Trandolapril 0.5mg Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Trandolapril 0.5 mg Capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains:
Trandolapril 0.5 mg
For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Capsules, Hard
Size “4” capsules with orange coloured cap imprinted with ‘TR’ in black ink and ivory coloured body imprinted with ‘0.5’ in black ink, containing white to off-white powder.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Mild or moderate hypertension.
Left ventricular dysfunction after myocardial infarction.
It has been demonstrated that Trandolapril Capsules improves survival following myocardial infarction in patients with left ventricular dysfunction (ejection fraction < 35 percent), with or without symptoms of heart failure, and/or with or without residual ischaemia.
Long-term treatment with Trandolapril Capsules significantly reduces the overall cardiovascular mortality. It significantly decreases the risk of sudden death and the occurrence of severe or resistant heart failure.
4.2 Posology and method of administration
Adults
Hypertension
For adults not taking diuretics, without congestive heart failure and without renal or hepatic insufficiency, the recommended initial dosage is 0.5mg as a single daily dose. A 0.5mg dose will only achieve a therapeutic response in a minority of patients. Dosage should be doubled incrementally at intervals of 2 to 4 weeks, based on patient response, up to a maximum of 4mg as a single daily dose.
The usual maintenance dose range is 1 to 2mg as a single daily dose. If the patient response is still unsatisfactory at a dose of 4mg Trandolapril Capsules, combination therapy should be considered.
Left ventricular dysfunction after myocardial infarction
Following a myocardial infarction, therapy may be initiated as early as the third day. Treatment should be initiated at a daily dose of 0.5mg. The dose should be progressively increased to a maximum of 4mg as a single daily dose. Depending upon the tolerability such as symptomatic hypotension, this forced titration can be temporarily suspended.
In the event of hypotension, all concomitant hypotensive therapies such as vasodilators, including nitrates and diuretics must be carefully checked and if possible, their dose reduced.
The dose of Trandolapril Capsules should be lowered only if the previous measures are not effective or not feasible.
Elderly
The dose in elderly patients is the same as in adults. There is no need to reduce the dose in elderly patients with normal renal and hepatic function. Caution is required in elderly patients with concomitant use of diuretics, congestive heart failure or renal or hepatic insufficiency. The dose should be titrated according to the need to control blood pressure.
Prior diuretic treatment
In patients who are at risk from a stimulated renin-angiotensin system (e.g. patients with water and sodium depletion), the diuretic should be discontinued 2-3 days before beginning therapy with 0.5mg trandolapril to reduce the likelihood of symptomatic hypotension. The diuretic may be resumed later if required.
Cardiac failure
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 0.5mg Trandolapril Capsules once daily under close medical supervision in hospital.
Dosage adjustment in renal impairment
For patients with mild or moderate renal impairment (creatinine clearance of 10-70ml/min), the usual adult and elderly doses are recommended.
For patients with severe renal impairment (creatinine clearance of <10ml/min), the usual adult and elderly starting doses are also recommended but the maximum daily dose should not exceed 2mg. In these patients, therapy should be under close medical supervision.
Dialysis: It is not known for certain if trandolapril or trandolaprilat are removed by dialysis. However, it would be expected that dialysis could remove the active moiety, trandolaprilat, from the circulation, resulting in a possible loss of control of blood pressure. Therefore careful monitoring of the patient's blood pressure during dialysis is required, and the dosage of trandolapril adjusted if needed.
Dosage adjustment in hepatic impairment
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 Capsules should therefore be initiated at a dose of 0.5mg once daily under close medical supervision.
Children
Trandolapril Capsules has not been studied in children and therefore use in this age group is not recommended.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or any other ACE inhibitor.
History of angioneurotic oedema associated with administration of an ACE inhibitor.
Hereditary/idiopathic angioneurotic oedema.
Second and third trimesters of pregnancy (see section 4.4. and 4.6).
Use in children.
The concomitant use of Trandolapril with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).
4.4 Special warnings and precautions for use
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
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 (see sections 4.5 and 5.1).
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.
Trandolapril Capsules should not be used in patients with aortic stenosis or outflow obstruction.
In these patients treatment should be started in hospital under close medical supervision with low doses and careful dose titration. Renal failure in association with ACE inhibitors has mainly been reported in patients with severe heart failure or underlying renal disease, including renal artery stenosis.
Assessment of renal function
Evaluation of the patient should include assessment of renal function prior to initiation of therapy and during treatment. Proteinuria may occur if renal impairment is present prior to therapy or relatively high doses are used.
