Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom
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).
ACE inhibitors may cause severe hypotension, especially when starting treatment. First-dose hypotension is most likely to occur in patients whose renin-angiotensin-aldosterone system is activated, such as in renovascular hypertension or other causes of renal hypoperfusion, sodium or volume depletion, or previous treatment with other vasodilators. These conditions can co-exist, particularly in severe heart failure.
Hypotension should be treated by placing the patient supine and volume expansion. Cilazapril may be continued once the patient is volume replete, but should be given at a lower dose or discontinued if hypotension persists.
At-risk patients should start treatment with cilazapril under medical supervision, with a low initial dose and careful titration. If possible, diuretic therapy should be discontinued temporarily.
Similar caution should be taken for patients with angina pectoris or cerebrovascular disease, in whom hypotension can cause myocardial or cerebral ischaemia.
In patients with renal impairment, the dosage of cilazapril should be adjusted according to creatinine clearance (see section 4.2). Routine monitoring of potassium and creatinine is part of normal medical practice for these patients.
ACE inhibitors have established renoprotective effects, but can cause reversible impairment of renal function in the setting of reduced renal perfusion, whether due to bilateral renal artery stenosis, severe congestive heart failure, volume depletion, hyponatraemia or high dosages of diuretics, and in those receiving treatment with NSAIDs. Preventive measures include withdrawing or temporarily withholding diuretics, beginning therapy with very small doses of ACE inhibitors, and cautious dose titration.
In patients with renal artery stenosis, activation of the renin-angiotensin-aldosterone system helps to maintain renal perfusion by causing constriction of the efferent arteriole. Hence, blockade of angiotensin II formation, and possibly also an increase in the formation of bradykinin, causes efferent arteriolar vasodilation resulting in a reduction in glomerular filtration pressure. Hypotension contributes further to a reduction in renal perfusion (see section 4.4 ‘Hypotension’). As with other agents acting on the renin-angiotensin system, there is an increased risk of renal insufficiency, including acute renal failure, when patients with renal artery stenosis are treated with cilazapril. Therefore, caution should be exercised in these patients. If renal failure occurs, treatment should be discontinued.
Angioedema has been associated with ACE inhibitors, with a reported incidence of 0.1-0.5%. Angioedema due to ACE inhibitors can present as recurrent episodes of facial swelling, which resolves on withdrawal, or as acute oropharyngeal edema and airways obstruction, which requires emergency treatment, and may be life-threatening. A variant form is angioedema of the intestine, which tends to occur within the first 24-48 hours of treatment. The risk of angioedema appears to be greater in black-skinned than non black-skinned patients. Patients with a history of angioedema unrelated to ACE inhibitors may be at greater risk.
Haemodialysis: Anaphylaxis has occurred in patients dialysed with high flux membranes (e.g. AN 69) receiving ACE inhibitors. Consideration should be given to using a different type of dialysis membrane or different class of antihypertensive agent in such patients.
Low-density lipoproteins (LDL) apheresis: Patients receiving ACE inhibitors during LDL apheresis with dextran sulphate have experienced life-threatening anaphylaxis. This can be avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
Desensitization: Anaphylactic reactions can occur in patients undergoing desensitization therapy with wasp or bee venom while receiving an ACE inhibitor. Cilazapril must be stopped before the start of desensitization therapy, and should not be replaced by a β- blocker.
Single cases of liver function disorders, such as increased values of liver function tests (transaminases, bilirubin, alkaline phosphatase, gamma GT) and cholestatic hepatitis with or without necrosis have been reported. Patients receiving cilazapril who develop jaundice or marked elevations of hepatic enzymes should discontinue cilazapril and receive appropriate medical follow-up. In patients with liver cirrhosis (but without ascites) who require therapy for hypertension, cilazapril should be initiated at a lower dose and with great caution because significant hypotension may occur (see section 4.2). In patients with ascites, cilazapril administration is not recommended.
Rarely, neutropenia and agranulocytosis have been associated with ACE inhibitors, especially in patients with renal failure or collagen vascular disease and those receiving immunosuppressive therapy. Periodic monitoring of leukocyte count is recommended in such patients.
ACE inhibitors can cause hyperkalemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. However, in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes) or potassium-sparing diuretics, and especially aldosterone antagonists, hyperkalemia can occur. Potassium-sparing diuretics should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored.
Administration of ACE inhibitors to patients with diabetes may potentiate the blood glucose-lowering effect of oral hypoglycaemic agents or insulin, especially in patients with renal impairment. In such patients, glucose levels should be carefully monitored during initiation of treatment with an ACE inhibitor.
Anaesthetic agents with blood pressure lowering effects can cause hypotension in patients receiving ACE inhibitors. Hypotension in this setting can be corrected with volume expansion.
ACE inhibitors should be used with caution in patients with obstructive cardiac disorders (e.g. mitral stenosis, aortic stenosis, hypertrophic cardiomyopathy), since cardiac output cannot increase to compensate for systemic vasodilation, and there is a risk of severe hypotension.
Owing to the presence of lactose monohydrate, patients with hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
ACE inhibitors are less effective as antihypertensives in patients with black skin colour. These patients also have a higher risk of angioedema.
