Trandolapril

Concomitant use of other NEP inhibitors (e.g. racecadotril) and ACE inhibitors may also increase the risk of angioedema. Hence, a careful benefit-risk assessment is needed before initiating treatment with NEP inhibitors (e.g. racecadotril) in patients on trandolapril.

As with all antihypertensives, non-steroidal anti-inflammatory drugs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effects of trandolapril. 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. These effects are, in principle, reversible and occur especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in older people. Patients should be adequately hydrated and consideration should be given to monitoring blood pressure and renal function after initiation or discontinuation of concomitant therapy, and periodically thereafter.

NSAIDs including acetylsalicylic acid, unless acetylsalicylic acid is used in lower doses as a platelet aggregation inhibitor, should be avoided with ACE inhibitors in patients with heart failure.

Sympathomimetics can reduce the hypotensive effect of ACE inhibitors. The patient should be closely monitored to ensure that the desired effect is achieved.

Drinking alcohol increases the hypotensive effect of trandolapril.

At a creatinine clearance of 0.2-0.5 ml/s (10-30 ml/min), treatment should be initiated with a daily dose of 0.5 mg. If required, the dose can be increased to 1 mg daily as a single dose. At a creatinine clearance below 0.2 ml/s (10 ml/min) and for patients in haemodialysis the dose is 0.5 mg daily as a single dose. For these patients regular supervision of serum potassium and serum creatinine is necessary.

Anaphylactoid reactions to high-flux polyacrylonitrile membranes used in haemodialysis have been reported in patients treated with ACE inhibitors. As with other antihypertensives of this chemical class, this combination should be avoided when prescribing ACE inhibitors to renal dialysis patients.

In patients with severely impaired liver function, a decrease in the metabolic clearance of the parent compound, trandolapril and the active metabolite trandolaprilat results in a large increase in plasma trandolapril levels and to a lesser extent, an increase in trandolaprilat levels. Treatment with trandolapril should therefore be initiated at a dose of 0.5 mg once daily under close medical supervision and adjusted according to therapeutic response.

Concurrent administration may lead to reduced bioavailability of ACE inhibitors. Therefore, at least two hours should elapse between administration of trandolapril and antacids.

As with all ACE inhibitors, concomitant use of antidiabetic medicines (insulin or oral hypoglycaemic agents) may cause an increased blood glucose lowering effect with greater risk of hypoglycaemia. Therefore, blood glucose should be closely monitored in diabetics, particularly when starting or increasing the dose of an ACE inhibitor.

The combination of trandolapril and other antihypertensive agents may potentiate the antihypertensive response to ACE inhibitors.

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.

In the event of prior diuretic treatment, special precautions must be taken: It is recommended either to discontinue the diuretic treatment at least 72 hours before the trandolapril treatment is begun and/or start with 0.5 mg daily. In that case the dose must be adjusted in accordance with the patient’s response. If the diuretic treatment must necessarily continue, medical supervision is necessary.

Patients in diuretic treatment, especially patients who have recently begun treatment or patients with volume and/or salt depletion, may develop a severe fall in blood pressure and/or pre-renal failure after initial treatment with an ACE inhibitor. The risk of hypotensive episodes can be reduced by discontinuing the diuretics, by increasing salt intake beforehand and by starting treatment with lower initial doses of ACE inhibitor. Further dose increase should be made with caution. Trandolapril may attenuate the potassium loss caused by thiazide-type and loop diuretics.

Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with trandolapril. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Care should also be taken when trandolapril is co-administered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole) as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Therefore, the combination of trandolapril 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 use of trandolapril with potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes particularly increases the risk of hyperkalaemia in renal failure, diabetes mellitus, and/or left ventricular dysfunction after myocardial infarction. In the randomized, placebo-controlled, parallel-group TRAndolapril Cardiac Evaluation (TRACE) Study in patients surviving an acute myocardial infarction with residual left ventricular systolic dysfunction hyperkalemia was observed as an adverse event in 5% (0.2% related) and 3% subjects (none related) in the trandolapril and placebo groups, respectively. Eighty (80%) subjects in this study received diuretics.

