Source: Health Products and Food Branch (CA) Revision Year: 2020
INHIBACE (cilazapril) is contraindicated in:
Angioedema has been reported in patients treated with angiotensin-converting enzyme inhibitors including INHIBACE. 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 resolve on withdrawal, or as acute oropharyngeal edema and potentially life-threatening airway obstruction, which requires emergency treatment. Angioedema associated with laryngeal edema and/or shock may be fatal. If angioedema occurs, INHIBACE (cilazapril) should be promptly discontinued and appropriate therapy instituted without delay. A variant form is angioedema of the intestine, which tends to occur within the first 24-48 hours of treatment.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at an increased risk of angioedema while receiving an ACE inhibitor (see CONTRAINDICATIONS).
Concomitant use of ACE inhibitors with drug products containing a neprilysin inhibitor (e.g., sacubitril/valsartan) is contraindicated due to the increased risk of angioedema. Treatment with sacubitril/valsartan must not be initiated earlier than 36 hours after the last dose of cilazapril. Treatment with cilazapril must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections CONTRAINDICATIONS and DRUG INTERACTIONS, DrugDrug Interactions).
Concomitant use of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors such as sirolimus, everolimus, temsirolimus, or dipeptidyl peptidase IV (DPP-IV) inhibitors such as alogliptin, linagliptin, saxagliptin and sitagliptin may lead to an increased risk for angioedema (sudden difficulty in breathing or swallowing, swelling of face, eyes, lips, tongues and/or throat, hands or feet). Caution should be used when using mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) or DPP-IV inhibitors (e.g. alogliptin, linagliptin, saxagliptin and sitagliptin) concomitantly with ACE inhibitors (see DRUG INTERACTIONS, Drug-Drug Interactions).
As with other ACE inhibitors, INHIBACE 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.
There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.
INHIBACE, like other ACE inhibitors, may cause severe hypotension, especially when starting treatment, usually after the first dose or when the dose had been increased. 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, previous treatment with other vasodilators and in patients with dietary salt restriction, dialysis, diarrhea, or vomiting. These conditions can co-exist, particularly in severe heart failure.
Patients with congestive heart failure, especially those vigorously treated with loop diuretics, may experience excessive hypotension in response to ACE inhibitors. Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of INHIBACE and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident (see ADVERSE REACTIONS).
Patients at risk for hypotension 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 ischemia.
In patients with severe heart failure, whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including INHIBACE, may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.
Hypotension should be treated by placing the patient supine and with 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.
There is evidence that co-administration of angiotensin-converting enzyme (ACE) inhibitors, such as INHIBACE, or of angiotensin receptor antagonists (ARBs) with aliskiren increases the risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe renal impairment (GFR <60 ml/min/1.73m²). Therefore, the use of INHIBACE in combination with aliskiren-containing drugs is contraindicated in these patients (see CONTRAINDICATIONS).
Further, co-administration of ACE inhibitors, including INHIBACE, with other agents blocking the RAS, such as ARBs or aliskiren-containing drugs, is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, renal failure, and hyperkalemia.
A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of INHIBACE, has been reported.
Such possibility should be considered as part of the differential diagnosis of the cough.
Administration of ACE inhibitors to patients with diabetes may potentiate the blood glucose lowering effect of oral hypoglycemic 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 are less effective as antihypertensives in black-skinned patients of African descent. Black-skinned patients also have a higher risk of angioedema.
Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Cases of leucopenia and neutropenia have rarely been reported in patients treated with ACE Inhibitors. Periodic monitoring of white blood cell counts should be considered in patients with collagen vascular disease and renal disease such as systemic lupus erythematosus and scleroderma, or in patients receiving immunosuppressive therapy, especially when they also have impaired renal function.
Hepatitis (hepatocellular and/or cholestatic), jaundice, elevations of liver enzymes and/or serum bilirubin have occurred during therapy with cilazapril in patients with or without pre-existing liver abnormalities. In most cases the changes were reversed on discontinuation of the drug.