Impaired renal function
Patients with severe renal insufficiency may require reduced doses of Trandolapril Capsules; their renal function should be closely monitored. In the majority, renal function will not alter. In patients with renal insufficiency, congestive heart failure or unilateral or bilateral renal artery stenosis, in the single kidney as well as after renal transplantation, there is a risk of impairment of renal function.
If recognised early, such impairment of renal function is reversible upon discontinuation of therapy.
Some hypertensive patients with no apparent pre-existing renal disease may develop minor and usually transient increases in blood urea nitrogen and serum creatinine when Trandolapril Capsules is given concomitantly with a diuretic. Dosage reduction of Trandolapril Capsules and/or discontinuation of the diuretic may be required. Additionally, in patients with renal insufficiency, the risk of hyperkalaemia should be considered and the patient's electrolyte status checked regularly.
Patients with renovascular hypertension
There is an increased risk of severe hypotension and renal insufficiency when patients with renovascular hypertension and pre-existing bilateral renal artery stenosis or stenosis of the artery to a solitary kidney are treated with ACE inhibitors. Treatment with diuretics may be a contributory factor. Loss of renal function may occur with only mild changes in serum creatinine even in patients with unilateral renal artery stenosis. In these patients treatment should be started in hospital under close medical supervision with low doses and careful dose titration. Diuretic treatment should be discontinued and renal function should be monitored during the first weeks of therapy
Impaired liver function
As trandolapril is a prodrug metabolised to its active moiety in the liver, thus particular caution and close monitoring should be applied to patients with impaired liver function as it may lead to elevated plasma levels, therefore dose adaptation may be required.
Symptomatic Hypotension
In patients with uncomplicated hypertension, symptomatic hypotension has been observed rarely after the initial dose of Trandolapril Capsules as well as after increasing the dose of Trandolapril Capsules, ACE inhibitors may cause a profound fall in blood pressure. It has been reported mainly in patients with severe heart failure with or without renal insufficiency. It is also more likely to occur in patients who have been volume-and salt-depleted by prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting. This is more likely to occur in patients on high dose loop diuretics, or those with hyponatraemia or functional renal impairment. Therefore, in these patients, diuretic therapy should be discontinued and volume and/or salt depletion should be corrected before initiating therapy with Trandolapril Capsules. These patients should also be kept under very close medical supervision when starting treatment preferably in hospital with low doses and careful titration. These considerations also apply to patients with angina pectoris or cerebrovascular disease in whom excessive hypotension could result in a myocardial infarction or cerebrovascular accident.
If symptomatic hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of physiological saline. Intravenous atropine may be necessary if there is associated bradycardia. Treatment with Trandolapril Capsules may usually be continued following restoration of effective blood volume and blood pressure. The appearance of hypotension after the initial dose does not preclude subsequent careful dose titration with drug after effective management.
Surgery/ Anaesthesia
In patients undergoing surgery or during anaesthesia ACE inhibitors may cause hypotension or even hypotensive shock due to enhancement of agents producing hypotension. Trandolapril Capsules may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by appropriate treatment. If it is not possible to withhold the ACE inhibitor, volume management should be handled with care.
Agranulocytosis and bone marrow depression
In patients on ACE inhibitors, agranulocytosis and bone marrow depression have been seen rarely. They are more frequent in patients with renal impairment, especially if they have a collagen vascular disease. However, regular monitoring of white blood cell counts and protein levels in urine should be considered in patients with collagen vascular disease (e.g. lupus erythematosus and scleroderma), especially associated with impaired renal function and concomitant therapy, particularly with corticosteroids and antimetabolites.
Aortic stenosis/hypertrophic cardiomyopathy
ACE inhibitors should be used with caution in patients with an obstruction in the outflow tract of the left ventricle.
Proteinnuria
It may occur particularly in patients with existing renal function impairment or on relatively high doses of ACE inhibitors.
Hyperkalaemia
Elevated serum potassium has been observed very rarely in hypertensive patients. Risk factors for the development of hyperkalaemia include renal insufficiency, potassium-sparing diuretics, the concomitant use of agents to treat hypokalaemia, diabetes mellitus and/or left ventricular dysfunction after myocardial infarction. Potassium supplements or potassium sparing diuretics are generally not recommended, since they may lead to significant increases in plasma potassium. If concomitant use of the above mentioned agents is deemed appropriate, they should be used with frequent monitoring of serum potassium.
