Chemical formula: C₂₂H₃₁N₃O₅ Molecular mass: 417.499 g/mol PubChem compound: 56330
Cilazapril interacts in the following cases:
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.
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. If concomitant use is indicated because of demonstrated hypokalaemia they should be used with caution and with frequent monitoring of serum potassium.
An additive effect may be observed when cilazapril is administered in combination with other antihypertensive agents.
Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with cilazapril. 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.
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.
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.
Reduced dosages are required for patients with renal impairment, depending on their creatinine clearance.
The following dosage schedules are recommended.
Recommended dosage schedule for patients with renal impairment:
| Creatinine clearance | Initial dose of cilazapril | Maximal dose of cilazapril |
|---|---|---|
| >40 ml/min | 1 mg once daily | 5 mg once daily |
| 10-40 ml/min | 0.5 mg once daily | 2.5 mg once daily |
| <10 ml/min | Not recommended | |
If renovascular hypertension is also present there is an increased risk of severe hypotension and renal insufficiency. In these patients, treatment should be started under close medical supervision with low doses and careful dose titration. Since treatment with diuretics may be a contributory factor, they should be discontinued and renal function should be monitored during the first weeks of cilazapril therapy.
Results from clinical trials showed that clearance of cilazapril was correlated with creatinine clearance in patients with chronic heart failure. The special dosage recommendation should thus be followed in chronic heart failure patients with impaired renal function.
Concomitant use of certain anesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure.
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.
In patients with liver cirrhosis (but without ascites) who require therapy for hypertension, cilazapril should be dosed with great caution not exceeding 0.5 mg/day accompanied by careful monitoring of the blood pressure, because significant hypotension may occur.
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.
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.
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.
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.
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. 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 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.
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.
ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. The use of cilazapril is contraindicated during pregnancy. Pregnant women should be informed of the potential hazards to the fetus and must not take cilazapril during pregnancy. 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.
Fetal exposure to ACE inhibitors during the first trimester of pregnancy has been reported to be associated with prematurity, an increased risk of malformations of the cardiovascular (atrial and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and central nervous system (microcephaly, spina bifida) and of kidney malformations.
Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (hypotension, hyperkalemia, neonatal skull hypoplasia, intrauterine growth restriction, anuria, renal tubular dysplasia, reversible or irreversible renal failure and death). Oligohydramnios reported with the use of ACE inhibitors presumably resulted from decreased fetal renal function, associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. 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.
Animal data show the presence of cilazaprilat in rat milk. However, no information is available regarding the safety of cilazapril during breast-feeding in humans. Cilazapril must not be administered to nursing mothers and alternative treatments with better established safety profiles during breast-feeding are preferable.
No data available.
When driving and operating machines, it should be taken into account that occasionally dizziness and fatigue may occur, especially when starting therapy.
Headache and dizziness were the most frequently reported events in patients taking cilazapril for hypertension. In chronic heart failure clinical trials, dizziness and coughing were the most frequently reported events in patients taking cilazapril.
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.
Hypotension and postural hypotension may occur when starting treatment or increasing dose, especially in at-risk patients.
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.
Hyperkalemia is most likely to occur in patients with renal impairment and those taking potassium sparing diuretics or potassium supplements.
The events of cerebral ischemia, transient ischemic attack and ischemic stroke reported rarely in association with ACE inhibitors may be related to hypotension in patients with underlying cerebrovascular disease. Similarly, myocardial ischemia may be related to hypotension in patients with underlying ischemic 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.
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Cilazapril has been evaluated for safety in 5,450 patients treated for essential hypertension and 1,106 patients treated for congestive heart failure.
Of these, 2,586 hypertensive and 900 congestive heart failure patients were treated with cilazapril in controlled clinical trials. Cilazapril was evaluated for long-term safety in 798 hypertensive and 264 congestive heart failure patients treated for one year or longer.
The most serious adverse reactions reported in the 5,450 patients treated with cilazapril for hypertension included: angioedema/face edema (0.1%), postural hypotension (0.3%), orthostatic hypotension (2.1%), myocardial infarction (0.1%), cerebrovascular disorder (0.04%), renal failure (0.09%), and thrombocytopenic purpura (0.02%).
In the 1,106 patients treated with cilazapril for congestive heart failure, the most serious adverse reactions were: postural hypotension (1.6%), symptomatic hypotension (1.2%), myocardial infarction (0.3%), renal failure (0.1%), and cardiogenic shock (1 patient).