Cases of liver function disorders, such as increased values of liver function tests (transaminases, bilirubin, alkaline phosphatase, gamma GT) and cholestatic hepatitis have been reported. Patients receiving cilazapril who develop jaundice or marked elevations of hepatic enzymes should discontinue cilazapril and receive appropriate medical follow-up.
There are no adequate studies in patients with cirrhosis and/or liver dysfunction. INHIBACE should be used with particular caution in patients with pre-existing liver abnormalities. In such patients, baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.
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, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis, and (sometimes) death. The mechanism of this syndrome is not understood.
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. Potassium-sparing diuretics and ARBs should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored (see DRUG INTERACTIONS, Drug-Drug Interactions).
In clinical trials, elevated serum potassium (greater than 5.5 mEq/L) was observed in approximately 0.7% of hypertensive patients and 0.8% of congestive heart failure patients receiving cilazapril. In most cases these were isolated values which resolved despite continued therapy, however in one case the patient discontinued treatment. Risk factors for the development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia (see DRUG INTERACTIONS, Drug-Drug Interactions and ADVERSE REACTIONS).
Hemodialysis: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (e.g. polyacrylonitrile [PAN], AN 69) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Patients receiving ACE inhibitors during LDL apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions can be avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
There have been reports of patients experiencing sustained life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitizing treatment with Hymenoptera (bees, wasps) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge.
Cilazapril use must be stopped before the start of desensitization therapy and must not be replaced by a beta-blocker.
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and symptomatic hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including INHIBACE (see DRUG INTERACTIONS, Drug-Drug Interactions).
In patients undergoing major surgery or during anesthesia with agents that produce hypotension, cilazapril blocks angiotensin II formation, secondary to compensatory renin release. This may result in arterial hypotension which can be corrected by volume expansion.
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, rarely, acute renal failure have been reported such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk and produce increases in blood urea nitrogen and/or serum creatinine. Although these alterations are usually reversible upon discontinuation of INHIBACE and/or diuretic therapy, cases of severe renal dysfunction and, rarely, acute renal failure have been reported. In susceptible patients, concomitant diuretic use may further increase risk.
When treated with cilazapril, patients with renal artery stenosis have an increased risk of renal insufficiency, including acute renal failure. Therefore, caution should be exercised in these patients.
Use of INHIBACE should include appropriate assessment of renal function.
Reduced dosages may be required for patients with renal impairment depending on their creatinine clearance (see DOSAGE AND ADMINISTRATION, Dosage Adjustment in Patients with Renal Impairment).
The use of ACE inhibitors – including INHIBACE – or ARBs with aliskiren-containing drugs is contraindicated in patients with moderate to severe renal impairment (GFR <60 ml/min/1.73m²). (See CONTRAINDICATIONS and DRUG INTERACTIONS, Drug-Drug Interactions, Dual Blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACE inhibitors, or aliskirencontaining drugs).
INHIBACE tablets contain lactose monohydrate. Therefore, patients with hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine (see CONTRAINDICATIONS).
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 INHIBACE during pregnancy (see CONTRAINDICATIONS). 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.
Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit.
Dialysis clearance was estimated to be 2.4 L/h for cilazapril and 2.2-2.8 L/h for cilazaprilat.
In fertility and general reproduction performance testing in rats, dosing with 50 mg/kg/day of cilazapril resulted in greater implantation losses, less viable fetuses, smaller pups, and dilatation of the renal pelvis in the pups. No teratogenic effects and no adverse effects on postnatal pup development were observed in rats and cynomolgus monkeys during embryotoxicity testing. In the rats, however, at a dose of 400 mg/kg/day, renal cavitation was observed in the pups. In periand post-natal toxicity testing in rats, dosing with 50 mg/kg/day resulted in greater pup mortality, smaller pups, and delayed unfolding of the pinna. On administration of 14C-cilazapril to pregnant mice, rats and monkeys, radioactivity was measured in the fetuses.
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. INHIBACE must not be administered to nursing mothers (see CONTRAINDICATIONS) and alternative treatments with better established safety profiles during breast-feeding are preferable.
