Version May 2024
Heart failure: Oral: Initial: 0.5 mg once daily; per response and tolerability, increase to 1 mg once daily within 5 days; may further titrate as necessary to usual maintenance dose of 2.5 mg once daily (maximum dose: 2.5 mg once daily). Note: Some additional benefit has been observed with doses up to 5 mg once daily in a few patients; however, data is limited.
Hypertension: Oral: Initial: 2.5 mg once daily; titrate to response at intervals of at least 2 weeks. Usual dose: 2.5 to 5 mg once daily (maximum dose: 10 mg/day). Note: May administer total daily dose in 2 divided doses if antihypertensive effect diminishes over 24-hour dosing interval. Patients with strongly activated renin-angiotensin-aldosterone system (eg, severe hypertension, salt and/or volume depletion, cardiac decompensation) may be susceptible to excessive hypotensive effects and should initiate therapy at 0.5 mg once daily under close supervision.
Combination therapy with diuretic: Initial: 0.5 mg once daily; titrate slowly as tolerated.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Heart failure:
CrCl >40 mL/minute: Initial 0.5 mg once daily (maximum dose: 2.5 mg once daily). Note: The manufacturer labeling does not define the estimated creatinine clearance value at which a dosage adjustment is not required.
CrCl 10 to 40 mL/minute: Initial: 0.25 to 0.5 mg once daily (maximum dose: 2.5 mg once daily).
CrCl <10 mL/minute: Use is not recommended.
Hypertension:
CrCl >40 mL/minute: Initial: 1 mg once daily (maximum dose: 5 mg once daily). Note: The manufacturer labeling does not define the estimated creatinine clearance value at which a dosage adjustment is not required.
CrCl 10 to 40 mL/minute: Initial: 0.5 mg once daily (maximum dose: 2.5 mg once daily).
CrCl <10 mL/minute: Use is not recommended.
Cirrhotic patients (without ascites): Hypertension: Initial: ≤0.5 mg once daily (use with caution); use with caution, particularly in patients with ascites due to cirrhosis (AASLD [Biggins 2021]; AASLD [Runyon 2013]).
Heart failure: Oral: Initial: 0.5 mg once daily; per response and tolerability, increase to 1 mg once daily within 5 days; may further titrate as necessary to usual maintenance dose of 1 mg to 2.5 mg once daily (maximum: 2.5 once daily)
Elderly patients with heart failure on high diuretic dosage: Do not initiate with doses >0.5 mg once daily.
Hypertension: Oral: Initial: ≤1.25 mg once daily; titrate slowly as tolerated. Patients with strongly activated renin-angiotensin-aldosterone system (eg, severe hypertension, salt and/or volume depletion, cardiac decompensation) may be susceptible to excessive hypotensive effects and should initiate therapy at 0.5 mg once daily under close supervision.
Combination therapy with diuretic: Initial: 0.5 mg once daily; titrate slowly as tolerated
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults treated for hypertension (HTN) and heart failure (HF), unless otherwise noted.
