Source: Health Sciences Authority (SG) Revision Year: 2023 Publisher: France: Les Laboratoires Servier, 50, rue Carnot, 92284 Suresnes cedex, France Singapore: Servier Singapore Pte Ltd, 67 Ubi Avenue 1, #06-09 StarHub Green, Singapore 408942
• Hypersensitivity to the active substances, or to any of the excipients listed in section 6.1, or to any other angiotensin converting enzyme (ACE) inhibitor.
• Acute heart failure or during episodes of heart failure decompensation requiring i.v. inotropic therapy.
• Cardiogenic shock.
• Second or third degree AV block (without pacemaker).
• Sick sinus syndrome.
• Sinoatrial block.
• Symptomatic bradycardia.
• Symptomatic hypotension.
• Severe bronchial asthma or severe chronic obstructive pulmonary disease.
• Severe forms of peripheral arterial occlusive disease or severe forms of Raynaud’s syndrome.
• Untreated phaeochromocytoma (see section 4.4).
• Metabolic acidosis.
• History of angioedema associated with previous ACE inhibitor therapy.
• Hereditary or idiopathic angioedema.
• Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
• Concomitant use of Cosyrel with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73m²) (see sections 4.4, 4.5 and 5.1).
• Concomitant use with sacubitril/valsartan therapy, Cosyrel must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.4 and 4.5).
• Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5).
• Significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney (see section 4.4).
All warnings and precautions for use related to each component are applicable to Cosyrel.
ACE inhibitors may cause a fall in blood pressure. Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients and is more likely to occur in patients who have been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or who have severe renin-dependent hypertension (see sections 4.5 and 4.8). In patients with symptomatic heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. In patients at increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be closely monitored. Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution. A transient hypotensive response is not a contraindication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion.
In some patients with congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with perindopril. This effect is anticipated and is usually not a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or gradual discontinuation of treatment, using the individual components, may be necessary.
Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx has been reported rarely in patients treated with ACE inhibitors, including perindopril (see section 4.8). This may occur at any time during therapy. In such cases, Cosyrel should promptly be discontinued. Therapy with beta-blocker must be continued. Appropriate monitoring should be initiated and continued until complete resolution of symptoms has occurred. In those instances where swelling was confined to the face and lips the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms.
Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, emergency therapy should be administered promptly. This may include the administration of adrenaline and/or the maintenance of a patent airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see section 4.3). Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan, or ultrasound or at surgery and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
The combination of perindopril with sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see section 4.3). Sacubitril/valsartan must not be initiated until 36 hours after taking the last dose of perindopril therapy. If treatment with sacubitril/valsartan is stopped, perindopril therapy must not be initiated until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5). Concomitant use of ACE inhibitors with NEP inhibitors (e.g. racecadotril), mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, 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. linagliptin, saxagliptin, sitagliptin, vildagliptin) in a patient already taking an ACE inhibitor.
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 (see section 4.8).
ACE inhibitors cause a higher rate of angioedema in black patients than in non-black patients. As with other ACE inhibitors, perindopril may be 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.
Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor induced cough should be considered as part of the differential diagnosis of cough.
Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including perindopril. ACE inhibitors can cause hyperkalaemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. Risk factors for the development of hyperkalemia include those with renal insufficiency, worsening of renal function, age (>70 years), diabetes mellitus, intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis and concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (e.g. heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole) and especially aldosterone antagonists or angiotensin-receptor blockers. The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalemia can cause serious, sometimes fatal arrhythmias. Potassium-sparing diuretics and angiotensinreceptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored. If concomitant use of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium (see section 4.5).
The combination of lithium and perindopril is generally not recommended (see section 4.5).
The combination of perindopril and potassium sparing drugs, potassium supplements or potassium-containing salt substitutes is generally not recommended (see section 4.5).
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.
Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type, with Class I antiarrhytmic drugs and with centrally acting antihypertensive drugs is generally not recommended see section 4.5)
Abrupt cessation of therapy with a beta-blocker should be avoided, especially in patients with ischaemic heart disease, because this may lead to transitional worsening of heart condition. The posology should be decreased gradually, using the individual components, ideally over a period of two weeks while at the same time starting the replacement therapy if necessary.