Occasionally dizziness and fatigue may occur, especially when starting therapy (see ADVERSE REACTIONS).
The safety and effectiveness of the use of INHIBACE in children have not been established. Therefore, use in this age group is not recommended.
Although clinical experience has not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. In elderly patients with congestive heart failure on high diuretic dosage, the recommended starting dose of INHIBACE 0.5 mg must be strictly followed (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension, and DOSAGE AND ADMINISTRATION).
Headache and dizziness were the most frequently reported events in patients taking INHIBACE for hypertension. In chronic heart failure clinical trials, dizziness and coughing were the most frequently reported events in patients taking INHIBACE.
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 (see WARNINGS AND PRECAUTIONS).
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 WARNINGS AND PRECAUTIONS).
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.
INHIBACE (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 INHIBACE in controlled clinical trials. INHIBACE 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 INHIBACE for hypertension included: angioedema/face edema (0.1%) (see WARNINGS AND PRECAUTIONS, Cardiovascular, Angioedema), 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 INHIBACE 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%) (see WARNINGS AND PRECAUTIONS, Renal), and cardiogenic shock (1 patient) (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension).
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 INHIBACE (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension).
Hypotension and syncope, each reported in 0.1% of the hypertensive patients treated with INHIBACE, were reported in 2.1% and 0.8% of the congestive heart failure patients treated with INHIBACE.
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 INHIBACE were:
Cardiovascular: Chest pain, angina pectoris, tachycardia, atrial fibrillation, arrhythmia, flushing.
In the patient population treated with INHIBACE 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 INHIBACE 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 (see WARNINGS AND PRECAUTIONS, Hepatic, Patients with Impaired Liver Function).
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: (see WARNINGS AND PRECAUTIONS)
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.
INHIBACE 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, see WARNINGS AND PRECAUTIONS)
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 INHIBACE.
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 INHIBACE. Since this syndrome can be associated with laryngeal edema, INHIBACE 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) (see WARNINGS AND PRECAUTIONS).
Rare: Anaphylaxis (see WARNINGS AND PRECAUTIONS), 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 (see WARNINGS AND PRECAUTIONS: Renal Impairment).
Rare: Renal impairment, acute renal failure, blood creatinine increased, blood urea increased, hyperkalemia, hyponatremia (see WARNINGS AND PRECAUTIONS, Renal).
Common: Fatigue
Hypotension may occur when starting treatment or increasing dose, especially in at-risk patients (see WARNINGS AND PRECAUTIONS). 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 (see WARNINGS AND PRECAUTIONS).
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.
| Proper Name | Ref. | Effect | Clinical comment |
|---|---|---|---|
| Agents increasing serum potassium (potassium sparing diuretics, trimethoprimcontaining products, cyclosporine, heparin, potassium supplements or potassium-containing salt substitutes) | CT,C | Hyperkalemia may occur in some patients treated with INHIBACE. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), trimethoprimcontaining products, cyclosporine, heparin, potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium impairment (see ACTION AND CLINICAL PHARMACOLOGY and WARNINGS AND PRECAUTIONS). | Therefore, the combination of cilazapril with agents increasing serum potassium (potassium sparing diuretics, trimethoprim-containing products, cyclosporine, heparin, potassium supplements or potassiumcontaining salt substitutes) is not recommended (see WARNINGS AND PRECAUTIONS). If concomitant use is indicated severe hyperkalemia may occur. They should be used with caution and with frequent monitoring of serum potassium. |
| Antidiabetics | CT* | Concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic 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. | Close monitoring of blood glucose levels is advised. |
| CT, CT* | Concomitant use of ACE inhibitors with DPP-IV inhibitors (e.g. alogliptin, linagliptin, saxagliptin and sitagliptin) may lead to an increased risk for angioedema. | See WARNINGS AND PRECAUTIONS, Cardiovascular, Angioedema | |