Angioneurotic Oedema
Rarely, ACE inhibitors (such as trandolapril) may cause angioneurotic oedema that includes swelling of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx especially during the first week of treatment. However in rare cases severe angioedema may develop after long term treatment with an ACE inhibitor. Patients experiencing angioneurotic oedema must immediately discontinue Trandolapril Capsules therapy and given an agent belonging to another class of drugs and be monitored until oedema resolution.
Angioneurotic oedema to the face will usually resolve spontaneously. Oedema involving not only the face but also the tongue, glottis or larynx may be life-threatening because of the risk of airway obstruction.
Angioneurotic oedema involving the tongue, glottis or larynx requires immediate subcutaneous administration of 0.3-0.5 ml of adrenaline solution (1:1000) or slow intravenous adrenal in (1mg/ml), with control of EGG and blood pressure. The patient should be hospitalised and observed for at least 12 to 24 hours and should not be discharged until complete resolution of symptoms has occurred.
Caution must be exercised in patients with a history of idiopathic angioneurotic oedema and Trandolapril Capsules is contraindicated if angioneurotic oedema was an adverse reaction to an ACE inhibitor (see Contraindications, section 4.3).
Cough:
During treatment with an ACE inhibitor, a dry and non-productive cough may occur which disappears after discontinuation.
Hereditary disorders:
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Elderlv
Some elderly patients may be more responsive to an ACE inhibitor than younger patients. Administration of low initial doses and evaluation of renal function at the beginning of the treatment is recommended.
Children
ACE inhibitors should not be administered to children unless safety and efficacy have been established.
Pregnancy
ACE inhibitors should not be initiated during pregnancy. 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 (see sections 4.3 and 4.6)
4.5 Interaction with other medicinal products and other forms of interaction
Drug interactions
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).
Combination with diuretics or other antihypertensive agents may potentiate the antihypertensive response to Trandolapril Capsules. Adrenergic-blocking drugs should only be combined with trandolapril under careful supervision. Potassium-sparing diuretics (spironolactone, amiloride, triamterene) or potassium supplements may increase the risk of hyperkalaemia, particularly in renal failure. Trandolapril Capsules may attenuate the potassium loss caused by thiazide-type diuretics. If concomitant use of these agents is indicated, they should be given with caution and serum potassium should be monitored regularly.
Antidiabetic agents
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 treated with a hypoglycaemic agent and Trandolapril Capsules, particularly when starting or increasing the dose of ACE inhibitor, or in patients with impaired renal function.
Combinations necessitating a warning
In some patients already receiving diuretic treatment or are volume and/or salt depleted, particularly if this treatment has been recently instituted, the fall in blood pressure on initiation of treatment with Trandolapril Capsules may be excessive. The risk of symptomatic hypotension may be reduced by stopping the diuretic a few days before starting treatment with Trandolapril Capsules. If it is necessary to continue the diuretic treatment, the patient should be monitored, at least after the initial administration of Trandolapril Capsules. As with all antihypertensives, combination with a neuroleptic or tricyclic antidepressant increases the risk of orthostatic hypotension. Trandolapril
Capsules may reduce the elimination of lithium and serum levels of lithium should be monitored.
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.
The effects of certain anaesthetics may be enhanced by ACE inhibitors .
Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide may increase the risk of leucopenia, if used concomitantly with ACE inhibitors.
The antihypertensive effect of ACE inhibitors may be reduced by the administration of NSAIDs. An additive effect on serum potassium increase has been described when NSAIDs and ACE inhibitors have been used concomitantly, while renal function may be reduced.
Antacids cause reduced bioavailability of ACE inhibitors.
The antihypertensive effects of ACE inhibitors may be reduced by sympathomimetics; patients should be carefully monitored.
No clinical interaction has been observed in patients with left ventricular dysfunction after myocardial infarction when Trandolapril Capsules has been concomitantly administered with thrombolytics, aspirin, beta-blockers, calcium channel blockers, nitrates, anticoagulants, diuretics or digoxin.
Alcohol enhances the hypotensive effect.
4.6 Fertility, pregnancy and lactation
Pregnancy
The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).
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). (See section 5.3.). 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 (see also section 4.3 and 4.4).
Lactation
Because no information is available regarding the use of Trandolapril capsules during breastfeeding, Trandolapril capsules are not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.
4.7 Effects on ability to drive and use machines
In individual cases as a result of a reduction in blood pressure, treatment with Trandolapril Capsules may affect the ability to drive and operate machinery. This may occur particularly at the start of treatment, when changing over from mother 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.
