Cilazapril

Pronunciation

(sye LAY za pril)

Synonyms

Cilazapril Monohydrate

Canadian Brand Names

Inhibace®

Use

Management of hypertension; treatment of congestive heart failure

Restrictions

Not available in U.S.

Pregnancy Risk Factor

Not assigned; C/D (2nd and 3rd trimesters) based on other ACE inhibitors

Pregnancy Implications

Cranial defects, hypocalvaria/acalvaria, oligohydramnios, persistent anuria following delivery, hypotension, renal defects, renal dysgenesis/dysplasia, renal failure, pulmonary hypoplasia, limb contractures secondary to oligohydramnios, and stillbirth reported. ACE inhibitors should be avoided during pregnancy, particularly in the 2nd and 3rd trimesters.

Lactation

Excretion in breast milk unknown/not recommended (similar agents compatible)

Contraindications

Hypersensitivity to cilazapril or any component of the formulation; angioedema related to previous treatment with an ACE inhibitor; idiopathic or hereditary angioedema; bilateral renal artery stenosis (unilateral if single kidney); ascites; pregnancy (2nd or 3rd trimester)

Warnings/Precautions

Anaphylactic reactions can occur. Angioedema can occur at any time during treatment (especially following first dose). Angioedema may involve head and neck (potentially affecting the airway) or the intestine (presenting with abdominal pain). Careful blood pressure monitoring with first dose (hypotension can occur especially in volume depleted patients). Dosage adjustment needed in renal impairment. Use with caution in hypovolemia; collagen vascular diseases; valvular stenosis (particularly aortic stenosis); hyperkalemia; or before, during, or immediately after anesthesia. Avoid rapid dosage escalation which may lead to renal insufficiency.

Rare toxicities associated with ACE inhibitors include cholestatic jaundice (which may progress to hepatic necrosis) and neutropenia/agranulocytosis with myeloid hyperplasia. Patients with collagen vascular diseases or renal impairment may be at increased risk for hematologic toxicity. Consider baseline and periodic monitoring of WBC and serum creatinine. Hypersensitivity reactions may be seen during hemodialysis with high-flux dialysis membranes (eg, AN69). Deterioration in renal function can occur with initiation. Use with caution in unilateral renal artery stenosis and pre-existing renal insufficiency.

Adverse Reactions

1% to 10%

Cardiovascular: Palpitation (up to 1%), hypotension (symptomatic, up to 1% in CHF patients), orthostatic hypotension (2%)

Central nervous system: Headache (3% to 5%), dizziness (3% to 8%), fatigue (2% to 3%)

Gastrointestinal: Nausea (1% to 3%)

Neuromuscular & skeletal: Weakness (0.3% to 2%)

Renal: Increased serum creatinine

Respiratory: Cough (2% in hypertension, up to 7.5% in CHF patients)

<1%: Angina, angioedema, anorexia, anxiety, arrhythmia, ataxia, atrial fibrillation, AV block, bradycardia, bronchospasm, cardiogenic shock, confusion, constipation, depression, diarrhea, dyspepsia, dyspnea, dysuria, gout, hemolytic anemia, hyperbilirubinemia, hyperglycemia, hyperkalemia, insomnia, leukopenia, MI, neutropenia, nervousness, pancreatitis, paresthesia, pemphigus, polyuria, proteinuria, pruritus, purpura, rash, renal failure, rhinitis, somnolence, Stevens-Johnson syndrome, stroke, syncope, taste perversion, thrombocytopenic purpura, tinnitus, transaminases increased, tremor, urticaria, vomiting

Overdosage/Toxicology

Mild hypotension has been the primary toxic effect seen with acute overdose. Bradycardia may also occur. Hyperkalemia occurs even with therapeutic doses, especially in patients with renal insufficiency and those taking NSAIDs. Treatment is symptom-directed and supportive.

Drug Interactions

Allopurinol: Case reports (rare) indicate a possible increased risk of Stevens-Johnson syndrome when combined with captopril. Risk with other ACE inhibitors not established.

Alpha1 blockers: Hypotensive effect increased.