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased risk of lithium toxicity with ACE inhibitors.
Use of cilazapril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed.
An additive effect may be observed when cilazapril is administered in combination with other antihypertensive agents.
Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with cilazapril. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, the combination of cilazapril with the above-mentioned drugs is not recommended (see section 4.4). If concomitant use is indicated because of demonstrated hypokalaemia they should be used with caution and with frequent monitoring of serum potassium.
Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with cilazapril (see section 4.4). The hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake or by initiating therapy with a low dose of cilazapril.
Concomitant use of certain anesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure (see section 4.4).
When ACE inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. 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.
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycemic agents) may cause an increased blood-glucose-lowering effect with risk of hypoglycemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.
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.
No clinically significant interactions were observed when cilazapril and digoxin, nitrates, coumarin anticoagulants, and H2 receptor blockers were concomitantly administered.
The use of ACE inhibitors such as cilazapril is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors such as cilazapril 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). Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound examination 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 safety of cilazapril during breast-feeding, cilazapril is not recommended, and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
When driving and operating machines, it should be taken into account that occasionally dizziness and fatigue may occur, especially when starting therapy (see sections 4.4 and 4.8).
The most frequent drug-attributable adverse events observed in patients taking ACE inhibitors are cough, skin rash and renal dysfunction. Cough is more common in women and non-smokers. Where the patient can tolerate the cough, it may be reasonable to continue treatment. In some cases, reducing the dose may help.
Treatment-related adverse events severe enough to stop treatment occur in less than 5% of patients receiving ACE inhibitors.
The following list of adverse reactions is derived from clinical trials and post-marketing data in association with cilazapril and/or other ACE inhibitors. Estimates of frequency are based on the proportion of patients reporting each adverse reaction during cilazapril clinical trials that included a total combined population of 7171 patients. Adverse reactions that were not observed during cilazapril clinical trials but have been reported in association with other ACE inhibitors or derived from post-marketing case reports are classified as ‘rare’.
Frequency categories are as follows:
Very common (≥1/10)
Common (≥1/100 and <1/10)
Uncommon (≥1/1,000 and <1/100)
Rare (<1/1,000)
Rare: Neutropenia, agranulocytosis, thrombocytopenia, anaemia
Uncommon: Angioedema (may involve the face, lips, tongue, larynx or gastrointestinal tract) (see section 4.4)
Rare: Anaphylaxis (see section 4.4)
Lupus-like syndrome (symptoms may include vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibodies, increased erythrocyte sedimentation rate, eosinophilia and leukocytosis)
Common: Headache
Uncommon: Dysgeusia
Rare: Cerebral ischaemia, transient ischaemic attack, ischaemic stroke
Peripheral neuropathy.
Uncommon: Myocardial ischaemia, angina pectoris, tachycardia, palpitations
Rare: Myocardial infarction, arrhythmia
Common: Dizziness
Uncommon: Hypotension, postural hypotension (see section 4.4). Symptoms of hypotension may include syncope, weakness, dizziness and visual impairment.
Common: Cough
Uncommon: Dyspnoea, bronchospasm, rhinitis
Rare: Interstitial lung disease, bronchitis, sinusitis
Common: Nausea
Uncommon: Dry mouth, aphthous stomatitis, decreased appetite, diarrhoea, vomiting
Rare: Glossitis, pancreatitis
Rare: Abnormal liver function test (including transaminases, bilirubin, alkaline phosphatase, gamma GT)
Cholestatic hepatitis with or without necrosis.
Uncommon: Rash, maculopapular rash
Rare: Psoriaform dermatitis, psoriasis (exacerbation), lichen planus, exfoliative dermatitis, urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous pemphigoid, pemphigus, Karposi’s sarcoma, vasculitis/purpura, photosensitivity reactions, alopecia, onycholysis
Uncommon: Muscle cramps, myalgia, arthralgia
Rare: Renal impairment, acute renal failure (see section 4.4), blood creatinine increased, blood urea increased.
Hyperkalaemia, hyponatraemia, proteinuria, nephrotic syndrome, nephritis.
Uncommon: Impotence
Rare: Gynaecomastia
Common: Fatigue
Uncommon: Excess sweating, flushing, asthenia, sleep disorder
Hypotension and postural hypotension may occur when starting treatment or increasing dose, especially in at-risk patients (see section 4.4).
Renal impairment and acute renal failure are more likely in patients with severe heart failure, renal artery stenosis, pre-existing renal disorders or volume depletion (see section 4.4).
Hyperkalaemia is most likely to occur in patients with renal impairment and those taking potassium sparing diuretics or potassium supplements.
The events of cerebral ischaemia, transient ischaemic attack and ischaemic stroke reported rarely in association with ACE inhibitors may be related to hypotension in patients with underlying cerebrovascular disease. Similarly, myocardial ischaemia may be related to hypotension in patients with underlying ischaemic heart disease.
Headache is a commonly reported adverse event, although the incidence of headache is greater in patients receiving placebo than in those receiving ACE inhibitors.
Not applicable.
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