1% to 10%:
Cardiovascular: Hypotension (≤2%), orthostatic hypotension (≤2%), palpitations (≤1%)
Gastrointestinal: Nausea (1% to 3%)
Genitourinary: Proteinuria (≤1%)
Hematologic & oncologic: Abnormal white blood cell count differential (≤1%), change in neutrophil count (1% to 2%)
Hepatic: Increased gamma-glutamyl transferase (1%), increased serum alanine aminotransferase (1% to 3%)
Nervous system: Asthenia (≤2%), dizziness (3% to 8%), fatigue (2% to 3%), headache (3% to 5%)
Renal: Increased blood urea nitrogen (≤3%), increased serum creatinine (≤3%)
Respiratory: Cough (HTN: 2%; HF: 8%)
<1% (any indication):
Cardiovascular: Acute myocardial infarction, angina pectoris, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrhythmia, cardiac decompensation, cardiogenic shock, chest pain, edema, extrasystoles, flushing, syncope, tachycardia
Dermatologic: Dermatitis, diaphoresis, erythematous rash, maculopapular rash, pruritus, skin rash, urticaria
Endocrine & metabolic: Decreased libido, hot flash, hyperglycemia, increased lactate dehydrogenase, increased serum potassium
Gastrointestinal: Abdominal pain, anorexia, constipation, diarrhea, dysgeusia, dyspepsia, flatulence, gastrointestinal hemorrhage, rectal hemorrhage, vomiting, xerostomia
Genitourinary: Dysuria, impotence, polyuria, uremia, urinary frequency
Hematologic & oncologic: Anemia, immune thrombocytopenia, leukopenia, neutropenia, purpuric disease, qualitative disorders of platelets
Hepatic: Increased serum bilirubin
Hypersensitivity: Angioedema, facial edema
Nervous system: Anxiety, ataxia, cerebrovascular disease, confusion, depression, drowsiness, hypoesthesia, insomnia, malaise, migraine, nervousness, pain, paresthesia, rigors, tremor, vertigo, voice disorder
Neuromuscular & skeletal: Arthralgia, gout, lower leg cramp, myalgia
Ophthalmic: Conjunctivitis, photophobia, visual disturbance
Otic: Tinnitus
Renal: Renal failure syndrome, renal pain
Respiratory: Bronchitis, bronchospasm, dyspnea, epistaxis, pharyngitis, respiratory tract infection, rhinitis, sinusitis
Postmarketing (any indication):
Dermatologic: Pemphigus foliaceus (Buzón 1998), subacute cutaneous lupus erythematosus (Fernández-Díaz 1995)
Endocrine & metabolic: SIADH (Arinzon 2001)
Gastrointestinal: Pancreatitis
Hepatic: Cholestatic hepatitis, hepatocellular hepatitis, increased serum alkaline phosphatase, increased serum aspartate aminotransferase, jaundice
Ophthalmic: Visual hallucination (Doane 2013)
Respiratory: Pleural effusion (Kupeli 2010)
Hypersensitivity to cilazapril, any other angiotensin-converting-enzyme (ACE) inhibitor, or any component of the formulation; angioedema related to previous treatment with an ACE inhibitor; hereditary or idiopathic angioedema; ascites; anuria; concomitant use with aliskiren-containing drugs in patients with diabetes mellitus (type 1 or 2) or moderate to severe renal impairment (GFR <60 mL/minute/1.73 m2); concomitant use with or within 36 hours of a neprilysin inhibitor (eg, sacubitril); patients who are pregnant, intend to become pregnant, or of childbearing potential who are not using adequate contraception; breastfeeding; hereditary problems of galactose intolerance, glucose-galactose malabsorption, or congenital lactase deficiency (lactose-containing products only).
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Angioedema: At any time during treatment (especially following first dose) angioedema may occur rarely with angiotensin-converting-enzyme (ACE) inhibitors; it may involve the head and neck (potentially compromising the airway) or the intestine (presenting with abdominal pain). Black-skinned patients of African descent and patients with idiopathic or hereditary angioedema may be at an increased risk. Risk may also be increased with concomitant use of mammalian target of rapamycin inhibitors (eg, everolimus, sirolimus, temsirolimus) or DPP-4 inhibitors (eg, alogliptin, linagliptin, saxagliptin, sitagliptin). Prolonged frequent monitoring may be required especially if tongue, glottis, or larynx are involved as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Aggressive early and appropriate management is critical. Use in patients with previous angioedema associated with ACE inhibitor therapy or hereditary or idiopathic angioedema is contraindicated.
• Cholestatic jaundice: A rare toxicity associated with ACE inhibitors includes cholestatic jaundice, which may progress to fulminant hepatic necrosis; discontinue if marked elevation of hepatic transaminases or jaundice occurs.
• Cough: An ACE inhibitor cough is a dry, hacking, nonproductive one that usually occurs within the first few months of treatment and should generally resolve within 1 to 4 weeks after discontinuation of the ACE inhibitor. Other causes of cough should be considered (eg, pulmonary congestion in patients with heart failure) and excluded prior to discontinuation.
