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Dual blockade of the renin-angiotensin-aldosterone system (RAAS): 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).
Medicines increasing the risk of angioedema: Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see Contraindications and Precautions).
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 Precautions).
Drugs inducing hyperkalaemia: Some drugs or therapeutic classes may increase the occurrence of hyperkalaemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin-II receptor antagonists, NSAIDs, heparins, immunosuppressant agents such as ciclosporin or tacrolimus, trimethoprim and Co-trimoxazole (trimethoprim/sulfamethoxazole). The combination of Viacoram with these drugs increases the risk of hyperkalaemia (see Precautions). Therefore, the combination of Viacoram with the previously mentioned drugs is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium.
Concomitant use contraindicated (see Contraindications): Aliskiren: In diabetic or impaired renal patients, 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 contraindicated, as the concomitant inhibition of neprilysin (NEP) 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 (see Precautions): 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). ACE inhibitors must not be associated with hyperkalaemic substances, except in hypokalaemia.
The combination of Viacoram with the previously 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 Viacoram with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see Precautions).
Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of Viacoram containing amlodipine, a calcium channel blocker, be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.
Concomitant use which requires special care: 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.
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 Viacoram.
In arterial hypertension, when prior diuretic therapy can have caused salt/volume depletion, the diuretic must be discontinued before initiating Viacoram, in which case a non-potassium-sparing diuretic can be thereafter reintroduced.
Renal function (creatinine levels) must be monitored during the first few weeks of Viacoram 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.
Non-steroidal anti-inflammatory medicinal products (NSAIDs) including aspirin ≥3 g/day: When ACE-inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of Viacoram 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.
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.
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) (see Precautions).
mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus): Patients taking concomitant mTOR inhibitors therapy may be at increased risk for angioedema (see Precautions).
Gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin): Increased risk of angioedema, due to dipeptidyl peptidase IV (DPP-IV) decreased activity by the gliptin, in patients co-treated with an ACE inhibitor.
CYP3A4 inducers: Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum).
CYP3A4 inhibitors: Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and Viacoram dose adjustment may thus be required.
There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Close observation of patients is recommended when amlodipine is co-administered with clarithromycin.
Concomitant use which requires some care: Antihypertensive agents (such as beta-blockers) and vasodilators: Concomitant use of these agents may increase the hypotensive effects of Viacoram. Concomitant use with nitroglycerine and other nitrates or other vasodilators, may further reduce blood pressure and therefore should be considered with caution.
Tricyclic antidepressants/Antipsychotics/Anaesthetics: Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with Viacoram may result in further reduction of blood pressure.
Sympathomimetics: Sympathomimetics may reduce the antihypertensive effects of Viacoram.
Corticosteroids, tetracosactide: Reduction in antihypertensive effect (salt and water retention due to corticosteroids).
Alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin): Increased antihypertensive effect and increased risk of orthostatic hypotension.
Amifostine: May potentiate the antihypertensive effect of amlodipine.
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.
Grapefruit: Administration of Viacoram with grapefruit or grapefruit juice is not recommended as amlodipine bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.
Tacrolimus: There is a risk of increased tacrolimus blood levels when co-administered with amlodipine. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.
Mechanistic Target of Rapamycin (mTOR) Inhibitors: mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.
Ciclosporine: No drug interaction studies have been conducted with ciclosporine and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0% - 40%) of ciclosporine were observed. Consideration should be given for monitoring ciclosporine levels in renal transplant patients on amlodipine, and ciclosporine dose reductions should be made as necessary.