If, during treatment, resting heart rate drops below 50-55 beats per minute and the patient experiences symptoms related to bradycardia, Cosyrel dose should be downtitrated using the individual components with an appropriate dose of bisoprolol.
Given their negative dromotropic effect, beta-blockers should be administered with caution to patients with first degree AV block.
As with other ACE inhibitors, perindopril should be given with caution to patients with mitral valve stenosis and obstruction in the outflow of the left ventricle such as aortic stenosis or hypertrophic cardiomyopathy.
Cases of coronary vasospasm have been observed. Despite its high beta 1-selectivity, angina attacks cannot be completely excluded when bisoprolol is administered to patients with Prinzmetal’s angina. Bisoprolol must be used with caution in Prinzmetal’s angina.
In case of renal impairment, the daily dose of Cosyrel should be adjusted according to creatinine clearance (see section 4.2). Routine monitoring of potassium and creatinine are part of normal medical practice for these patients (see section 4.8).
In patients with symptomatic heart failure, hypotension following the initiation of therapy with ACE inhibitors may lead to some further impairment in renal function. Acute renal failure, usually reversible, has been reported in this situation.
In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, who have been treated with ACE inhibitors, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal insufficiency. If renovascular hypertension is also present there is an increased risk of severe hypotension and renal insufficiency. In these patients, treatment should be started under close medical supervision with low doses and careful dose titration. Since treatment with diuretics may be a contributory factor to the above, they should be discontinued and renal function should be monitored during the first weeks of treatment therapy.
Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when perindopril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or perindopril may be required.
There is an increased risk of hypotension and renal insufficiency when patient with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors (see section 4.3). Treatment with diuretics may be a contributory factor. Loss of renal function may occur with only minor changes in serum creatinine even in patients with unilateral renal artery stenosis.
There is no experience regarding the administration of perindopril arginine in patients with recent kidney transplantation.
Anaphylactoid reactions have been reported in patients dialysed with high flux membranes, and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or different class of antihypertensive agent.
Rarely, patients receiving ACE inhibitors during LDL apheresis with dextran sulphate have experienced lifethreatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
Patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) have experienced anaphylactoid reactions. In the same patients, these reactions have been avoided when the ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the severity of anaphylactoid reactions. Epinephrine treatment does not always yield the expected therapeutic effect.
Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Perindopril 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 perindopril is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection (e.g. sore throat, fever).
In bronchial asthma or other chronic obstructive lung diseases, which may cause symptoms, bronchodilating therapy should be given concomitantly. Occasionally an increase of the airway resistance may occur when beta-blockers are used in patients with asthma, therefore the dose of beta2-stimulants may have to be increased.
Caution is advised when Cosyrel is used in patients with diabetes mellitus with large fluctuations in blood glucose values. Symptoms of hypoglycaemia can be masked by beta-blockers.
Caution is advised in patients with strict fasting.
Aggravation of symptoms may occur with beta-blockers, especially when starting therapy.
In patients undergoing general anaesthesia beta-blockade reduces the incidence of arrhythmias and myocardial ischemia during induction and intubation, and the post-operative period. It is currently recommended that maintenance beta-blockade be continued peri-operatively. The anaesthesist must be aware of beta-blockade because of the potential for interactions with other drugs, resulting in bradyarrhythmias, attenuation of the reflex tachycardia and the decreased reflex ability to compensate for blood loss. If it is thought necessary to withdraw beta-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia.
In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, perindopril may block angiotensin II formation secondary to compensatory renin release. The treatment should be discontinued one day prior to the surgery. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
Patients with psoriasis or with a history of psoriasis should only be given beta-blockers after carefully balancing the benefits against the risks.
In patients with known or suspected to have phaeochromocytoma bisoprolol should always be given in combination with an alpha-receptor blocker.
Under treatment with bisoprolol the symptoms of a thyreotoxicosis may be masked.
Patients with primary hyperaldosteronism generally will not respond to anti-hypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of this product is not recommended.
Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive 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).
There is no therapeutic experience of bisoprolol treatment of heart failure in patients with the following diseases and conditions:
Cosyrel contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially ‘sodium-free’.
No interactions between bisoprolol and perindopril have been observed in an interaction study conducted in healthy volunteers. Only information on interactions with other products that are known for the individual active substances is provided below.
