All warnings and precautions for use related to each component are applicable to Cosyrel.
Hypotension: 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 Interactions and Adverse Reactions). 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.
Hypersensitivity/Angioedema: 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 Adverse Reactions). 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 Contraindications).
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 Contraindications). 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 Contraindications and Interactions). Concomitant use of other NEP inhibitors (e.g. racecadotril) and ACE inhibitors may also increase the risk of angioedema (see Interactions). Hence, a careful benefit-risk assessment is needed before initiating treatment with NEP inhibitors (e.g. racecadotril) in patients on perindopril.
Concomitant use of mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus): Patients taking concomitant mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see Interactions).
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 (see Adverse Reactions).
Race: 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: 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.
Hyperkalaemia: Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including perindopril. 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). 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. 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 Interactions).
Combination with lithium: The combination of lithium and perindopril is generally not recommended (see Interactions).
Combination with potassium sparing drugs, potassium supplements or potassium-containing salt substitutes: The combination of perindopril and potassium sparing drugs, potassium supplements or potassium-containing salt substitutes is generally not recommended (see Interaction).
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 Interactions and Pharmacology: Pharmacodynamics under Actions).
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 with calcium antagonists, Class I antiarrhytmic drugs and centrally acting antihypertensive drugs: 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 Interactions).
Stopping treatment: 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.
Bradycardia: 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.
First degree AV block: Given their negative dromotropic effect, beta-blockers should be administered with caution to patients with first degree AV block.
Aortic and mitral valve stenosis / hypertrophic cardiomyopathy: 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.
Prinzmetal's angina: Beta-blockers may increase the number and the duration of angina episodes in patients with Prinzmetal's angina. The use of selective blockers of beta-1 adrenergic receptors is possible in mild cases and only in combination with vasodilators.
Renal impairment: In case of renal impairment, the daily dose of Cosyrel should be adjusted according to creatinine clearance (see Dosage & Administration). Routine monitoring of potassium and creatinine are part of normal medical practice for these patients (see Adverse Reactions).
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 previously mentioned, 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.
Renovascular hypertension: 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 Contraindications). 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.
Kidney transplantation: There is no experience regarding the administration of perindopril arginine in patients with recent kidney transplantation.
Haemodialysis patients: 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.
Anaphylactoid reactions during low-density lipoproteins (LDL) apheresis: Rarely, patients receiving ACE inhibitors during LDL apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
Anaphylactic reactions during desensitisation: 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 anaphylactic reactions. Epinephrine treatment does not always yield the expected therapeutic effect.
Neutropenia/Agranulocytosis/Thrombocytopenia/Anaemia: 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).
Bronchospasm (Bronchial asthma, obstructive airways diseases): 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.
Diabetic patients: 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.
Strict fasting: Caution is advised in patients with strict fasting.
Peripheral arterial occlusive disease: Aggravation of symptoms may occur with beta-blockers, especially when starting therapy.
Anaesthesia: 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.
Psoriasis: Patients with psoriasis or with a history of psoriasis should only be given beta-blockers after carefully balancing the benefits against the risks.
Phaeochromocytoma: In patients with known or suspected to have phaeochromocytoma bisoprolol should always be given in combination with an alpha-receptor blocker.
Thyreotoxicosis: Under treatment with bisoprolol the symptoms of a thyreotoxicosis may be masked.
Primary aldosteronism: 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.
Heart failure: There is no therapeutic experience of bisoprolol treatment of heart failure in patients with the following diseases and conditions: insulin dependent diabetes mellitus (type I), severely impaired renal function, severely impaired hepatic function, restrictive cardiomyopathy, congenital heart disease, haemodynamically significant organic valvular disease, myocardial infarction within the last 3 months.
Excipients: Level of sodium.
Cosyrel contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially 'sodium-free'.
Effects on ability to drive and use machines: 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.
Use in Pregnancy: 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. Increased risk of birth defects, foetal and neonatal morbidity and death when ACE inhibitors used throughout pregnancy (see Contraindications and Use in Pregnancy & Lactation).