• Hyperkalemia: May occur with ACE inhibitors; risk factors include renal dysfunction, diabetes mellitus, and concomitant use of medications that may increase potassium (eg, potassium-sparing diuretics, potassium supplements, potassium-containing salts). Use cautiously, if at all, with these agents and monitor potassium closely.
• Hypersensitivity reactions: Anaphylactic/anaphylactoid reactions can occur with ACE inhibitors. Severe anaphylactoid reactions may be seen during hemodialysis (eg, CVVHD) with high-flux dialysis membranes (eg, AN69), and rarely, during low-density lipoprotein apheresis with dextran sulfate cellulose. Rare cases of anaphylactoid reactions have been reported in patients undergoing sensitization treatment with hymenoptera (bee, wasp) venom while receiving ACE inhibitors.
• Hypotension/syncope: Symptomatic hypotension with or without syncope can occur with ACE inhibitors (usually with the first several doses); effects are most often observed in volume-depleted patients; correct volume depletion prior to initiation; close monitoring of patient is required especially with initial dosing and dosing increases; BP must be lowered at a rate appropriate for the patient's clinical condition. Although dose reduction may be necessary, hypotension is not a reason for discontinuation of future ACE inhibitor use especially in patients with heart failure where a reduction in systolic BP is a desirable observation.
• Neutropenia/agranulocytosis: Another ACE inhibitor, captopril, has been associated with rare cases of agranulocytosis, neutropenia, or leukopenia with myeloid hypoplasia. Patients with renal impairment are at high risk of developing neutropenia. Patients with both renal impairment and collagen vascular disease (eg, systemic lupus erythematosus) are at an even higher risk of developing neutropenia. Periodically monitor CBC with differential in these patients.
• Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose GFR is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function.
Disease-related concerns:
• Aortic stenosis: Use with caution in patients with severe aortic stenosis; may reduce coronary perfusion resulting in ischemia.
• Ascites: Generally, avoid use in patients with ascites due to cirrhosis or refractory ascites; if use cannot be avoided in patients with ascites due to cirrhosis, monitor BP and renal function carefully to avoid rapid development of renal failure (AASLD [Runyon 2013]).
• Cardiovascular disease: Initiation of therapy in patients with ischemic heart disease or cerebrovascular disease warrants close observation due to the potential consequences posed by falling BP (eg, myocardial infarction, stroke). Fluid replacement, if needed, may restore BP; therapy may then be resumed. Discontinue therapy in patients whose hypotension recurs.
• Collagen vascular disease: Use with caution in patients with collagen vascular disease especially with concomitant renal impairment; may be at increased risk for hematologic toxicity.
• Hepatic impairment: Use with caution in patients with preexisting liver dysfunction and/or cirrhosis without ascites (contraindicated in patients with ascites); close monitoring is required and a dose reduction may be necessary.
• Hypertrophic cardiomyopathy with outflow tract obstruction: Use with caution in patients with hypertrophic cardiomyopathy and outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition.
• Renal artery stenosis: Use with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.
• Renal impairment: Use with caution in preexisting renal insufficiency; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further renal impairment.
Special populations:
• Pregnancy: [Canadian Boxed Warning]: Use is contraindicated during pregnancy. Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.
• Race/Ethnicity: In Black patients, the BP-lowering effects of ACE inhibitors may be less pronounced. The exact mechanism is not known; differences in the renin-angiotensin-aldosterone system, low renin levels, and salt sensitivity more commonly found in Black patients may contribute (Brewster 2013; Helmer 2018). In addition, Black patients may be at an increased risk of angioedema associated with ACE inhibitors (Brown 1996; Maroteau 2020; Miller 2008; Montinaro 2020; Woodard-Grice 2010).
• Surgery: In patients on chronic ACE inhibitor therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; use with caution before, during, or immediately after major surgery. Cardiopulmonary bypass, intraoperative blood loss, or vasodilating anesthesia increases endogenous renin release. Use of ACE inhibitors perioperatively will blunt angiotensin II formation and may result in hypotension. However, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent (Hillis 2011). Based on current research and clinical guidelines in patients undergoing non-cardiac surgery, continuing ACE inhibitors is reasonable in the perioperative period. If ACE inhibitors are held before surgery, it is reasonable to restart postoperatively as soon as clinically feasible (ACC/AHA [Fleisher 2014]).