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see section 4.3 and 4.4). Sacubitril/valsartan must not be started until 36 hours after taking the last dose of perindopril therapy. Perindopril therapy must not be started until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.4).
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) may lead to an increased risk for angioedema (see section 4.4).
Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with Cosyrel. Some drugs or therapeutic classes may increase the occurrence of hyperkalaemia: aliskiren, potassium salts, potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), ACE inhibitors, angiotensin-II receptors antagonists, NSAIDs, heparins, immunosuppressant agents such as ciclosporin or tacrolimus, trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. The combination of these drugs increases the risk of hyperkalaemia. Therefore, the combination of Cosyrel 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.
The concomitant therapy with Cosyrel and aliskiren is contra-indicated in diabetic or impaired renal patients, due to the risk of hyperkalaemia, worsening of renal function and cardiovascular morbidity and mortality increase.
Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Centrally acting antihypertensives such as clonidine and others (e.g. methyldopa, moxonidine, rilmenidine):
Concomitant use of centrally acting antihypertensives may worsen heart failure by lowering the central sympathetic tonus (reduced heart rate and cardiac output, vasodilation). Abrupt termination, particularly before down-titration of beta-blocker therapy, may increase the risk of rebound hypertension.
Class I antiarrhythmic drugs (e.g. quinidine, disopyramide; lidocaine, phenytoin; flecainide, propafenone):
Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.
Calcium antagonists of the verapamil type and to a lesser extent of the diltiazem type:
Negative influence on contractility and atrio-ventricular conduction. Intravenous administration of verapamil in patients on beta-blocker treatment may lead to profound hypotension and atrio-ventricular block.
Centrally acting antihypertensive drugs (e.g. clonidine, methyldopa, moxonodine, rilmenidine):
Concomitant use of centrally acting antihypertensive drugs may further decrease the central sympathetic tonus and may thus lead to reduction of heart rate and cardiac output and to vasodilatation. Abrupt withdrawal, particularly if prior to beta-blocker discontinuation, may increase the risk of “rebound hypertension”.
Aliskiren:
In patients other than diabetic or impaired renal patients, risk of hyperkalaemia, worsening of renal function and cardiovascular morbidity and mortality increase.
Concomitant therapy with ACE inhibitor and angiotensin-receptor blocker:
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).
It has been reported in the literature that in patients with established atherosclerotic disease, heart failure, or with diabetes with end organ damage, concomitant therapy with ACE inhibitor and angiotensin-receptor blocker is associated with a higher frequency of hypotension, syncope, hyperkalaemia, and worsening renal function (including acute renal failure) as compared to use of a single renin-angiotensin-aldosterone system agent. Dual blockade (e.g, by combining an ACE inhibitor with an angiotensin II receptor antagonist) should be limited to individually defined cases with close monitoring of renal function, potassium levels, and blood pressure.
Estramustine:
Risk of increased adverse effects such as angioneurotic oedema (angioedema).
Potassium sparing diuretics (e.g. triamterene, amiloride...), potassium (salts):
Hyperkalaemia (potentially lethal), especially in conjunction with renal impairment (additive hyperkalaemic effects).
The combination of perindopril with the above-mentioned drugs is not recommended (see section 4.4). If concomitant use is nonetheless indicated they should be used with caution and with frequent monitoring of serum potassium. For use of spironolactone in heart failure, see below.
Lithium:
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Use of perindopril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see section 4.4).
Antidiabetic agents (insulins, oral hypoglycaemic agents):
Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood-glucose lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.
Concomitant administration of bisoprolol with insulin and oral antidiabetic drugs may increase blood sugar lowering effect. Blockade of beta-adrenoreceptors may mask symptoms of hypoglycaemia.
Non-steroidal anti-inflammatory medicinal products (NSAIDs) (including acetylsalicylic acid ≥3 g/day):
The administration of Cosyrel simultaneously with non-steroidal anti-inflammatory drugs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs) may attenuate the antihypertensive effect of bisoprolol and perindopril.
In addition, concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
Antihypertensive agents and vasodilators:
Concomitant use with antihypertensive agents, vasodilators (such as nitroglycerin, other nitrates or other vasodilators) or with other medications which have a blood-pressure-reducing potential (e.g. tricyclic antidepressants, barbiturates, phenothiazines) may increase the risk of hypotensive effects of perindopril and bisoprolol.
