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 as follows.
Drugs inducing hyperkalaemia: Some drugs or therapeutic classes may increase the occurrence of hyperkalaemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin-II receptors antagonists, NSAIDs, heparins, immunosuppressant agents such as ciclosporin or tacrolimus, trimethoprim. The combination of these drugs increases the risk of hyperkalaemia.
Concomitant use contraindicated (see Contraindications): Aliskiren: 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: 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 Contraindications). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Sacubitril/Valsartan: The concomitant use of perindopril with sacubitril/valsartan is contra-indicated as the concomitant inhibition of neprilysin and ACE may increase the risk of angioedema. 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 Contraindications and Precautions).
Concomitant use not recommended: Linked to bisoprolol: 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.
Linked to perindopril: 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 Contraindications, Precautions and Pharmacology: Pharmacodynamics under Actions).
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).
Co-trimoxazole (trimethoprim/sulfamethoxazole): Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk for hyperkalaemia (see Precautions).
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 Precautions). 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 as follows.
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 Precautions).
Concomitant use which require special care: Linked to bisoprolol and perindopril: 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 aspirin ≥ 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.
Tricyclic antidepressants/Antipsychotics/Anesthetics: Concomitant use of ACE inhibitors with certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics may result in further reduction of blood pressure.
Concomitant use of bisoprolol with anaesthesics may lead to reduced reflex tachycardia and increased risk of hypotension.
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.
Linked to bisoprolol: Calcium antagonists of the dihydropyridine type such as felodipine and amlodipine: Concomitant use may increase the risk of hypotension, and an increase in the risk of a further deterioration of the ventricular pump function in patients with heart failure cannot be excluded.
Class-III antiarrhythmic drugs (e.g. amiodarone): Effect on atrio-ventricular conduction time may be potentiated.
Parasympathomimetic drugs: Concomitant use may increase atrio-ventricular conduction time and the risk of bradycardia.
Topical beta-blockers (e.g. eye drops for glaucoma treatment): Concomitant use may add to the systemic effects of bisoprolol.
Digitalis glycosides: Reduction of heart rate, increase of atrio-ventricular conduction time.
Linked to perindopril: Baclofen: Increased antihypertensive effect. Monitor blood pressure and adapt antihypertensive dosage if necessary.
Non-potassium-sparing diuretics: Patients on diuretics, and especially those who are volume and/or salt depleted, may experience excessive reduction in blood pressure after initiation of therapy with an ACE inhibitor. The possibility of hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake prior to initiating therapy with low and progressive doses of perindopril.
In arterial hypertension, when prior diuretic therapy can have caused salt/volume depletion, either the diuretic must be discontinued before initiating the ACE inhibitor, in which case a non-potassium-sparing diuretic can be thereafter reintroduced or the ACE inhibitor must be initiated with a low dosage and progressively increased.
In diuretic-treated congestive heart failure, the ACE inhibitor should be initiated at a very low dosage, possibly after reducing the dosage of the associated non-potassium-sparing diuretic. In all cases, renal function (creatinine levels) must be monitored during the first few weeks of ACE inhibitor therapy.
Potassium-sparing diuretics (eplerenone, spironolactone): With eplerenone or spironolactone at doses between 12,5 mg to 50 mg by day and with low doses of ACE inhibitors: In the treatment of class II-IV heart failure (NYHA) with an ejection fraction < 40%, and previously treated with ACE inhibitors and loop diuretics, risk of hyperkalaemia, potentially lethal, especially in case of non-observance of the prescription recommendations on this combination.
Before initiating the combination, check the absence of hyperkalaemia and renal impairment.
A close monitoring of the kalaemia and creatininemia is recommended in the first month of the treatment once a week at the beginning and, monthly thereafter.
Racecadotril: ACE inhibitors (e.g. perindopril) are known to cause angioedema. This risk may be elevated when used concomitantly with racecadotril (a drug used against acute diarrhoea).
mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus): Patients taking concomitant mTOR inhibitors therapy may be at increased risk for angioedema (see Precautions).
Combination use to be taken into consideration: Linked to bisoprolol: Mefloquine: Increased risk of bradycardia.
Monoamine oxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of the beta-blockers but also risk for hypertensive crisis.
Linked to perindopril: Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin): Increased risk of angio-oedema, due to dipeptidyl peptidase IV (DPP-IV) decreased activity by the gliptine, in patients co-treated with an ACE inhibitor.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including perindopril.