Trandolapril

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.

The normal dose for adults and older people is recommended to patients with a creatinine clearance between 30-70 ml/min. It is not necessary to adjust the starting dose in patients with a creatinine clearance above 30 ml/min.

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.

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.

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.

Concurrent administration of potassium or potassium-sparing diuretics increases the risk of hyperkalaemia, particularly in renal failure, diabetes mellitus, and/or left ventricular dysfunction after myocardial infarction. In the randomised placebo-controlled, parallel-group Trandolapril Cardiac Evaluation (TRACE) study in patients surviving an acute myocardial infarction with residual left ventricular systolic dysfunction hyperkalaemia 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. Should this combination be considered necessary, frequent monitoring of serum potassium is essential.

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.

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.

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.

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.

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.

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.

There is an increased likelihood of haematological reactions in coadministration of ramipril with allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood cell count. 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.

Concomitant use of trandolapril with lithium may result in an increased plasma lithium concentration, potentially to toxic levels (decreases renal lithium excretion). Use of trandolapril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed.

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.

Initial treatment should be 0.5 mg daily. The dose should be adjusted according to the blood pressure response.

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.

Proteinuria may occur particularly in patients with existing renal function impairment or relatively high doses of ACE inhibitors. Trandolapril should only be administered after critical evaluation of the risk/benefit of treatment of patients with clinically relevant proteinuria (more than 1 g/day).

Anaphylactoid reactions such as facial flushing, hypotension and dyspnoea have been reported in patients dialysed with high-flux membranes (e.g. AN 69) and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Rarely, patients receiving ACE inhibitors during desensitisation with animal venom have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitisation.

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.

ACE inhibitors can cause hyperkalemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. However, in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim or co-trimoxazole also known as trimethoprim/sulfamethoxazole and especially aldosterone antagonists or angiotensin-receptor blockers, hyperkalemia can occur. Potassium-sparing diuretics and angiotensin-receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored.

Risk factors for the development of hyperkalemia include renal insufficiency, worsening of the renal condition, age (>70 years), diabetes mellitus, intercurrent events, in particular dehydration, left ventricular dysfunction after myocardial infarction, 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). Hyperkalaemia can cause serious, sometimes fatal arrhythmias.

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.

In patients on ACE inhibitors, neutropenia/agranulocytosis and bone marrow depression have been seen. These reactions are more frequent in patients with patients with renal impairment, especially those with a collagen vascular disease (e.g. lupus erythematosus disseminatus and scleroderma), as well as immunosuppressive therapy with agents having a potential risk of leucopenia. Neutropenia is reversible after discontinuation of the ACE inhibitor. The best prevention is to keep carefully to the recommended dose. If treatment with an ACE inhibitor is deemed necessary in such risk patients, the risk/benefit ratio must be considered carefully.

Regular monitoring of the white blood cell counts and protein in the urine must be considered in patients with collagen vascular diseases (e.g. lupus erythematosus and scleroderma), especially associated with impaired renal function and concomitant therapy, particularly with corticosteroids and antimetabolites, or treatment with allopurinol or procainamide.

During treatment with an ACE inhibitor, a dry and non-productive cough may occur which disappears after discontinuation. If treatment with an ACE inhibitor is considered essential, a resumption of treatment may be considered.

ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

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.

Intestinal angioedema has been reported 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.

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.

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 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.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, 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 breast-feeding, 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.

Due to individual differences in reaction to an ACE inhibitor, the ability to drive or operate machinery may be reduced due to the side effects seen such as dizziness and fatigue.

This may occur particularly at the start of treatment or when changing over from other medication, after increases in dose or during concurrent 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.

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

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness, when the seriousness could be assessed.

Undesirable side effects are listed below using the following convention: 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), not known (cannot be estimated from the available data).

Infections and infestations

Uncommon: Upper respiratory tract infection.

Rare: Urinary tract infection, bronchitis, pharyngitis.

Blood and lymphatic system disorders

Rare: Leucopenia, anaemia, platelet disorder, white blood cell disorder.

Not known: Agranulocytosis, pancytopenia, platelet count decreased, haemoglobin decreased, haematocrit decreased.

Immune system disorders

Rare: Hypersensitivity.

