Interactions : אינטראקציות

4.5 Interaction with other medicinal products and other forms of interaction

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) 
Contra-indicated combinations

The concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see sections 4.3 and 4.4). Treatment with ramipril must not be started until 36 hours after taking the last dose of sacubitril/valsartan.
Sacubitril/valsartan must not be started until 36 hours after the last dose of TRITACE COMP.

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.

Precautions for use

Potassium salts, heparin, potassium-retaining diuretics and other plasma potassium increasing active substances (including Angiotensin II antagonists, trimethoprim and in fixed dose combination with sulfamethoxazole, tacrolimus, ciclosporin): Hyperkalaemia may occur; therefore close monitoring of serum potassium is required.

Antihypertensive agents (e.g. diuretics) and other substances that may decrease blood pressure (e.g. nitrates, tricyclic antidepressants, anaesthetics, acute alcohol intake, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): Potentiation of the risk of hypotension is to be anticipated (see section 4.2 for diuretics).

Vasopressor sympathomimetics and other substances (epinephrine) that may reduce the antihypertensive effect of ramipril: Blood pressure monitoring is recommended.
Furthermore, the effect of the vasopressor sympathomimetics may be attenuated by hydrochlorothiazide.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood cell count: Increased likelihood of haematological reactions (see section 4.4).

Lithium salts: Excretion of lithium may be reduced by ACE inhibitors and therefore lithium toxicity may be increased. Lithium levels must be monitored. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased risk of lithium toxicity with ACE inhibitors. The combination of ramipril and hydrochlorothiazide with lithium is therefore not recommended.

Antidiabetic agents including insulin: Hypoglycaemic reactions may occur.
Hydrochlorothiazide may attenuate the effect of antidiabetic medicines. Particularly close blood glucose monitoring is therefore recommended in the initial phase of co- administration.

Nonsteroidal anti-inflammatory drugs and acetylsalicylic acid: Reduction of the antihypertensive effect of TRITACE COMP is to be anticipated. Furthermore, concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function and to an increase in kalaemia.

Oral anticoagulants: Anticoagulant effect may be decreased due to concomitant use of hydrochlorothiazide.

Corticosteroids, ACTH, amphotericin B, carbenoxolone, large amounts of liquorice, laxatives (in case of a prolonged use), and other kaliuretic or plasma potassium decreasing agents: Increased risk of hypokalaemia.

Digitalis preparations, active substances known to prolong the QT interval and antiarrhythmics: Their proarrhythmic toxicity may be increased or their antiarrhythmic effect decreased in the presence of electrolyte disturbances (e.g. hypokalaemia, hypomagnesaemia).

Methyldopa: Haemolysis possible.

Colestyramine or other enterally administered ion exchangers: Reduced absorption of hydrochlorothiazide. Sulphonamide diuretics should be taken at least one hour before or four to six hours after these medications.

Curare-type muscle relaxants: Possible intensification and prolongation of the muscular relaxing effect.

Calcium salts and plasma calcium increasing medicinal products: Rise in serum calcium concentration is to be anticipated in case of concomitant administration of hydrochlorothiazide; therefore close monitoring of serum calcium is required.

Carbamazepine: Risk of hyponatraemia due to additive effect with hydrochlorothiazide.

Iodine containing contrast media: In case of dehydration induced by diuretics including hydrochlorothiazide, there is increased risk of acute renal impairment, in particular when use of important doses of iodine containing contrast media.

Penicillin: Hydrochlorothiazide is excreted in the distal tubulus, and reduces excretion of penicillin.

Quinine: Hydrochlorothiazide reduces quinine excretion.

Heparin: Rise in serum potassium concentration possible.
mTOR inhibitors or vildagliptin: An increased risk of angioedema is possible in patients taking concomitant medications such as mTOR inhibitors (e.g. temsirolimus, everolimus, sirolimus) or vildagliptin. Caution should be used when starting therapy (see section 4.4).

Neprilysin (NEP) inhibitors: An increased risk of angioedema has been reported with concomitant use of ACE inhibitors and NEP inhibitor such as racecadotril (see section 4.4)

Sacubitril/valsartan
The concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema.