Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2014 Publisher: Mitsubishi Tanabe Pharma Europe Limited, 6<sup>th</sup> Floor, Dashwood House, 69 Old Broad Street, London, EC2M 1QS, United Kingdom
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.
As with others ACE inhibitors, imidapril should be used with caution in patients with an obstruction in the outflow tract of the left ventricle.
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 1000/mm³) is detected or suspected.
In most patients neutrophil counts rapidly return to normal upon discontinuing imidapril.
Changes in renal function may be anticipated in susceptible individuals due to the inhibition of the renin-angiotensin-aldosterone system. Therefore imidapril like other ACE inhibitors should be used with caution in patients with renal insufficiency. Reduced doses are required for patients with creatinine clearance between 30ml/min to 80ml/min (see section 4.2).
Imidapril should not be administered in patients with creatinine clearance less than 30 ml/min because of limited experience in these patients (see section 4.2 and section 5.2).
Close monitoring of renal function during therapy should be performed as deemed appropriate.
Renal failure has been reported in association with ACE inhibitors, mainly in patients with severe cardiac failure or underlying renal disease, including renal artery stenosis. Some patients, with no apparent pre-existing renal disease, may develop increases in blood urea and creatinine concentrations when a diuretic is given concomitantly. Dosage reduction of the ACE inhibitor and/or discontinuation of the diuretic may be required. It is recommended that the renal function be monitored during the first weeks of therapy.
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.
Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., AN 69) 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.
There is no experience regarding the administration of imidapril in patients with a recent kidney transplantation
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 1:1000 (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 (see section 4.3).
Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors (see section 4.8).
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 (see above). It is recommended that an agent from another class of antihypertensive drugs is used in these patients.
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.
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.
During treatment with imidapril a dry and non-productive cough may occur which disappears after discontinuation.
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.
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 (see section 4.5).
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.
The glycaemia levels should be closely monitored in diabetic patients previously treated with oral antidiabetic drugs or insulin, namely during the first month of treatment with an ACE inhibitor.
Some elderly, especially very old patients, may be more responsive to imidapril than younger patients. For elderly patients aged 65 years or older, the initial daily dose should be imidapril 2.5 mg. Evaluation of the renal function at the beginning of the treatment is recommended.
Imidapril should not be administered to children until safety and efficacy have been established.
ACE-inhibitors are less effective in lowering blood pressure in black people than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.
Tanatril contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Tanatril is generally not recommended in combination with potassium-sparing diuretics, potassium salts and lithium (see section 4.5).
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.
ACE inhibitors should not be initiated during pregnancy. 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 (see sections 4.3 and 4.6).
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.
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.
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 (see section 4.4).
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.
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.
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 (see sections 4.3, 4.4 and 5.1).
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 may be used concomitantly with acetylsalicylic acid (when used as a thrombolytic), thrombolytics, and beta-blockers.
Increased antihypertensive effect and risk of orthostatic hypotension (additive effect).
The administration of rifampicin reduced the plasma level of imidaprilat, the active metabolite of imidapril. The antihypertensive effect of imidapril might therefore be reduced.
May induce decreased bioavailability of imidapril.
May reduce the antihypertensive effects of ACE inhibitors; patients should be carefully monitored to confirm that the desired effect is obtained.
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 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) (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 sections 4.3 and 4.4).
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.
Tanatril 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.
The incidence of adverse events in hypertensive patients on imidapril was 34% with 36% for placebo. Cough, dizziness, fatigue/somnolence, dyspepsia and vomiting occurred more frequently in the imidapril group.
The undesirable effects that have been observed and reported during treatment with imidapril in pre-approval studies are presented in the table below with the following frequencies: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to 1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
Uncommon
Bronchitis, Viral infection, Upper respiratory tract infection
Rare
Leucopenia, Anaemia
Common
Headache, Dizziness, Fatigue/Somnolence
Uncommon
Cerebrovascular disorders, Syncope, Paraesthesia
Uncommon
Palpitations
Common
Cough
Uncommon
Rhinitis
Common
Nausea
Uncommon
Vomiting, Epigastric pain, Dyspepsia
Uncommon
Rash, Pruritus
Uncommon
Chest pain, Pain in limbs, Oedema (joint, peripheral)
Uncommon
Hyperkalaemia, Creatinine increased, Urea increased, GPT/ALAT increased, Gamma-GT increased
Rare
Blood amylase increased, GOT/ASAT increased, Decreased albumin, AP increased, Serum protein decreased, Impaired renal function
The following adverse reactions have been observed in association with imidapril or with other ACE inhibitors. Please also refer to section 4.4 to avoid these reactions:
Neutropenia/agranulocytosis, thrombocytopenia, pancytopenia and anaemia have been reported rarely in patients receiving ACE inhibitors. In patients with a congenital deficiency concerning G-6-PDH individual cases of haemolytic anaemia have been reported under other ACE inhibitors.
Dizziness, weariness and fatigue have been reported. Rarely depression, sleep disorders, paresthesias, impotence, disorder of balance, confusion, tinnitus, blurred vision, headache and taste disturbance may occur with ACE inhibitors.
Severe hypotension may occur after initiation of therapy or increase of dose in certain risk groups. Symptoms like dizziness, feeling of weakness, impaired vision, rarely with disturbance of consciousness (syncope) can occur in association with hypotension. Individual cases of tachycardia, palpitations, arrhythmias, angina pectoris, myocardial infarction, transient ischemic attacks and cerebral haemorrhage have been reported for ACE inhibitors in association with hypotension.
ACE inhibitors have been documented to induce cough in a substantial number of patients. Rarely dyspnoea, sinusitis, rhinitis, glossitis, bronchitis, bronchiospasm and angioedema involving the upper airways, and very rarely allergic alveolits/eosinophilic pneumonia may occur with ACE inhibitors.
Diarrhoea, nausea, vomiting, gastritis, abdominal pain, constipation, dry mouth, cholestatic icterus, hepatitis, pancreatitis and ileus may occur with ACE-inhibitors.
Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. Symptoms are abdominal pain with or without nausea or vomiting.
Patients receiving ACE inhibitors have developed jaundice or had marked elevations of hepatic enzymes.
Occasionally allergic and hypersensitivity reactions such as rash, pruritus, exanthema and urticaria can occur. ACE inhibitors have been associated with the onset of angioneurotic oedema involving the face and oropharyngeal tissues.
Cases of erythema multiforme, Steven-Johnson syndrome, toxic epidermic necrolysis, psoriasis-like efflorescences and alopecia were reported for ACE inhibitors. Cutaneous symptoms can be accompanied by fever, myalgia, arthralgia, eosinophilia and/or increased ANA titers.
Renal insufficiency may rarely occur or be intensified. Acute renal failure has been reported for other ACE inhibitors.
Decreases in haemoglobin, haematocrit, platelets and white cell count as well as elevation of liver enzymes, serum bilirubin and creatine phosphokinase (CPK) have been reported in a few patients. Elevation of serum potassium may occur since imidapril leads to a decrease in aldosterone secretion. Increases in blood urea and plasma creatinine, reversible on discontinuation, may occur, especially in the presence of renal insufficiency.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.
Not applicable.
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