions) and dyspnea.

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

Gastrointestinal disorders

• Common: nausea, vomiting, gastric irritation, abdominal pain, diarrhea, constipation, dry mouth.

• Rare: stomatitis / aphthous ulceration, intestinal angioedema (see section Warnings and precautions).

• Very rare: glossitis, gastroduodenal ulcer, pancreatitis.

Hepatobiliary disorders

• Very rare: hepatic failure and cholestasis (including jaundice), hepatitis, possibly necrotic, elevated liver enzymes and bilirubin.

Skin and subcutaneous tissue disorders

• Frequent: pruritus with or without rash, rash and alopecia.

• Rare: angioedema (see section Warnings and precautions).

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

Musculoskeletal and systemic disorders

• Very rare: myalgia, arthralgia.

Renal and urinary disorders

• Rare: renal function disorders including renal failure, polyuria, oliguria, increased frequency of urination.

• Very rare: nephrotic syndrome.

Disorders of the reproductive organs and breast

• Very rare: impotence, gynecomastia.

General disorders and administration site conditions

• Rare: chest pain, fatigue, malaise.

• Very rare: fever.

As with other ACE inhibitors, a syndrome that may include fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash or other dermatological manifestations, eosinophilia and an elevated erythrocyte sedimentation rate has been reported.

BIOCHEMISTRY

Very rare: proteinuria, eosinophilia, hyperkalemia, hyponatremia, increased blood urea, serum creatinine and bilirubin, decreased hemoglobin, hematocrit, leukocytes, platelets, positive antinuclear antibodies, increased erythrocyte sedimentation rate.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals report any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres – Website: https://signalement.social-sante.gouv.fr/

Symptoms of overdose are severe hypotension, shock, stupor, bradycardia, electrolyte disturbance and renal failure.

In case of overdose, the patient should be closely monitored, preferably in an intensive care unit. Serum electrolyte levels and creatinine should be frequently monitored, as well as blood pressure. Therapeutic measures depend on the nature and severity of the symptoms.

In case of recent ingestion, measures should be taken to prevent absorption and accelerate elimination, for example gastric lavage, administration of adsorbent agents and sodium sulfate within 30 minutes after taking the medicinal product.

In case of hypotension, place the patient in a shock position and rapidly administer a supplement of sodium chloride and plasma-expanding solution. Treatment with angiotensin II may be considered. Bradycardia or extensive vagal reaction should be treated by administration of atropine. Placement of a pacemaker may be considered. Captopril is hemodialyzable. The use of high-flux polyacrylonitrile membranes is not recommended.

Pharmacotherapeutic class: angiotensin-converting enzyme inhibitor, ATC code: C09AA01.

Captopril is an inhibitor of the angiotensin-converting enzyme (ACE) that converts angiotensin I into angiotensin II, a vasoconstrictor substance that also stimulates aldosterone secretion by the adrenal cortex.

This results in: 

• a decrease in aldosterone secretion,

• an increase in plasma renin activity, aldosterone no longer exerting negative feedback,

• a decrease in total peripheral resistance with a preferential action on muscular and renal vascular beds, without this decrease being accompanied by sodium and water retention or reflex tachycardia.

The antihypertensive action of captopril is also seen in subjects with low or normal renin concentrations.

Characteristics of antihypertensive activity

Captopril is active at all stages of arterial hypertension: mild, moderate or severe; a reduction in systolic and diastolic blood pressure is observed, both supine and orthostatic.

Antihypertensive activity after a single dose becomes evident from the fifteenth minute, and is maximal between 1 hour and 1 hour 30 after intake. The duration of action is dose-dependent: it ranges from 6 to 12 hours.

In responder patients, blood pressure normalisation occurs after 15 days to one month of treatment, and is maintained without escape.

Discontinuation of treatment is not accompanied by a rebound of arterial hypertension.

Treatment of arterial hypertension with captopril leads to an increase in arterial compliance, an increase in renal blood flow without a significant decrease in glomerular filtration rate, as well as a reduction in left ventricular hypertrophy.

If necessary, the addition of a thiazide diuretic results in an additive-type synergy.

The combination of an angiotensin-converting enzyme inhibitor and a thiazide further reduces the risk of hypokalaemia induced by the diuretic alone.

The use of the combination of an angiotensin-converting enzyme (ACE) inhibitor with an angiotensin II receptor antagonist (ARB II) has been analysed in 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).