Two elderly male patients, with a history of previous myocardial infarctions, on high diuretic dosage (240 mg and 120 mg of furosemide daily, respectively) for congestive heart failure NYHA Class III died within 8 hours after the addition of a single dose of 2.5 mg of cilazapril.
Hypotension and syncope, each reported in 0.1% of the hypertensive patients treated with cilazapril, were reported in 2.1% and 0.8% of the congestive heart failure patients treated with cilazapril.
Discontinuation of therapy was required in 63 (2.4%) of the hypertensive patients and 143 (12.9%) of the congestive heart failure patients.
See Table 1 for the most frequent adverse reactions reported in controlled clinical trials (≥1% and more frequent than in placebo treated patients).
Table 1. The Most Frequent Adverse Reactions in Controlled Clinical Trials (≥1% and More Frequent than in Placebo Treated Patients):
| Hypertension n=2,586 | Congestive Heart Failure n=900 | |
|---|---|---|
| headache | 5.1% | 3.2% |
| dizziness | 3.0% | 8.2% |
| fatigue | 2.1% | 2.6% |
| cough | 1.8% | 7.5% |
| nausea | 1.3% | 2.9% |
| asthenia | 0.3% | 1.6% |
| palpitation | 0.2% | 1.2% |
Other adverse reactions occurring in less than 1% of the 5,450 hypertension patients and the 1,106 congestive heart failure patients treated with cilazapril were:
Cardiovascular: Chest pain, angina pectoris, tachycardia, atrial fibrillation, arrhythmia, flushing.
In the patient population treated with cilazapril for congestive heart failure, there were reports of bradycardia, AV block, extra systoles, cardiac failure and cardiac decompensation.
Renal: Micturition frequency, polyuria, dysuria, uremia, renal pain.
Hematologic: Epistaxis, anemia, purpura.
Gastrointestinal: Dyspepsia, abdominal pain, diarrhea, constipation, vomiting, flatulence, GI bleeding, rectum bleeding, anorexia.
Dermatologic/Allergic: Rash (includes maculo-papular rash and erythematous rash), dermatitis, pruritus, urticaria, angioedema (including face edema).
Nervous System: Increased sweating, paresthesia, hypoesthesia, impotence, decreased libido, depression, anxiety, dry mouth, vertigo, migraine, tremor, dysphonia, ataxia, confusion, somnolence, insomnia, nervousness.
Musculoskeletal: Myalgia, leg cramps, arthralgia.
Special Senses: Tinnitus, abnormal vision, photophobia, conjunctivitis, taste perversion.
Respiratory: Rhinitis, sinusitis, pharyngitis, bronchitis, respiratory tract infection, dyspnea, bronchospasm.
In the congestive heart failure patient database, the overall incidence of dyspnea was 3.1%. Dyspnea however was less frequent after cilazapril than after placebo.
Metabolic: Gout.
Body as a Whole: Malaise, hot flushes, pain, edema, rigors.
Patients had clinically relevant changes in platelet (0.4% and 0.7%), neutrophil (1.9% and 1.4%) or white blood cell counts (1.3% and 0.7%) while treated for hypertension and congestive heart failure respectively.
Leucopenia was observed in 0.2% (10/3,580) and 0% (0/1,163) and neutropenia in 0.4% (22/5,720) and 0.6% (7/1,163) of the hypertensive and congestive heart failure patients respectively. Most of these were single transient occurrences; one case with two successive abnormalities showed no associated clinical symptoms.
Clinically relevant changes in the values associated with liver function (SGOT, SGPT, GGTP, LDH, total bilirubin and alkaline phosphatase) occurred in 0.1% (bilirubin) to 1.1% (SGPT, GGTP) of the hypertensive patients and in 0.8% (LDH) to 2.9% (SGPT) of the congestive heart failure patients. Most of these abnormalities were transient.
Clinically relevant changes in renal function test results (BUN or serum creatinine concentrations) occurred in 0.6% or less of the hypertensive patients and in 2.6% and 0.9% respectively of the congestive heart failure patients.
Hyperkalemia: 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, other drugs that may increase serum potassium (e.g. trimethoprim or co-trimoxazole (also known as trimethoprim/sulfamethoxazole)) and especially aldosterone antagonists or ARBs, hyperkalemia can occur.