Dosage form specific issues:
• Lactose: Some products contain lactose; use is contraindicated in patients with galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption.
Not available in the US
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Inhibace: 2.5 mg, 5 mg [contains corn starch]
Generic: 1 mg, 2.5 mg, 5 mg
Oral: May be administered with or without food.
Note: Not approved in the US
Heart failure: Adjunctive treatment of heart failure
Guideline recommendations:The American College of Cardiology/American Heart Association (ACC/AHA) 2013 Heart Failure Guidelines recommend the use of ACE inhibitors, along with other guideline-directed medical therapies, to prevent progression of HF and reduced ejection fraction in asymptomatic patients with or without a history of myocardial infarction (Stage B HF), or to treat those with symptomatic heart failure and reduced ejection fraction to reduce morbidity and mortality (Stage C HFrEF).
Hypertension: Management of hypertension
Guideline recommendations: The 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults recommends if monotherapy is warranted, in the absence of comorbidities (eg, cerebrovascular disease, chronic kidney disease, diabetes, heart failure, ischemic heart disease, etc.), that thiazide-like diuretics or dihydropyridine calcium channel blockers may be preferred options due to improved cardiovascular endpoints (eg, prevention of heart failure and stroke). ACE inhibitors and ARBs are also acceptable for monotherapy. Combination therapy may be required to achieve blood pressure goals and is initially preferred in patients at high risk (stage 2 hypertension or atherosclerotic cardiovascular disease [ASCVD] risk ≥10%) (ACC/AHA [Whelton 2018]).
Non-ST-elevation acute coronary syndrome; Stable coronary artery disease; ST-elevation acute coronary syndrome
ALERT: Canadian Boxed Warning: Health Canada-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Aliskiren: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Aliskiren may enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Aliskiren may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Management: Aliskiren use with ACEIs or ARBs in patients with diabetes is contraindicated. Combined use in other patients should be avoided, particularly when CrCl is less than 60 mL/min. If combined, monitor potassium, creatinine, and blood pressure closely. Risk D: Consider therapy modification
Allopurinol: Angiotensin-Converting Enzyme Inhibitors may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Risk C: Monitor therapy
Alteplase: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Alteplase. Specifically, the risk for angioedema may be increased. Risk C: Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Angiotensin II: Angiotensin-Converting Enzyme Inhibitors may enhance the therapeutic effect of Angiotensin II. Risk C: Monitor therapy
Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Angiotensin II Receptor Blockers may increase the serum concentration of Angiotensin-Converting Enzyme Inhibitors. Management: Use of telmisartan and ramipril is not recommended. It is not clear if any other combination of an ACE inhibitor and an ARB would be any safer. Consider alternatives when possible. Monitor blood pressure, renal function, and potassium if combined. Risk D: Consider therapy modification
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Aprotinin: May diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Arginine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
AzaTHIOprine: Angiotensin-Converting Enzyme Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine. Risk C: Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
Dapoxetine: May enhance the orthostatic hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Dipeptidyl Peptidase-IV Inhibitors: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Drospirenone-Containing Products: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Eplerenone: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Everolimus: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Ferric Gluconate: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Ferric Gluconate. Risk C: Monitor therapy
Ferric Hydroxide Polymaltose Complex: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Ferric Hydroxide Polymaltose Complex. Specifically, the risk for angioedema or allergic reactions may be increased. Risk C: Monitor therapy
Finerenone: Angiotensin-Converting Enzyme Inhibitors may enhance the hyperkalemic effect of Finerenone. Risk C: Monitor therapy
Flunarizine: May enhance the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Gelatin (Succinylated): Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Gelatin (Succinylated). Specifically, the risk of a paradoxical hypotensive reaction may be increased. Risk C: Monitor therapy
Grass Pollen Allergen Extract (5 Grass Extract): Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). Specifically, ACE inhibitors may increase the risk of severe allergic reaction to Grass Pollen Allergen Extract (5 Grass Extract). Risk X: Avoid combination