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

Compared with monotherapy, these studies did not demonstrate a significant beneficial effect on the course of renal and/or cardiovascular damage or on mortality, whereas an increased risk of hyperkalaemia, acute renal failure and/or hypotension was observed.

These results are also applicable to other ACE inhibitors and ARB IIs, given the similarity of their pharmacodynamic properties.

ACE inhibitors and ARB IIs should therefore not be combined in patients with diabetic nephropathy.

The ALTITUDE study (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoint) was conducted to assess the benefit of adding aliskiren to standard treatment with an ACE inhibitor or an ARB II in patients with type 2 diabetes and chronic renal failure, with or without cardiovascular disorders. This study was stopped prematurely due to an increased risk of adverse events. Deaths of cardiovascular origin and strokes were more frequent in the aliskiren group than in the placebo group; likewise, adverse events and certain serious adverse events such as hyperkalaemia, hypotension and renal failure were reported more frequently in the aliskiren group than in the placebo group.

Haemodynamic mode of action in heart failure

Captopril reduces the work of the heart: 

• by a venous vasodilatory effect probably due to a modification of prostaglandin metabolism: reduction of preload,

• by reduction of total peripheral resistance: reduction of afterload.

Studies carried out in patients with cardiac insufficiency have demonstrated: 

• a reduction in left and right ventricular filling pressures,

• a reduction in total peripheral vascular resistance,

• a reduction in mean arterial pressure,

• an increase in cardiac output and an improvement in cardiac index,

• an increase in regional muscle blood flows.

Exercise tolerance tests are also improved.

Characteristics in acute myocardial infarction

In the acute phase of myocardial infarction, a multicentre controlled versus placebo-controlled trial (ISIS 4) including 58050 patients showed that administration of captopril within the first 24 hours of myocardial infarction and continued for 4 weeks significantly reduces total mortality by 5 deaths per 1000 patients.

Characteristics in the post-infarction period

In patients who had a myocardial infarction with left ventricular dysfunction (ejection fraction ≤ 40 %), another controlled versus placebo-controlled study (SAVE) in a large number of patients followed for an average of 3,5 years showed that captopril: 

• reduces total mortality,

• reduces cardiovascular mortality,

• reduces recurrences of myocardial infarction,

• reduces progression to heart failure,

• reduces hospitalisations for heart failure.

The results are demonstrated only for patients whose post-infarction isotopic ejection fraction is less than 40 %.

These effects on mortality and morbidity are additive to those of other treatments for myocardial infarction.

The cardioprotective effects of captopril are observed regardless of age, sex, location of the infarction, and concomitant treatments with proven efficacy in post-infarction (thrombolytics, beta-blockers, aspirin).

Characteristics in diabetic nephropathy

A multicentre controlled versus placebo trial showed that administration of captopril to patients with insulin-dependent diabetes, macroscopic proteinuria, with or without arterial hypertension, and a serum creatinine <25 mg/l resulted in a 51 % reduction in the risk of doubling of serum creatinine (p<0,01) and a 51 % reduction in mortality and morbidity (dialysis or renal transplantation) (p<0,01).

The renoprotective effect is related not only to the reduction in blood pressure but also to a specific renoprotective effect independent of blood pressure.

Orally, captopril is rapidly absorbed (peak blood level reached at the first hour).

The amount absorbed represents 75 % of the administered dose and is decreased by 30 to 35 % by food intake, without influence on efficacy.

In plasma, 30 % is bound to plasma albumin. The elimination half-life of unchanged captopril is close to 2 hours.

Captopril eliminated in urine represents approximately 95 % (of which 40 to 50 % in unchanged form) of the administered captopril dose.

In renally impaired patients, plasma captopril concentrations are significantly higher in patients with a creatinine clearance less than or equal to 40 ml/min; the half-life may reach 30 hours.

Captopril crosses the placenta.

Passage into breast milk occurs in very small amounts (see section Fertility, pregnancy and breastfeeding).

Breast-feeding

After administration of a dose of 100 mg of captopril given orally 3 times daily to 12 women, maximum captopril concentrations in milk were 4,7 μg/L 3,8 hours after intake. It is estimated that a child exclusively breastfed would be exposed to a maximum dose corresponding to 0,002 % of the mother's daily captopril dose.

3 years.

This medicine does not require any particular storage precautions.

No special requirements.

List I

Marketing authorisation (AMM)

CIP 3400934857881 (Plq/3x10 (30)).

Price:

3,64 euros (Plq/3x10 (30)).

Social Security reimbursement at 65%.
Collection.