Creatinine: Serum creatinine values >2 mg/dL were reported in 1.3% (44/3,468) of the hypertensive patients. Two thirds of these patients had renal impairment at baseline. Serum creatinine values >2.8 mg/dL were reported in 0.4% (5/1,163) of the congestive heart failure patients. Of these, four of the five had abnormal serum creatinine values at baseline.
Proteinuria (≥2+ dipstick reaction or excretion of ≥1 g/24h): Proteinuria considered remotely, possibly or probably related to therapy was reported in 0.5% (17/3,421) of the hypertensive patients. Five patients had prior renal impairment. In congestive heart failure patients, 1.4% (16/1,106) experienced potentially clinically relevant proteinuria.
Other: In congestive heart failure patients, hyperglycemia considered remotely, possibly or probably related to therapy was reported in 0.2% (2/1,106) patients.
Cilazapril is usually well tolerated. In most cases, side effects are transient, mild or moderate in degree, and do not require discontinuation of therapy. The most common adverse effects include dry cough, rash, hypotension, dizziness, fatigue, headache, and nausea, dyspepsia and other gastrointestinal disturbances.
The following adverse reactions have been seen in association with cilazapril and/or other ACE inhibitors.
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
Blood disorders have been reported with ACE inhibitors and include neutropenia and agranulocytosis (especially in patients with renal failure and those with collagen-vascular disorders such as systemic lupus erythematosus and scleroderma), thrombocytopenia, and hemolytic anemia.
Rare: Neutropenia, agranulocytosis, thrombocytopenia, anemia
Pronounced hypotension may occur at the start of therapy with ACE inhibitors, particularly in patients with heart failure and in sodium- or volume depleted patients. Myocardial infarction and stroke have been reported and may relate to severe falls in blood pressure in patients with ischemic heart disease or cerebrovascular disease. Other cardiovascular effects that have occurred include tachycardia, palpitations, and chest pain.
Uncommon: Angina pectoris, tachycardia, palpitations
Rare: Myocardial infarction
Common: Dizziness
Uncommon: Hypotension (sometimes severe)
Symptoms of hypotension may include syncope, weakness, dizziness and visual impairment.
Common: Cough (sometimes severe)
As for other ACE inhibitors, isolated cases of pancreatitis, in some cases fatal, have been reported in patients treated with cilazapril.
Common: Nausea
Rare: Pancreatitis
Rare: Abnormal liver function test including transaminases, bilirubin, alkaline phosphatase, gamma GT) and cholestatic hepatitis with or without necrosis.
As with other ACE inhibitors, angioneurotic edema has been reported, although rarely, in patients receiving cilazapril. Since this syndrome can be associated with laryngeal edema, cilazapril should be discontinued and appropriate therapy instituted without delay when involvement of the face, lips, tongue, glottis and/or larynx occurs.
Uncommon: Angioedema (may involve the face, lips, tongue, larynx or gastrointestinal tract).
Rare: Anaphylaxis, 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: Transient ischemic attack, ischemic stroke (may be related in some cases to hypotension in patients with underlying cerebrovascular disease).
Skin rashes (including pemphigus, Stevens-Johnson syndrome, erythema multiforme, and toxic epidermal necrolysis) may occur; photosensitivity, alopecia, and other hypersensitivity reactions have also been reported.
Uncommon: Rash
Rare: Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, erythema multiforme, pemphigus, bullous pemphigoid, exfoliative dermatitis, psoriasiform dermatitis, psoriasis (exacerbation), lichen planus, urticaria, vasculitis/purpura, photosensitivity reactions, alopecia, onycholysis.
Cases of acute renal failure have been reported in patients with severe heart failure, renal artery stenosis or renal disorders.
Rare: Renal impairment, acute renal failure, blood creatinine increased, blood urea increased, hyperkalemia, hyponatremia.
Common: Fatigue
Hypotension may occur when starting treatment or increasing dose, especially in at-risk patients. Symptoms of hypotension may include syncope, weakness, dizziness and visual impairment.
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.
Hyperkalemia is most likely to occur in patients with renal impairment and those taking potassium sparing diuretics or potassium supplements.
The events of transient ischemic attack and ischemic stroke reported rarely in association with ACE inhibitors may be related to hypotension in patients with underlying cerebrovascular disease. Similarly, myocardial ischemia may be related to hypotension in patients with underlying ischemic heart disease.
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