Imidapril

When ACE-inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (ie acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs), attenuation of the antihypertensive effect may occur.

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, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

May reduce the antihypertensive effects of ACE inhibitors; patients should be carefully monitored to confirm that the desired effect is obtained.

Increased antihypertensive effect and risk of orthostatic hypotension (additive effect).

Reduced doses are required for these patients and therefore it is recommended that treatment be initiated with 2.5 mg.

Because of limited experience which has shown an increase in the AUC of imidaprilat, imidapril should not be administered to these patients.

May induce decreased bioavailability of imidapril.

The use of ACE inhibitors may increase the hypoglycaemic effect in diabetic patients treated with insulin or hypoglycaemia sulphonamides.

Hypoglycaemic episodes appear to be rare (improved glucose tolerance which could lead to reduced need for insulin).

Self-monitoring of glycaemia should be reinforced.

Imidapril, like other ACE inhibitors, attenuates diuretic induced potassium loss. Potassium sparing diuretics, e.g. spironolactone, triamterene or amiloride, potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium (potentially lethal), especially in conjunction with renal impairment (additive hyperkalemic effects). ACE inhibitors must not be associated with hyperkalemic substances, except in hypokalemia. If concomitant use is indicated because of demonstrated hypokalemia they should be used with caution and with frequent monitoring of serum potassium.

Concomitant use of these agents may increase the hypotensive effects of imidapril. Concomitant use with nitroglycerin and other nitrates, or other vasodilators, may further reduce blood pressure.

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.

Risk of sudden hypotension and/or acute renal impairment on initiation of treatment with an ACE inhibitor in patients with pre-existing salt/volume depletion.

In arterial hypertension, when prior diuretic therapy can have caused salt/volume depletion, either the diuretic must be discontinued before initiating the ACE inhibitor, in which case a non-potassium-sparing diuretic can be thereafter reintroduced, or the ACE inhibitor must be initiated with a low dosage and progressively increase.

The renal function (creatinine levels) should be monitored during the first few weeks of ACE inhibitor therapy.

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy.

The recommended starting dose in patients with hepatic impairment is 2.5 mg once a day. Imidapril should be used with caution in patients with hepatic impairment.

Increased lithium concentration, potentially to toxic levels (decreased renal lithium excretion).

Use of imidapril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed.

The administration of rifampicin reduced the plasma level of imidaprilat, the active metabolite of imidapril. The antihypertensive effect of imidapril might therefore be reduced.

There is an increased risk of hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors. Loss of renal function may occur with only mild changes in serum creatinine. In these patients, therapy should be initiated under close medical supervision with low doses, careful titration, and monitoring of renal function.

Imidapril like other ACE inhibitors may cause a profound fall in blood pressure especially after the first dose. Symptomatic hypotension is rare in uncomplicated hypertensive patients. It is more likely to occur in patients who have been volume depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting.

It has been reported mainly in patients with severe cardiac failure with or without associated renal insufficiency. This is more likely in patients on high doses of loop diuretics, or those with hyponatraemia or functional renal impairment. In these patients treatment should be started under very close medical supervision, preferably in a hospital, with imidapril 2.5 mg and careful dose titration. If possible, diuretic treatment should be discontinued temporarily. Such considerations apply also to patients with ischaemic heart- or cerebrovascular disease in whom excessive hypotension could result in a myocardial infarction or cerebrovascular accident.

If hypotension develops, the patient should be placed in a supine position. Volume repletion with intravenous normal saline may be required. The appearance of hypotension after the initial dose does not preclude subsequent careful dose titration with imidapril after effective management.

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including imidapril. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, uncontrolled diabetes mellitus, or those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (e.g. heparin). If concomitant use of imidapril and any of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended.

Proteinuria was rarely seen with imidapril. It may occur particularly in patients with existing renal function impairment but was also seen on relatively high doses of other ACE inhibitors.

Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., AN69) 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.

Sustained life-threatening anaphylactoid reactions have been rarely reported for patients undergoing desensitising treatment with hymenoptera venom while receiving another ACE inhibitor. In the same patients, these reactions were avoided when the ACE inhibitor was temporarily withheld, but they reappeared upon inadvertent rechallenge. Therefore, caution should be used in patients treated with ACE inhibitors undergoing such desensitisation procedures.

No data are available on the use of imidapril under conditions of surgery or anaesthesia. However, imidapril, like other ACE inhibitors, may cause hypotension or even hypotensive shock in patients undergoing major surgery or during anaesthesia through the enhancement of other hypotensive potentials. If it is not possible to withhold imidapril volume management should be handled with care.

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Patients treated with an ACE inhibitor undergoing LDL lipid apheresis with dextrane sulfate may experience anaphylactoid reactions similar to those seen in patients under-going haemodialysis with high-flux membranes. It is recommended that an agent from another class of antihypertensive drugs is used in these patients.

Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported rarely in patients receiving ACE inhibitors, including imidapril. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Imidapril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections which in a few instances did not respond to intensive antibiotic therapy.

If imidapril is used in such patients, it is advised that white blood cell count and differential counts should be performed prior to therapy, every 2 weeks during the first 3 months of imidapril therapy, and periodically thereafter. During treatment all patients should be instructed to report any sign of infection (e.g. sore throat, fever) when a differential white blood cell count should be performed.

Imidapril and other concomitant medication should be withdrawn if neutropenia (neutrophils less than 1,000/mm³) is detected or suspected.

In most patients neutrophil counts rapidly return to normal upon discontinuing imidapril.

During treatment with imidapril a dry and non-productive cough may occur which disappears after discontinuation.

As with others ACE inhibitors, imidapril should be used with caution in patients with an obstruction in the outflow tract of the left ventricle.

Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including imidapril. This may occur at any time during treatment. In such cases, imidapril should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. In those instances where swelling has been confined to the face and lips the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms.

Angioneurotic oedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, which may include subcutaneous epinephrine solution 1:1,000 (0.3 ml to 0.5 ml) and/or measures to ensure a patent airway, should be administered promptly.

Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor.

Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors.

The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contraindicated 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 antihypertensive 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 imidapril during breast-feeding, imidapril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Imidapril has minor influence on the ability to drive and use machines. It should be taken into account that occasionally dizziness or weariness may occur. No studies on the effects on the ability to drive have been performed.