Metabolism and nutrition disorders

Rare: Hyperglycaemia, hyponatraemia, hypercholesterolaemia, hyperlipidaemia, hyperuricaemia, gout, anorexia, increased appetite, enzyme abnormality.

Not known: Hyperkalaemia

Psychiatric disorders

Uncommon: Insomnia, libido decreased.

Rare: Hallucination, depression, sleep disorder, anxiety, agitation, apathy, nervousness.

Nervous system disorders

Common: Headache, dizziness

Uncommon: Somnolence

Rare: Cerebrovascular accident, syncope, myoclonus, paraesthesia, migraine, migraine without aura, dysgeusia

Not known: Transient ischaemic attack, cerebral haemorrhage, balance disorder

Eye disorders

Rare: Blepharitis, conjunctival oedema, visual impairment, eye disorder

Ear and labyrinth disorders

Uncommon: Vertigo

Rare: Tinnitus

Cardiac disorders

Uncommon: Palpitations

Rare: Myocardial infarction, myocardial ischaemia, angina pectoris, cardiac failure, ventricular tachycardia, tachycardia, bradycardia

Not known: Atrioventricular block, cardiac arrest, arrhythmia, electrocardiogram abnormal

Vascular disorders

Common: Hypotension^*

Uncommon: Hot flushes

Rare: Hypertension, angiopathy, orthostatic hypotension, peripheral vascular disorder, varicose vein

Not known: Cerebrovascular infarction

Respiratory, thoracic and mediastinal disorders

Common: Cough

Uncommon: Upper respiratory tract inflammation, upper respiratory tract congestion

Rare: Dyspnoea, epistaxis, pharyngeal inflammation, oropharyngeal pain, productive cough, respiratory disorder, throat irritation, rhinorrhoea.

Not known: Bronchospasm

Gastrointestinal disorders

Uncommon: Nausea, diarrhoea, constipation, gastro-intestinal pain, gastro-intestinal disorder

Rare: Haematemesis, gastritis, vomiting, abdominal pain, dyspepsia, dry mouth, flatulence.

Not known: Ileus, pancreatitis

Hepatobiliary disorders

Rare: Hepatitis, hyperbilirubinaemia

Very rare: Cholestasis

Not known: Jaundice, liver function test abnormal, transaminases increased

Skin and subcutaneous tissue disorders

Uncommon: Pruritus, skin rash

Rare: Angioedema, hyperhidrosis, psoriasis, eczema, acne, dry skin, skin disorder

Very rare: Dermatitis

Not known: Urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis, alopecia.

Musculoskeletal and connective tissue disorders

Uncommon: Back pain, muscle spasms, pain in extremity

Rare: Myalgia, arthralgia, bone pain, osteoarthritis

Renal and urinary disorders

Rare: Renal failure, azotaemia, polyuria, pollakiuria

Not known: Blood creatinine increased, blood urea increased, proteinuria

Reproductive system and breast disorders

Uncommon: Erectile dysfunction

Congenital, familial and genetic disorders

Rare: Congenital arterial malformation, ichthyosis

General disorders and administration site conditions

Common: Asthenia

Uncommon: Malaise, chest pain, oedema peripheral, feeling abnormal

Rare: Oedema, fatigue

Not known: Pyrexia

Investigations

Very rare: Raised potassium blood levels, gamma-glutamyl transferase, raised lipase, raised immunoglobulin.

Not known: Increased serum urea, increased serum creatinine, reduced platelet count, increased liver function tests (including ASAT and ALAT), blood alkaline phosphatase increased, blood lactate dehydrogenase increased, laboratory test abnormal.

Injury, poisoning and procedural complications

Rare: Injury

* 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).

Undesirable effects reported for ACE inhibitors as a class (frequency not given):

Blood and lymphatic system disorders: Haemolytic anaemia, eosinophilia and/or increased ANA (anti-nuclear antibody)

Nervous system disorders: Confusional state

Eye disorders: Vision blurred

Respiratory, thoracic and mediastinal disorders: Sinusitis, rhinitis, glossitis

Gastrointestinal disorders: Intestinal angioedema.

Skin and subcutaneous tissue disorders: Erythema multiforme, psoriasis-like efflorescences

Congenital, familial and genetic disorders: Haemolytic anaemia with a congenital deficiency concerning G-6 PDH (glucose-6-phosphate dehydrogenase).