Sympathomimetics:
Beta-sympathomimetics (e.g. isoprenaline, dobutamine): combination with bisoprolol may reduce the effects of both agents.
Sympathomimetics that activate both beta- and alpha-adrenoceptors (e.g. norepinephrine, epinephrine): combination with bisoprolol may unmask the alpha-adrenoceptor-mediated vasoconstrictor effects of these agents, leading to blood pressure increase and exacerbated intermittent claudication. Such interactions are considered to be more likely with nonselective beta-blockers.
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
Based on existing data on monocomponents, Cosyrel is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy.
Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn (reduce placental perfusion associated with growth retardation, intrauterine death, abortion or early labour and adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the foetus and newborn infant). If treatment with beta-adrenoceptor blockers is necessary, beta-1-selective adrenoceptor blockers are preferable.
Bisoprolol should not be used during pregnancy unless clearly necessary. If treatment with bisoprolol is considered necessary, the uteroplacental blood flow and the foetal growth should be monitored. In case of harmful effects on pregnancy or the foetus alternative treatment should be considered. The newborn infant must be closely monitored.
Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days.
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 anti-hypertensive 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 foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3). Should exposure to ACE inhibitor 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 also sections 4.3 and 4.4).
Cosyrel is not recommended during lactation.
It is not known whether bisoprolol is excreted in human milk. Therefore, breastfeeding is not recommended during administration of bisoprolol.
Because no information is available regarding the use of perindopril during breastfeeding, perindopril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
There are no clinical data on fertility with the use of Cosyrel.
Cosyrel has no direct influence on the ability to drive and use machines but individual reactions related to low blood pressure may occur in some patients, particularly at the start of treatment or upon change of medication as well as in conjunction with alcohol.
As a result the ability to drive or operate machinery may be impaired.
The most common adverse reactions to bisoprolol include headache, dizziness, worsening of heart failure, hypotension, cold extremities, nausea, vomiting, abdominal pain, diarrhoea, constipation, asthenia and fatigue.
The most common adverse reactions reported in clinical trials and observed with perindopril include headache, dizziness, vertigo, paraesthesia, visual disturbance, tinnitus, hypotension, cough, dyspnoea, nausea, vomiting, abdominal pain, diarrhoea, constipation, dysgeusia, dyspepsia, rash, pruritus, muscle cramps and asthenia.
The following undesirable effects have been observed during clinical trials and/or post-marketing use with bisoprolol or perindopril given separately and ranked under the MedDRA classification by body system and under the following frequency: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); not known (cannot be estimated from the available data).
| MedDRA System Organ Class | Undesirable Effects | Frequency | |
|---|---|---|---|
| Bisoprolol | Perindopril | ||
| Infections and infestations | Rhinitis | Rare | Very rare |
| Blood and lymphatic System Disorders | Eosinophilia | - | Uncommon* |
| Agranulocytosis (see section 4.4) | - | Very rare | |
| Pancytopenia | - | Very rare | |
| Leukopenia | - | Very rare | |
| Neutropenia (see section 4.4) | - | Very rare | |
| Thrombocytopenia (see section 4.4) | - | Very rare | |
| Haemolytic anaemia in patients with a congenital deficiency of G-6PDH | - | Very rare | |
| Endocrine disorders | Syndrome of inappropriate antidiuretic hormone secretion (SIADH) | - | Rare |
| Metabolism and nutrition disorders | Hypoglycaemia (see sections 4.4 and 4.5) | - | Uncommon* |
| Hyperkalaemia, reversible on discontinuation | - | Uncommon* | |
| Hyponatraemia | - | Uncommon* | |