4.8 Undesirable effects
Generally, adverse reactions are mild and transient, and do not require discontinuation of therapy. The most frequently reported adverse reactions are nausea, dizziness and headache.
The following undesirable effects have been observed during treatment with trandolapril and other ACE inhibitors with the following frequencies: Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare
(>1/10,000, <1/1,000), very rare (<1/10,000) including isolated reports.
Blood and the lymphatic system disorders:
Rare: decreases in haemoglobin, decreases in haematocrit.
Very rare: bone marrow depression, anaemia, thrombocytopenia, leucopenia, neutropenia, eosinophilia, agranulocytosis, haemolytic anaemia, lymphadenopathy, autoimmune disease.
These changes in blood picture occur more often in patients with renal insufficiency and in patients with a vascular collagen disease, such as lupus erythematodes and sclerodermia, and in simultaneous use of medicines that may also instigate changes in blood picture.
Isolated cases of hemolytic anaemia in patients with congenital loss of the enzyme glucose-6-phosphate-dehydrogenasee (G-6-PD) have been reported.
Metabolism and nutrition disorders
Nervous system and psychiatric disorders:
Common: dizziness, headache
Uncommon: mood alterations, paraesthesia, vertigo, taste disturbance, sleep disturbances.
Rare: mental confusion, somnolence, depression, disturbance of balance, muscle convulsions, nervousness, tinnitus, blurred vision
Cardiac and vascular disorders:
Common: orthostatic effects (including hypotension)
Uncommon: myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients, palpitations, tachycardia, Raynaud’s phenomenon
Occasionally at the beginning of treatment or at increase of the dose of trandolapril and/or diuretic, hypotension may occur. This is especially observed in high risk patients i.e. patients who are salt- or volume depleted after diuretic treatment, heart failure and severe or renal hypertension. Symptoms such as dizziness, sense of fatigue, disturbed vision, rarely accompanied by loss of consciousness (syncope) may occur.
Individual cases of tachycardia, palpitations, arrhythmia, chest pain, angina pectoris, myocardial infarction, transient ischemic attacks and strokes have been reported for ACE-inhibitors in connection with a profound fall in blood pressure.
If trandolapril is administered to patients with acute myocardial infarction, an AV block of second or third degree and/or severe hypotension and/or renal failure, and in rare cases cardiogenic shock, may occasionally occur, especially within the first 24 hours.
Respiratory, thoracic and mediastinal disorders:
Common: cough
Uncommon: dyspnoea, rhinitis, sore throat, hoarseness
Very rare: bronchospasm, sinusitis, stomatitis, glossitis, lung infiltration, allergic alveolitis/eosinophilic pneumonia
Gastrointestinal disorders:
Common: diarrhoea, vomiting
Uncommon: nausea, abdominal pain and indigestion, anorexia Rare: dry mouth, constipation, loss of appetite
Very rare: pancreatitis, hepatitis- either hepatocellular or cholestatic, jaundice, intestinal angioedema.
Skin and subcutaneous tissue disorders:
Uncommon: rash, pruritus
Rare: hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported rarely, urticaria, alopecia, psoriasis
Very rare: diaphoresis, pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme, photosensitivity, blushing, onycholysis, aggravation of Raynaud’s disease.
A symptom complex has been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia/arthritis, a positive antinuclear antibodies (ANA), elevated red blood cell sedimentation rate (ESR), eosinophilia and leucocytosis, rash, photosensitivity or other dermatological manifestations may occur.
Renal and urinary disorders:
Common: renal dysfunction
Rare: uraemia, acute renal failure, proteinuria
Very rare: oliguria/anuria, bacterial interstitial nephritis
Reproductive system and breast disorders:
Uncommon: impotence Rare: gynaecomastia
General disorders and administration site conditions:
Uncommon: fatigue, asthenia
Investigations:
Uncommon: increases in blood urea, increases in serum creatinine, increases in liver enzymes, hyperkalaemia
Rare: increases in serum bilirubin, hyponatraemia.
4.9 Overdose
Symptoms expected with ACE inhibitors are severe hypotension, shock, stupor, bradycardia, electrolyte disturbance and renal failure. In the event of overdosage following recent ingestion, consideration should be given to emptying the stomach contents. Blood pressure should be monitored and if hypotension develops, volume expansion should be considered.
