Source: Health Products Regulatory Authority (IE) Revision Year: 2020 Publisher: Mylan IRE Healthcare Limited, Unit 35/36, Grange Parade, Baldoyle Industrial, Estate, Dublin 13, Ireland
Pharmacotherapeutic group: ACE inhibitors, plain
ATC Code: C09AA10
Results obtained with trandolapril have shown 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.
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 very rapidly absorbed after oral administration. The amount absorbed is equivalent to 40 to 60% of the administered dose and is not affected by food consumption.
The peak plasma concentration of trandolapril is observed 30 minutes after administration. Trandolapril disappears rapidly from the plasma with a half-life of less than one hour.
Trandolapril is hydrolysed to trandolaprilat, a specific ACE inhibitor. The amount of trandolaprilat formed is not modified by food consumption. The median peak plasma concentration values of trandolaprilat are reached after 3 to 8 hours. The absolute bioavailability following trandolapril dose is about 13%.
In the plasma, trandolaprilat is more than 80% protein-bound. It binds saturably, with a high affinity, to ACE. The major proportion of circulating trandolaprilat is also nonsaturably bound to albumin.
After repeated administration of Odrik in a single daily dose, steady state of trandolaprilat is reached on average in four days, both in healthy volunteers and in young or older hypertensives. The effective half-life of trandolaprilat is between 15 and 23 hours. The terminal half-life of elimination is between 47 hours and 98 hours, depending on dose. This terminal phase probably represents binding/dissociation kinetics of the trandolaprilat/ACE complex.
About 9-14% of an administered trandolapril dose is excreted as trandolaprilat in urine. A negligible amount of trandolapril is excreted unchanged in the urine (<0.5%). After oral administration of the labelled product in man, 33% of the radioactivity is found in the urine and 66% in the faeces.
Trandolapril pharmacokinetics have not been evaluated in patients less than 18 years of age.
Trandolapril pharmacokinetics have been investigated in older people (over 65 years) and in both genders. The plasma concentration of trandolapril is increased in older hypertensive patients, but the plasma concentration of trandolaprilat and inhibition of ACE activity are similar in old and young hypertensive patients.
The pharmacokinetics of trandolapril and trandolaprilat and inhibition of ACE activity are similar in older male and female hypertensive patients.
Compared to normal subjects, the plasma concentrations of trandolapril and trandolaprilat are approximately two-fold greater and renal clearance is reduced by about 85% in patients with creatinine clearance below 30 mL/min and in patients on haemodialysis. Dosage adjustment is recommended in renal impaired patients.
Following oral administration in patients with mild to moderate alcoholic cirrhosis, plasma concentrations of trandolapril and trandolaprilat were, respectively, nine-fold and two-fold greater than in normal subjects, but inhibition of ACE activity was not affected. Lower doses should be considered in patients with hepatic insufficiency.
Acute oral toxicity studies of trandolapril and its active metabolite, trandolaprilat, in rats and mice showed both compounds to be non-toxic with respective LD50 values of >4000 mg/kg and >5000 mg/kg.
Repeat dose oral toxicity was evaluated in the rat and dog with studies of up to 18 and 12 months' duration, respectively.
The principal observations in these studies were of anaemia (doses of 20 mg/kg/day and above in the rat 30-day study and 25 mg/kg/day and above in the dog 6-month study), gastric irritation and ulceration (doses of 20 mg/kg/day and above in the rat 30-day study and 125 mg/kg/day in the dog 6-month study) and renal lesions (20 mg/kg/day and above in the rat 30-day study and 10 mg/kg/day in the dog 30-day study). Renal lesions were also seen in the 6-month studies in the rat and dog (from doses of 0.25 and 25 mg/kg/day, respectively); these were reversible on cessation of treatment.
Reproduction toxicity studies showed effects on renal development in offspring with increased incidence of renal pelvic dilation; this was seen at doses of 10 mg/kg/day and above in the rat but these changes did not affect the normal development of the offspring (see Section 4.6 Pregnancy and Lactation).
Trandolapril was not mutagenic or carcinogenic.
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