ACE inhibitors.

Trandolapril - hypertension

Trandolapril, 0.5mg Trandolapril, 1.0mg Trandolapril, 2.0mg Trandolapril, 4.0mg

Capsules, Hard 0.5mg: opaque red/yellow capsules 1.0mg: opaque red/orange capsules 2.0mg: opaque red/red capsules 4.0mg: opaque red/maroon capsules

Mild or moderate hypertension. Left ventricular dysfunction after myocardial infarction. It has been demonstrated that Gopten 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 Gopten significantly reduces the overall cardiovascular mortality.

It significantly decreases the risk of sudden death and the occurrence of severe or resistant heart failure.

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 Gopten, 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 Gopten should be lowered only if the previous measures are not effective or not feasible

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 Gopten 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 Gopten should therefore be initiated at a dose of 0.5mg once daily under close medical supervision.

Gopten has not been studied in children and therefore use in this age group is not recommended.

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.

Known hypersensitivity to trandolapril.

History of angioedema associated with administration of an ACE inhibitor.

Hereditary/idiopathic angioneurotic oedema.

Second and third trimester of pregnancy.

Lactation.

Use in children

Gopten should not be used in patients with aortic stenosis or outflow obstruction.

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 Gopten; 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 Gopten is given concomitantly with a diuretic. Dosage reduction of Gopten 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.

Impaired liver function

As trandolapril is a prodrug metabolised to its active moiety in the liver, particular caution and close monitoring should be applied to patients with impaired liver function.

Symptomatic hypotension

In patients with uncomplicated hypertension, symptomatic hypotension has been observed rarely after the initial dose of Gopten, as well as after increasing the dose of Gopten. It is more likely to occur in patients who have been volume- and salt-depleted by prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting. Therefore, in these patients, diuretic therapy should be discontinued and volume and/or salt depletion should be corrected before initiating therapy with Gopten.

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 Gopten may usually be continued following restoration of effective blood volume and blood pressure.

Surgery/anaesthesia

In patients undergoing surgery or during anaesthesia with agents producing hypotension, Gopten 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.

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.

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.

Angioedema:

Rarely, ACE inhibitors (such as trandolapril) may cause angioedema that includes swelling of the face, extremities, tongue, glottis, and/or larynx. Patients experiencing angioneurotic oedema must immediately discontinue Gopten therapy and be monitored until oedema resolution.

Angioedema of the face will usually resolve spontaneously. Oedema involving not only the face but also the glottis may be life-threatening because of the risk of airway obstruction.

Angioedema involving the tongue, glottis or larynx requires immediate subcutaneous administration of 0.3-0.5ml of adrenaline solution (1:1000) along with other therapeutic measures as appropriate.

Caution must be exercised in patients with a history of idiopathic angioneurotic oedema, and Gopten is contra-indicated if angioneurotic oedema was an adverse reaction to an ACE inhibitor.

ACE inhibitors have been shown to cause a higher rate of angioedema in black patients than in non-black patients.

Intestinal angioedema has also been reported in patients treated with ACE inhibitors. This should be considered in patients on trandolapril presenting with abdominal pain (with or without nausea or vomiting).

Cough:

During treatment with an ACE inhibitor, a dry and non-productive cough may occur which disappears after discontinuation.

Hereditary disorders:

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Pregnancy

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor use 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

Drug interactions

Combination with diuretics or other antihypertensive agents may potentiate the antihypertensive response to Gopten. 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. Gopten 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 Gopten, 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, particularly if this treatment has been recently instituted, the fall in blood pressure on initiation of treatment with Gopten may be excessive. The risk of symptomatic hypotension may be reduced by stopping the diuretic a few days before starting treatment with Gopten. If it is necessary to continue the diuretic treatment, the patient should be monitored, at least after the initial administration of Gopten. As with all antihypertensives, combination with a neuroleptic or tricyclic antidepressant increases the risk of orthostatic hypotension. Gopten 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 hypotensive effects of certain inhalation anaesthetics may be enhanced by ACE inhibitors .

Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide may increase the risk of leucopoenia, if used concomitantly with ACE inhibitors.

As with all antihypertensives, NSAIDs may reduce the antihypertensive effects of trandolapril. Blood pressure monitoring should be increased when any NSAID is added or discontinued in a patient treated with trandolapril. 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 may 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 Gopten has been concomitantly administered with thrombolytics, aspirin, beta-blockers, calcium channel blockers, nitrates, anticoagulants, diuretics or digoxin.

The following adverse reactions have been reported in long-term hypertension clinical trials with trandolapril. Within each system organ class, the reactions are ranked under headings of frequency, using the following convention: common (>1/100 to 1/10), uncommon (>1/1000 to 1/100).

Adverse Reactions Reported In Long Term Hypertension Trials With Trandolapril (n = 1049) That Occurred At A Frequency Greater Than Or Equal To 0.5%

The following adverse reactions have been reported in the post myocardial infarction clinical trial with trandolapril. Within each system organ class, the reactions are ranked under headings of frequency, using the following convention: common (>1/100, 1/10), uncommon (>1/1000, 1/100).

Adverse Reactions Reported With Trandolapril In Post Myocardial Infarction Patients In The TRACE Study (n = 876) That Occurred At A Frequency Greater Than Or Equal To 0.5%

In addition, other significant adverse events seen in clinical trials and postmarketing surveillance seen with trandolapril and those reported with other ACE inhibitors are listed below:

Nervous system disorders:

Transient ischaemic attacks have been reported with the use of ACE inhibitors.

Cardiac disorders:

Tachycardia, arrhythmias, angina pectoris, and myocardial infarction have been reported in association with hypotension during ACE inhibitor treatment.

Vascular disorders:

Cerebral haemorrhage has been reported with the use of ACE inhibitors.

Respiratory, thoracic and mediastinal disorders:

Sinusitis, rhinitis, glossitis, and bronchospasm have been reported, but rarely in association with ACE inhibitor treatment. Dyspnoea and bronchitis have been observed with ACE inhibitors, including trandolapril.

Gastrointestinal disorders:

Vomiting, abdominal pain, diarrhoea, constipation and dry mouth have been reported with ACE inhibitors, including trandolapril. Indigestion and ileus have been occasionally reported with ACE inhibitor treatment. Pancreatitis has also been observed in postmarketing reports with trandolapril.

Hepatobiliary disorders:

There have been reports of individual incidents of cholestatic jaundice and hepatitis connected with the use of ACE inhibitors.

Skin and subcutaneous tissue disorders:

Allergic hypersensitivity reactions such as pruritus and rash have been reported. Urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, psoriasis-like efflorescences, and alopecia, which may be accompanied by fever, myalgia, arthralgia, eosinophilia and/or increased ANA (anti-nuclear antibody) -titres have been occasionally reported with ACE inhibitor treatment. Alopecia and sweating have also been observed in postmarketing reports with trandolapril.

In very rare cases, angioneurotic oedema has occurred. If laryngeal stridor or angioedema of the face, tongue or glottis occurs, treatment with Gopten must be discontinued and appropriate therapy instituted immediately.

Renal and urinary disorders:

Deterioration of renal function and acute renal failure have been reported with the use of ACE inhibitors.

Investigations:

Reversible (on stopping treatment) increases in blood urea and plasma creatinine may result, particularly if renal insufficiency, severe heart failure or renovascular hypertension are present. Decreased haemoglobin, haematocrit, platelets and white cell count, and individual cases of agranulocytosis or pancytopenia and serum bilirubin have been reported with ACE inhibitor treatment. Haemolytic anaemia has been reported in some patients with a congenital deficiency concerning G-6 PDH (glucose-6-phosphate dehydrogenase) during treatment with ACE inhibitors. Leucopoenia and elevated liver enzymes (including SGOT and SGPT) have also been observed in postmarketing reports with trandolapril.

Abbott Laboratories Limited

(POM)

26 June 2009