After ingestion of an overdose, the patient should be kept under close supervision, preferably in an intensive care unit. Serum electrolytes and creatinine should be monitored frequently
Therapeutic measures depend on. the nature and severity of the symptoms. Measurements to prevent absorption such as gastric lavage, administration of adsorbents and sodium sulphate within 30 minutes after intake and hasten elimination should be applied if ingestion is recent. If hypotension occurs, the patient should be placed in the shock position and salt and volume. Supplementation should be given rapidly. Treatment with angiotensin II should be considered. Bradycardia or extensive vagal reactions should be treated by administering atropine. The use of a pacemaker may be considered, ACE inhibitors may be removed from the circulation by hemodialysis. The use of high-flux polyacrylonitrile membranes should be avoided
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC Code: C 09A A10
Trandolapril Capsules contain the prodrug, trandolapril, a non-peptide ACE inhibitor with a carboxyl group but without a sulphydryl group. Trandolapril is rapidly absorbed and then non-specifically hydrolysed to its potent, long-acting active metabolite, trandolaprilat.
Trandolaprilat binds tightly and in a saturable manner to ACE.
The beneficial effects of ACE inhibitors in hypertension and in heart failure appear to result primarily from the suppression of the plasma angiotensin aldosterone system.
The administration of trandolapril causes decreases in the concentrations of angiotensin II, aldosterone and atrial natriuretic factor and increases in plasma renin activity and concentrations of angiotensin I. Renin is an endogenous enzyme synthesized by the kidneys and released into the circulation where it converts angiotensinogen to angiotensin I. Angiotensin I is then converted by angiotensin converting enzyme to angiotensin II which is a potent vasoconstrictor responsible for arterial vasoconstriction and increased blood pressure, as well as for stimulation of the adrenal gland to secrete aldosterone. Inhibition of ACE results in a decreased plasma angiotensin II leading to decreased vasopressor activity and to reduced aldosterone secretion. The cessation of the negative feedback of angiotensin II on the renin secretion results in an increase of the plasma renin activity. ACE also degrades the potent vasodepressive kinin peptide bradykinin to inactive metabolites. Therefore inhibition of ACE results in an increased activity of circulating and local kallikrein-kinin-system which contributes to peripheral vasodilation by activating the prostaglandin system. Trandolapril Capsules thus modulates the reninangiotensin-aldosterone system which plays a major part in regulating blood volume and blood pressure and consequently has a beneficial antihypertensive effect.
The properties of trandolapril might 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.
Achievement of optimal blood pressure reduction may require several weeks of therapy in some patients. The antihypertensive effects are maintained during long term therapy.
The haemodynamic effects of ACE therapy in patients with heart failure result from both arteriolar and venodilatation. Systemic vascular resistance is decreased and venous capacity increased. Thus, pre and after - load are reduced. Consequences are a decrease in left ventricular filling pressure/capillary wedge pressure and an increase in cardiac output; heart rate remains unchanged or may even decrease. Clinically, signs and symptoms of the heart failure will improve and exercise capacity will increase. These effects are maintained during long term treatment.
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.
5.2 Pharmacokinetic properties
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 peak plasma concentration of trandolaprilat is reached after 4 to 6 hours.
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 non-saturably bound to albumin.
After repeated administration of Trandolapril 0.5 mg Capsules in a single daily dose, steady state is reached on average in four days, both in healthy volunteers and in young or elderly hypertensives. The effective half-life of trandolaprilat is between 16 and 24 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.
Trandolaprilat eliminated in the urine in the unchanged form accounts for 10 to 15% of the dose of trandolapril administered. After oral administration of the labeled product in man, 33% of the radioactivity is found in the urine and 66% in the faeces.
The renal clearance of trandolaprilat is proportional to the creatinine clearance. The plasma concentrations of trandolaprilat are significantly higher in patients with a creatinine clearance less than or equal to 30ml/min. However, after repeated dosing in patients with chronic renal failure, steady state is also reached on average in four days, whatever the degree of renal failure.
5.3 Preclinical safety data
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 of20 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. Trandolapril was not mutagenic or carcinogenic.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Capsule
Maize starch Lactose monohydrate Povidone
Sodium stearyl fumarate
Capsule Shell
Erythrosine- FD&C Red 3 (E127)
Titanium dioxide (E171)
Yellow iron oxide (E 172)
Gelatin
Printing Ink:
Shellac
Potassium Hydroxide Black iron Oxide (E172)
6.2 Incompatibilities
None
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 25 °C.
6.5 Nature and contents of container
Cold forming Alu/Alu blister calendar pack containing 14 capsules
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Lupin (Europe) Limited Victoria Court, Bexton Road Knutsford
Cheshire W A 16 0PF United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 35507/0025
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
September 2009
10 DATE OF REVISION OF THE TEXT
28/10/2014