Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Generics [UK] Ltd. t/a Mylan, Station Close, Potters Bar, Herts EN6 1TL, U.K.
Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, ACE inhibitors, plain
ATC code: C09AA10
Trandolapril is a prodrug, which is rapidly, non-specifically hydrolysed to its potent, long-acting active metabolite, trandolaprilat (other metabolites are inactive) and acts as an orally-active angiotensin converting enzyme inhibitor (ACE inhibitor) without a sulphydryl group. In addition to inhibition of plasma ACE, trandolapril has been experimentally shown to inhibit tissue ACE (particularly vascular, cardial and adrenal). The clinical relevance of tissue ACE inhibition has not been established in humans.
The angiotensin converting enzyme is a peptidyl-dipeptidase, which catalyses the transformation of angiotensin I to the vasoconstrictive angiotensin II and promotes metabolism of bradykinin to inactive fragments.
Small doses of trandolapril induce a potent ACE inhibition, which reduces the angiotensin II production, decreases the aldosterone secretion and increases plasma renin activity by inhibition of the negative feedback regulation.
Trandolapril thus modulates the renin/angiotensin/aldosterone system, which plays a significant role in regulating blood volume and blood pressure.
Inhibition of bradykinin degradation, prostaglandin release and reduced activity in the sympathetic nervous system are other mechanisms of action which may be of importance for ACE inhibitors' vasodilatory activity.
The properties of trandolapril may explain the results obtained in the regression of cardiac hypertrophy with improvement of diastolic function, and improvement of arterial compliance in humans. In addition, a decrease in vascular hypertrophy has been shown in animals.
The drop in peripheral resistance induced by trandolapril is accompanied neither by fluid and salt retention nor by tachycardia.
In hypertensive patients trandolapril reduces the systolic and diastolic blood pressure. Trandolapril has an antihypertensive activity which is independent of the plasma renin level.
In humans the antihypertensive effect of trandolapril is evident about 1 hour after administration, and persists for at least 24 hours, enabling dosage once daily. Trandolapril does not affect the circadian (24-hour) rhythm of the blood pressure.
The antihypertensive effect is maintained during long term treatment without the development of tolerance. There is no rebound effect after discontinuation of treatment. Trandolapril treatment is accompanied by a higher score in evaluating the quality of life.
Combination with a diuretic or a calcium antagonist potentiates the antihypertensive effect of trandolapril.
A multi-centre, placebo-controlled clinical study was performed on patients with left ventricular dysfunction after acute myocardial infarction. A total of 1749 patients were randomised to receive either placebo or trandolapril from the third day after acute myocardial infarction and were followed for at least 24 months.
Trandolapril treatment resulted in 22% reduction in total mortality, 25% reduction of cardio- vascular mortality, 24% reduction of risk of sudden death, 29% reduction in the incidence of severe or resistant cardiac insufficiency and 14% reduction of recurrent myocardial infarction.
Compared with placebo the patients in trandolapril treatment had significantly fewer clinical symptoms of cardiac insufficiency, peripheral oedema, dyspnoea, orthopnoea, paroxysmal nocturnal dyspnoea and fatigue.
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
Trandolapril is absorbed rapidly after oral administration. The amount absorbed is equivalent to 40 to 60% of the administered dose and is not affected by food consumption. About 36% of the absorbed amount is converted to trandolaprilat. The bioavailability of trandolaprilat is about 13% following oral administration of trandolapril.
Peak plasma concentration for trandolapril is achieved about 30 minutes after administration. Trandolapril disappears rapidly from the plasma with a half-life of less than one hour.
Trandolapril is hydrolysed to the active metabolite trandolaprilat, a specific ACE (angiotensin converting enzyme) inhibitor. The amount of trandolaprilat formed is not modified by food consumption. Peak plasma concentration for trandolaprilat is reached 3 to 8 hours after administration.
In the plasma, trandolaprilat is more than 80% protein-bound. It binds saturably, with a high affinity, to ACE. Trandolaprilat is also non-saturably bound to albumin.
After repeated administration of single daily doses of trandolaprilat, steady state was reached on average in four days, both in healthy volunteers and in young or older hypertensives as well as patients with cardiac insufficiency. The effective half-life of trandolaprilat accumulation is between 15 and 23 hours.
Excretion of non-metabolised trandolaprilat in the urine accounts for 10-15 % of the dose administered. After oral administration of the labelled product, 33% of the radioactivity is found in the urine and 66% in the faeces. Renal clearance of trandolaprilat varies from 0.5 to 4 litres per hour, depending on dose.
The renal clearance of trandolaprilat (about 70 ml/min) is proportional to the creatinine clearance. The plasma concentrations of trandolaprilat are significantly higher in patients with a creatinine clearance of ≤30 ml/min and in patients in haemodialysis. A dose adjustment is recommended in these patients (see 4.2).
After repeated dosing in patients with chronic renal failure, steady state is also reached in about four days, whatever the degree of renal failure.
Acute oral toxicity studies of trandolapril and its active metabolite trandolaprilat in rats and mice found both drugs non-toxic with an LD50 values greater than 4,000 mg/kg.
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. These include anaemia and gastric irritation and ulceration.
Studies of reproductive toxicity found affected renal development in rat young with increased incidence of renal pelvis dilatation after doses of at least 10 mg/kg/day, but the normal development of the offspring was not affected.
Trandolapril was not mutagenic or carcinogenic.
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