| Allopurinol, immunosuppressants, and steroid medicines | T | Concomitant administration with ACE inhibitors may lead to an increased risk of hematological reactions. | Increased likelihood of hematological reactions. |
| Digoxin | CT | No pharmacodynamic or pharmacokinetic interactions (and no increase in plasma digoxin concentrations) were observed when cilazapril therapy (5 mg once daily) was administered to healthy volunteers receiving digoxin (0.25 mg twice daily). | |
| Diuretic therapy (thiazide or loop diuretics) | CT | Patients concomitantly taking ACE inhibitors and diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy. | The possibility of hypotensive effects after the first dose of INHIBACE can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with INHIBACE. If it is not possible to discontinue the diuretic, the starting dose of INHIBACE should be reduced and the patient should be closely observed for several hours following the initial dose and until blood pressure has stabilized (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION). |
| Gold | C | 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. | Use with caution when INHIBACE is coadministered with gold salts. |
| Lithium Salts | CT | Reversible increases in serum lithium concentrations 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. Lithium toxicity, including CNS symptoms, ECG changes and renal failure, has occurred in patients taking ACE inhibitors. Proposed mechanisms include decreased renal elimination of lithium due to decreased aldosterone secretion or decreased renal function. | Lithium should generally not be given with ACE inhibitors. Use of cilazapril with lithium is not recommended, but if the combination proves necessary, careful and frequent monitoring of serum lithium levels should be performed. |
| Non-steroidal antiinflammatory medicinal products (NSAIDs) including aspirin ≥3 g/day | CT | When ACE inhibitors, including INHIBACE, are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. acetylsalicylic acid at antiinflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of ACE inhibitors, including INHIBACE, 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 introduction of therapy with cilazapril (2.5 mg once daily) in hypertensive patients receiving indomethacin (50 mg twice daily) did not result in a reduction in blood pressure. However, the introduction of therapy with indomethacin (50 mg twice daily) in hypertensive patients receiving cilazapril (2.5 mg once daily) did not attenuate the blood pressure lowering effects of cilazapril. The interaction does not appear to occur in patients treated with cilazapril prior to the administration of a NSAID. There was no evidence of a pharmacokinetic interaction between cilazapril and indomethacin. | The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring for signs of worsening heart failure or renal function or loss of blood pressure control after initiation of concomitant therapy, and periodically thereafter. |
| Other antihypertensive agents | CT | An additive effect may be observed when INHIBACE is administered in combination with other blood pressure-lowering agents (e.g. diuretics, betaadrenergic blocking drugs). Agents affecting sympathetic activity (e.g. ganglionic blocking agents or adrenergic neuron blocking agents) should be used with caution. Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors. | These drugs should be introduced at a low initial dosage, and used with caution. Close monitoring of blood pressure is advised, and dose/regimen adjustment should be considered if necessary. |
| Tricyclic antidepressants/antipsy chotics/anesthetics/nar cotics | C | Concomitant use of anesthetics during the course of general anesthesia, as well as tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure (see WARNINGS AND PRECAUTIONS). | Close monitoring of blood pressure is advised, and dose/regimen adjustment should be considered if necessary. |
| Dual blockade of the Renin-AngiotensinSystem (RAS) with ACE inhibitors, ARBs or aliskirencontaining drugs | CT | Dual Blockade of the ReninAngiotensin-System (RAS) with ACE inhibitors, ARBs or aliskiren containing drugs is contraindicated in patients with diabetes and/or renal impairment, and is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, renal failure, and hyperkalemia. | See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Dual Blockade of the Renin-AngiotensinSystem (RAS). |
| Sacubitril/valsartan | C | Concomitant use of ACE inhibitors with sacubitril/valsartan increases the risk of angioedema. | Concomitant use is contraindicated (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS). |
| mTOR inhibitors | C,RCS | Concomitant use of ACE inhibitors with mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) may lead to an increased risk for Angioedema. | See WARNINGS AND PRECAUTIONS, Cardiovascular, Angioedema |
Legend: C = Case Study; RCS = Retrospective Cohort Study; CT = Clinical Trial; T =
Theoretical, CT*: Epidemiological studies.
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