ACE inhibitors may potentiate the hypotensive effects of certain inhalation anaesthetic agents.

Postural hypotension may occur if trandolapril and opiates or antipsychotic agents administered concurrently.

There is an increased risk of orthostatic hypotension, as with all other antihypertensives, in combination with neuroleptics or tricyclic antidepressants.

If used concomitantly with ACE inhibitors, they may increase the risk of leucopoenia.

Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.

Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.

Trandolapril may reduce the elimination of lithium. Serum lithium levels should be monitored.

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment). Caution should be used when starting racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin in a patient already taking an ACE inhibitor.

Treatment of renovascular hypertension is carried out by revascularisation.

However, ACE inhibitors may be of use until revascularisation can be effected, or if such a procedure is not to be carried out. The risk of severe arterial hypotension and renal insufficiency is increased when patients with prior unilateral or bilateral renal artery stenosis are treated with an ACE inhibitor. Diuretics may further increase the risk. Loss of renal function may occur with only small changes in the serum creatinine, even in patients with unilateral renal artery stenosis. For these patients treatment should be initiated in the hospital under close medical supervision with low doses and careful dose adjustment. Diuretic treatment should be discontinued, and renal function and serum potassium monitored during the early weeks of treatment.

Anaphylactoid reactions (in some cases life threatening) may develop in patients receiving ACE inhibitor therapy and concomitant desensitization against animal venoms.

Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions did not occur when ACE inhibitors were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently readministered.

In patients undergoing major surgery or during anaesthesia with potentially hypotensive agents, ACE inhibitors including trandolapril may block angiotensin II formation secondary to compensatory renin release which may induce a possibly severe arterial hypotension, which can be corrected with plasma expanders. If it is not possible to discontinue treatment with the ACE inhibitor, volume therapy should be given with care.

In hypertensive patients who also have congestive heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed after treatment with ACE inhibitors. In these patients, therapy should be started at a dose of 0.5 mg trandolapril once daily under close medical supervision in hospital.

Rarely, patients receiving ACE inhibitors during low density lipoprotein (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.

ACE inhibitors should not be used in patients with aortic stenosis or obstructed outflow from the left ventricle.

There is no experience regarding the administration of trandolapril in patients with a recent kidney transplantation. Treatment with trandolapril is therefore not recommended.

There are rare reports of nitritoid reactions (symptoms include flushing of the face, nausea, vomiting and hypotension) in patients receiving concomitant injection treatment with gold (sodium aurothiomalate) and treatment with an ACE inhibitor.

As is the case with other ACE inhibitors, trandolapril may be less effective lowering blood pressure in black than in non black patients. This may possibly be due to a higher incidence of low renin conditions in hypertensive black patients.

The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contra-indicated during the second and third trimester of pregnancy.

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 the 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.

ACE inhibitor therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased, renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia). Should exposure to trandolapril have occurred from the second trimester of pregnancy, an ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension.

Because no information is available regarding the use of trandolapril during breastfeeding, trandolapril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Given the pharmacological properties of trandolapril, no particular effect is expected. However, in some individuals, ACE inhibitors may affect the ability to drive or operate machinery, particularly at the start of treatment, when changing over from other medication or during concomitant use of alcohol. Therefore, after the first dose or subsequent increases in dose, it is not advisable to drive or operate machinery for several hours.

Tabulated list of adverse drug reactions

The listed ADRs have been reported during the clinical phase, the post-marketing surveillance or the phase IV clinical trials

The following convention is used for the frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). When frequency cannot be estimated from the available data, category frequency: Not known (cannot be estimated from the available data) applies.

The following table displays adverse reactions reported in hypertension (n=2,520) and post myocardial infarction (n=876) clinical trials and from postmarketing experience with trandolapril.

^* Hypotension has a common frequency in patients with left ventricular dysfunction following myocardial infarction from the TRACE clinical study (n=876). However, it has an uncommon frequency in those patients from hypertension clinical trials (n=2,520).
^** Indicates ACEis' class ADR’s