Source: Υπουργείο Υγείας (CY) Revision Year: 2019 Publisher: MEDOCHEMIE LTD, 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus
The concomitant use of Rilcapton 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).
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.
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 sections 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: Angioedema of the extremities, face, lips, mucous membranes, tongue, glottis or larynx may occur in patients treated with ACE inhibitors particularly during the first weeks 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. 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 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: 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).
Lithium: the combination of lithium and captopril is not recommended (see sections 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 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 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.
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).
Rilcapton contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take this medicine.
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).
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 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.
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 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.
Treatment 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-steroid anti-inflammatory medicinal products: it has been described that non-steroidal anti-inflammatory medicinal products (NSAIDEs) 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.
mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus): Patients taking concomitant mTOR inhibitors therapy may be at increased risk for angioedema (see section 4.4).
Co-trimoxazole (trimethoprim/sulfamethoxazole): Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk for hyperkalaemia (see section 4.4).
Clinical chemistry: Captopril may cause a false-positive urine test for acetone.
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).
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 Rilcapton in breastfeeding is not recommended for preterm infants and for the first 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 Rilcapton 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.
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.
The following convention has been used for the classification of undesirable effects in terms of frequency: Very common 1/10, Common 1/100 to <1/10, Uncommon 1/1000 to <1/100, Rare 1/10,000 to <1/1000, Very rare <1/10,000, Not known (cannot be estimated from the available data).
Undesirable effects reported for captopril and/or ACE inhibitor therapy include: Blood and lymphatic disorders: Very rare: neutropenia/agranulocytosis (see section 4.4), pancytopenia particularly in patients with renal dysfunction (see section 4.4), anaemia (including aplastic and haemolytic), thrombocytopenia, lymphadenopathy, eosinophilia, auto-immune diseases and/or positive ANA-titres.
Rare: anorexia.
Very rare: hyperkalaemia, hypoglycaemia (see section 4.4).
Common: sleep disorders.
Very rare: confusion, depression.
Common: taste impairment, dizziness.
Rare: drowsiness, headache and paraesthesia.
Very rare: cerebrovascular incidents, including stroke, and syncope.
Very rare: blurred vision.
Uncommon: tachycardia or tachyarrhythmia, angina pectoris, palpitations.
Very rare: cardiac arrest, cardiogenic shock.
Uncommon: hypotension (see section 4.4), Raynaud syndrome, flush, pallor.
Common: dry, irritating (non-productive) cough (see section 4.4) and dyspnea.
Very rare: bronchospasm, rhinitis, allergic alveolitis/eosinophilic pneumonia.
Common: nausea, vomiting, gastric irritations, abdominal pain, diarrhoea, constipation, dry mouth.
Rare: stomatitis/aphthous ulcerations.
Very rare: glossitis, peptic ulcer, pancreatitis.
Very rare: impaired hepatic function and cholestasis (including jaundice), hepatitis including necrosis, elevated liver enzymes and bilirubin.
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.
Very rare: myalgia, arthralgia.
Rare: renal function disorders including renal failure, polyuria, oliguria, increased urine frequency.
Very rare: nephrotic syndrome.
Very rare: impotence, gynaecomastia.
Uncommon: chest pain, fatigue, malaise.
Very rare: fever.
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.
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 to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649.
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