Aspirin: The effects of ACE inhibitors may be blunted by aspirin administration, particularly at higher dosages and/or increase adverse renal effects.

Diuretics: Hypovolemia due to diuretics may precipitate acute hypotensive events or acute renal failure.

Insulin: Risk of hypoglycemia may be increased.

Lithium: Risk of lithium toxicity may be increased; monitor lithium levels, especially the first 4 weeks of therapy.

Mercaptopurine: Risk of neutropenia may be increased.

NSAIDs: May attenuate hypertensive efficacy; effect has been seen with captopril and may occur with other ACE inhibitors; monitor blood pressure. May increase adverse renal effects.

Potassium-sparing diuretics (amiloride, potassium, spironolactone, triamterene): Increased risk of hyperkalemia.

Potassium supplements: May increase the risk of hyperkalemia.

Trimethoprim (high dose): May increase the risk of hyperkalemia.

Ethanol/Nutrition/Herb Interactions

Food: Cilazapril serum concentrations may be decreased if taken with food (no apparent effect on activity). Long-term use of ACE inhibitors may result in a zinc deficiency which can result in a decrease in taste perception.

Herb/Nutraceutical: Avoid dong quai if using for hypertension (has estrogenic activity). Avoid ephedra, yohimbe, ginseng (may worsen hypertension). Avoid garlic (may have increased antihypertensive effect). Long-term use may result in zinc deficiency.

Stability

Store at 15°C to 30°C (59°F to 86°F).

Mechanism of Action

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.

Pharmacodynamics/Kinetics

Onset: Antihypertensive: ~1 hour

Duration: Therapeutic effect: 24 hours

Absorption: Rapid

Metabolism: To active form (cilazaprilat)

Bioavailability: 57%

Half-life elimination: Cilazaprilat: Terminal: 36-49 hours

Time to peak: 3-7 hours

Excretion: In urine (91%)

Dosage

Oral:

Hypertension: 2.5-5 mg once daily (maximum dose: 10 mg/day)

Congestive heart failure: Initial: 0.5 mg once daily; if tolerated, after 5 days increase to 1 mg/day (lowest maintenance dose); may increase to maximum of 2.5 mg once daily

Elderly: Initial: 1.25 mg once daily; titrate slowly as tolerated

Dosage adjustment in renal impairment:

Hypertension:

Clcr 10-40 mL/minute: Initial: 0.5 mg once daily (maximum dose: 2.5 mg once daily)

Clcr<10 mL/minute: 0.25-0.5 mg once or twice weekly

Congestive heart failure:

Clcr 10-40 mL/minute: Initial: 0.25-0.5 mg once daily (maximum dose: 2.5 mg once daily)

Clcr<10 mL/minute: 0.25-0.5 mg once or twice weekly

Dosage adjustment in hepatic impairment: Initial: 0.5 mg once daily (with caution)

Administration

May be administered with or without food.

Dietary Considerations

May be taken with or without food.

Patient Education

Take exactly as directed; do not discontinue without consulting prescriber. Take first dose at bedtime. Do not use NSAIDs (like indomethacin or naproxen), potassium supplements, or salt substitutes containing potassium without consulting prescriber. May cause dizziness, fainting, or lightheadedness (use caution when driving or engaging in tasks requiring alertness until response to drug is known); postural hypotension (use caution when rising from lying or sitting position or climbing stairs); nausea or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help) - report if these persist. Report chest pain or palpitations; respiratory difficulty or unusual cough; or other persistent adverse reactions. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. This drug should not be used in the 2nd or 3rd trimester of pregnancy. Consult prescriber for appropriate contraceptive measures if necessary. Breast-feeding is not recommended.

Additional Information

Not available in U.S.

Cardiovascular Considerations

ACE inhibitors decrease morbidity and mortality in patients with asymptomatic and symptomatic left ventricular dysfunction. In this situation, they decrease hospitalizations for, and retard progression to, congestive heart failure. According to 2004 ACC/AHA STEMI guidelines, an ACE inhibitor should be administered orally within the first 24 hours of STEMI to patients with anterior infarction, pulmonary congestion or LVEF <0.4, in the absence of hypotension or known contraindications to that class of medicines. In the emergency management of complicated STEMI, a short-acting ACEI (eg, captopril 1-6.25 mg) may be added once the patient's systolic blood pressure is >100 mm Hg and not <30 mm Hg below baseline. ACE inhibitors have renal protective effects in patients with proteinuria and possibly cardioprotective effects in high-risk patients.