Heparin: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Heparins (Low Molecular Weight): May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Herbal Products with Blood Pressure Increasing Effects: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Icatibant: May diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Indoramin: May enhance the hypotensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Iron Dextran Complex: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Iron Dextran Complex. Specifically, patients receiving an ACE inhibitor may be at an increased risk for anaphylactic-type reactions. Risk C: Monitor therapy
Lanthanum: May decrease the serum concentration of Angiotensin-Converting Enzyme Inhibitors. Management: Administer angiotensin-converting enzyme (ACE) inhibitors at least two hours before or after lanthanum. Risk D: Consider therapy modification
Levodopa-Foslevodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Foslevodopa. Risk C: Monitor therapy
Lithium: Angiotensin-Converting Enzyme Inhibitors may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an ACE inhibitor. Monitor for increased concentrations/toxic effects of lithium if an ACE inhibitor is initiated/dose increased, or if switching between ACE inhibitors. Risk D: Consider therapy modification
Loop Diuretics: May enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Loop Diuretics may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Topical): May diminish the therapeutic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Polyethylene Glycol-Electrolyte Solution: Angiotensin-Converting Enzyme Inhibitors may enhance the nephrotoxic effect of Polyethylene Glycol-Electrolyte Solution. Risk C: Monitor therapy
Potassium Salts: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Prazosin: Antihypertensive Agents may enhance the hypotensive effect of Prazosin. Risk C: Monitor therapy
Pregabalin: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Pregabalin. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Racecadotril: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk for angioedema may be increased with this combination. Risk C: Monitor therapy
Ranolazine: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Sacubitril: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Sacubitril. Specifically, the risk of angioedema may be increased with this combination. Risk X: Avoid combination
Salicylates: May enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Salicylates may diminish the therapeutic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Silodosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Sirolimus Products: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk for angioedema may be increased. Risk C: Monitor therapy
Sodium Phosphates: Angiotensin-Converting Enzyme Inhibitors may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Risk C: Monitor therapy
Sparsentan: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk X: Avoid combination
Tacrolimus (Systemic): Angiotensin-Converting Enzyme Inhibitors may enhance the hyperkalemic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Temsirolimus: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Terazosin: Antihypertensive Agents may enhance the hypotensive effect of Terazosin. Risk C: Monitor therapy
Thiazide and Thiazide-Like Diuretics: May enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Tolvaptan: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Trimethoprim: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Urapidil: May interact via an unknown mechanism with Angiotensin-Converting Enzyme Inhibitors. Management: Avoid concomitant use of urapidil and angiotensin-converting enzyme (ACE) inhibitors. Risk D: Consider therapy modification
Urokinase: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Cilazapril serum concentrations may be decreased if taken with food (no apparent effect on activity). Management: Administer without regard to food.
Cilazapril is contraindicated in patients who may become pregnant and are not using adequate contraception.
Medications considered acceptable for the treatment of chronic hypertension during pregnancy may generally be used in patients trying to conceive. Angiotensin-converting enzyme (ACE) inhibitors are fetotoxic. Transition patients prior to conception to an agent preferred for use during pregnancy unless treatment with an ACE inhibitor is absolutely necessary (ACC/AHA [Whelton 2018]; ACOG 2019; NICE 2019).
ACE inhibitors are not recommended for the treatment of heart failure in patients planning to become pregnant (AHA/ACC/HFSA [Heidenreich 2022]).
Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Exposure to an angiotensin-converting enzyme (ACE) inhibitor during the first trimester of pregnancy may be associated with an increased risk of fetal malformations (ACOG 2019; ESC [Regitz-Zagrosek 2018]). Following exposure during the second or third trimesters, drugs that act on the renin-angiotensin system are associated with oligohydramnios. Oligohydramnios, due to decreased fetal renal function, may lead to fetal lung hypoplasia and skeletal malformations. Oligohydramnios may not appear until after an irreversible fetal injury has occurred. ACE inhibitor use during pregnancy is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. Monitor infants exposed to an ACE inhibitor in utero for hyperkalemia, hypotension, and oliguria. Exchange transfusions or dialysis may be required to reverse hypotension or improve renal function.