| Psychiatric disorders | Mood altered | - | Uncommon |
| Sleep disorder | Uncommon | Uncommon | |
| Depression | Uncommon | Uncommon* | |
| Nightmares, Hallucinations | Rare | - | |
| Confusion | - | Very rare | |
| Nervous system disorders | Headache** | Common | Common |
| Dizziness** | Common | Common | |
| Vertigo | - | Common | |
| Dysgeusia | - | Common | |
| Paraesthesia | - | Common | |
| Somnolence | - | Uncommon* | |
| Syncope | Rare | Uncommon* | |
| Eye disorders | Visual impairment | - | Common |
| Reduced tear flow (to be considered if the patient uses lenses) | Rare | - | |
| Conjunctivitis | Very rare | - | |
| Ear and labyrinth disorders | Tinnitus | - | Common |
| Hearing disorders | Rare | - | |
| Cardiac disorders | Palpitations | - | Uncommon* |
| Tachycardia | - | Uncommon* | |
| Bradycardia | Very common | - | |
| Worsening of heart failure | Common | - | |
| AV-conduction disturbances | Uncommon | - | |
| Arrhythmia | - | Very rare | |
| Angina pectoris | - | Very rare | |
| Myocardial infarction possibly secondary to excessive hypotension in high-risk patients (see section 4.4) | - | Very rare | |
| Vascular disorders | Hypotension and effects related to hypotension | Common | Common |
| Feeling of coldness or numbness in the extremities | Common | - | |
| Orthostatic hypotension | Uncommon | - | |
| Vasculitis | - | Uncommon* | |
| Flushing | - | Rare* | |
| Stroke possibly secondary to excessive hypotension in high-risk patients (see section 4.4) | - | Very rare | |
| Raynaud’s phenomenon | - | Not known | |
| Respiratory, thoracic and mediastinal disorders | Cough | - | Common |
| Dyspnoea | - | Common | |
| Bronchospasm | Uncommon | Uncommon | |
| Eosinophilic pneumonia | - | Very rare | |
| Gastro-intestinal disorders | Abdominal pain | Common | Common |
| Constipation | Common | Common | |
| Diarrhoea | Common | Common | |
| Nausea | Common | Common | |
| Vomiting | Common | Common | |
| Dyspepsia | - | Common | |
| Dry mouth | - | Uncommon | |
| Pancreatitis | - | Very rare | |
| Hepato-biliary disorders | Hepatitis either cytolytic or cholestatic (see section 4.4) | Rare | Very rare |
| Skin and subcutaneous tissue disorders | |||
| Rash | - | Common | |
| Pruritus | - | Common | |
| Angioedema of face, extremities, lips, mucous membranes, tongue, glottis and/or larynx (see section 4.4) | - | Uncommon | |
| Urticaria | - | Uncommon | |
| Photosensitivity reactions | - | Uncommon* | |
| Pemphigoid | - | Uncommon* | |
| Hyperhidrosis | - | Uncommon | |
| Hypersensitivity reactions (pruritus, flush, rash and angioedema) | Rare | - | |
| Psoriasis aggravation | - | Rare* | |
| Erythema multiform | - | Very rare | |
| Alopecia | Very rare | - | |
| Beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash | Very rare | - | |
| Musculoskeletal and connective tissue disorders | Muscle cramps | Uncommon | Common |
| Muscular weakness | Uncommon | - | |
| Arthralgia | - | Uncommon* | |
| Myalgia | - | Uncommon* | |
| Renal and urinary disorders | Renal insufficiency | - | Uncommon |
| Acute renal failure | - | Rare | |
| Anuria/Oliguria | - | Rare* | |
| Reproductive system and breast disorders | Erectile dysfunction | Rare | Uncommon |
| General disorders and administration site conditions | Asthenia | Common | Common |
| Fatigue | Common | - | |
| Chest pain | - | Uncommon* | |
| Malaise | - | Uncommon* | |
| Oedema peripheral | - | Uncommon* | |
| Pyrexia | - | Uncommon* | |
| Investigations | Blood urea increased | - | Uncommon* |
| Blood creatinine increased | - | Uncommon* | |
| Hepatic enzyme increased | Rare | Rare | |
| Blood bilirubin increased | - | Rare | |
| Increased triglycerides | Rare | - | |
| Haemoglobin decreased and haematocrit decreased (see section 4.4) | - | Very rare | |
| Injury, poisoning and procedural complications | Fall | - | Uncommon* |
* Frequency calculated from clinical trials for adverse events detected from spontaneous report.
** These symptoms especially occur at the beginning of the therapy. They are generally mild and often disappear within 1-2 weeks.
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 national reporting system.
Not applicable.
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