ACE inhibitor therapy may elicit rapid increases in potassium and creatinine, especially when used in patients with bilateral renal artery stenosis. When ACE inhibition is introduced in patients with pre-existing diuretic therapy who are hypovolemic, the ACE inhibitor may induce acute hypotension. In those patients experiencing cough on an ACE inhibitor, the ACE inhibitor may be discontinued and, if necessary, angiotensin receptor blocker therapy instituted. Concomitant NSAID therapy may attenuate blood pressure control; use of NSAIDs should be avoided or limited, with monitoring of blood pressure control. In the setting of heart failure, NSAID use may be associated with an increased risk for fluid accumulation and edema. Because of the potent teratogenic effects of ACE inhibitors, these drugs should be avoided, if possible, when treating women of childbearing potential not on effective birth control measures.

In the treatment of unstable angina/non-ST-segment elevation MI, ACE inhibitors are recommended when hypertension persists despite treatment with nitroglycerin and a beta-blocker in patients with LV systolic dysfunction or CHF and in ischemic patients with diabetes (Class I). ACE inhibitors are also recommended following acute coronary syndrome (Class IIa).

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Orthostatic hypotension.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Dosage Forms

Tablet: 1 mg, 2.5 mg, 5 mg

References

Antman EM, Anbe SC, Alpert JS, et al, "ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction)," Circulation, 2004, 110:588-636. Available at: http://www.circulationaha.org/cgi/content/full/110/5/588. Last accessed October 26, 2004.

Chase MP, Fiarman GS, Scholz FJ, et al, "Angioedema of the Small Bowel Due to an Angiotensin-Converting Enzyme Inhibitor,"J Clin Gastroenterol, 2000, 31(3):254-7.

Chobanian AV, Bakris GL, Black HR, et al, "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report,"JAMA, 2003, 289(19):2560-71.

Deget F and Brogden RN, "Cilazapril. A Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Cardiovascular Disease,"Drugs, 1991, 41(5):799-820.

Dossegger L, Nielsen T, Preston C, et al, "Heart Failure Therapy With Cilazapril: An Overview,"J Cardiovasc Pharmacol, 1994, 24(Suppl 3):38-41.

Inhibace® product monograph, Hoffman-La Roche Ltd, Ontario, July 2001.

"K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Kidney Disease Outcome Quality Initiative,"Am J Kidney Dis, 2002, 39(2 Suppl 2):1-246. Available at: http://www.kidney.org/professionals/doqi/kdoqi/toc.htm. Accessed August 1, 2003.

Rosenthal JH, "Therapeutic Experience With Cilazapril,"J Cardiovasc Pharmacol, 1994, 24(Suppl2):65-9.

Smoger SH and Sayed MA, "Simultaneous Mucosal and Small Bowel Angioedema Due to Captopril,"South Med J, 1998, 91(11):1060-3.

Song JC and White CM, "Clinical Pharmacokinetics and Selective Pharmacodynamics of New Angiotensin Converting Enzyme Inhibitors: An Update,"Clin Pharmacokinet, 2002, 41(3):207-24.

Szues T, "Cilazapril. A Review,"Drugs, 1991, 41(Suppl 1):18-24.

International Brand Names

Cilazil® (HR, SI); Dynorm® (DE); Inhibace® (AR, AT, BD, BE, CA, CH, CL, CO, CZ, ES, HK, HU, ID, NZ, PL, RO, RU, SE, SG, TH, TR, YU, ZA); Inhibace Roche® (AT); Inibace® (IT, LU, MX, PT); Initiss® (IT); Inobes® (ID); Inocar® (ES); Justor® (FR); Prilazid® (YU); Vascace® (GB, IE, IL); Vascase® (BR, NL, PT)