Chronic maternal hypertension may increase the risk of birth defects, low birth weight, preterm delivery, stillbirth, and neonatal death. Actual fetal/neonatal risks may be related to the duration and severity of maternal hypertension. Untreated hypertension may also increase the risks of adverse maternal outcomes, including gestational diabetes, myocardial infarction, preeclampsia, stroke, and delivery complications (ACOG 2019).
Cilazapril is contraindicated for use during pregnancy. Discontinue ACE inhibitors as soon as possible once pregnancy is detected. Agents other than ACE inhibitors are recommended for the treatment of chronic hypertension during pregnancy (ACOG 2019; ESC [Cífková 2020]; SOGC [Magee 2022]). Closely monitor pregnant patients on ACE inhibitors with serial ultrasounds.
ACE inhibitors are not recommended for the treatment of heart failure during pregnancy (AHA/ACC/HFSA [Heidenreich 2022]; ESC [Regitz-Zagrosek 2018]).
It is not known if cilazapril is present in breast milk.
Use is contraindicated in breastfeeding patients.
BP; BUN; serum creatinine; electrolytes (eg, potassium [especially in patients on concomitant potassium-sparing diuretics, potassium supplements and/or potassium containing salts]); LFT (at baseline and periodically thereafter in patients with preexisting hepatic impairment), CBC with differential (in patients with kidney impairment and/or collagen vascular disease); serum glucose (in patients with diabetes).
Cilazapril is a prodrug that is rapidly converted to cilazaprilat (active metabolite), a competitive inhibitor of angiotensin-converting enzyme (ACE); prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor; results in lower levels of angiotensin II which causes an increase in plasma renin activity and a reduction in aldosterone secretion.
Onset of action: ~1 to 2 hours
Peak effect: Antihypertensive effect: 3 to 7 hours; Heart failure (reduction of systemic vascular resistance and pulmonary capillary wedge pressure): 2 to 4 hours
Duration: Therapeutic effect: Up to 24 hours
Absorption: Rapid
Metabolism: Cilazapril (prodrug) hydrolyzed to active metabolite (cilazaprilat)
Bioavailability: Cilazaprilat: 57%
Half-life elimination: Cilazaprilat: Terminal: Single dose: 36 to 49 hours; Multidose: ~54 hours
Time to peak: Cilazaprilat: Within 2 hours
Excretion: Cilazaprilat: Urine (53% unchanged)
Altered kidney function: Cilazaprilat time to peak plasma concentrations, Cmax, AUC, early elimination phase half-life, and 24 hour plasma concentrations increases as creatinine clearance decreases. Changes in these parameters are small when creatinine clearance ≥40 mL/minute. Cilazaprilat clearance (total and renal) decreases in parallel with creatinine clearance and cilazaprilat is not eliminated in patients with complete renal failure. Hemodialysis removes cilazapril and cilazaprilat to a limited extent.
Hepatic function impairment: Following administration of cilazapril to patients with compensated moderate-to-severe hepatic cirrhosis and healthy subjects, the hepatically-impaired group experienced greater increases in cilazapril and cilazaprilat Cmax (57% and 28%, respectively), shorter times to peak concentrations (30 minutes and 45 minutes earlier, respectively) and decreased total clearances (51% and 31%, respectively) as compared to healthy subjects. Cilazaprilat renal clearance and early and terminal elimination half-lives decreased (52%, 42%, and 62%, respectively) in the hepatically impaired group.
Older adult: Following administration of cilazapril to healthy elderly and young subjects, elderly subjects experienced greater increases in cilazaprilat Cmax and AUC (39% and 25%, respectively) and decreased total clearance and renal clearance (20% and 28%, respectively) as compared to young subjects.
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