Inhibace (Cilazapril)

INHIBACE®

Roche

Cilazapril

Angiotensin Converting Enzyme Inhibitor

Action And Clinical Pharmacology: Cilazapril is an angiotensin converting enzyme (ACE) inhibitor, which is used in the treatment of hypertension and congestive heart failure.

Cilazapril suppresses the renin-angiotensin-aldosterone system and thereby reduces both supine and standing systolic and diastolic blood pressures. Renin is an enzyme that is released by the kidneys into the circulation to stimulate the production of angiotensin I, an inactive decapeptide. Angiotensin I is converted by ACE to angiotensin II, a potent vasoconstrictor. Angiotensin II also stimulates aldosterone secretion, leading to sodium and fluid retention. After absorption, cilazapril, a pro-drug, is hydrolyzed to cilazaprilat, the active metabolite, which prevents the conversion of angiotensin I to angiotensin II by inhibition of ACE. Following the administration of cilazapril, plasma ACE activity is inhibited more than 90% within 2 hours at therapeutic doses. Plasma renin activity (PRA) and angiotensin I concentrations are increased and angiotensin II concentrations and aldosterone secretion are decreased. The increase in PRA comes as a result of the loss of negative feedback on renin release caused by the reduction in angiotensin II. The decreased aldosterone secretion may lead to small increases in serum potassium along with sodium and fluid loss. In patients with normal renal function, serum potassium usually remains within the normal range during cilazapril treatment. Mean serum potassium values increased by 0.02 mEq/L in patients with a normal baseline serum creatinine and by 0.11 mEq/L in patients with a raised serum creatinine. In patients concomitantly taking potassium-sparing diuretics, potassium levels may rise.

ACE is identical to kininase II. Therefore, cilazapril may interfere with the degradation of the vasodepressor peptide bradykinin. The role that this plays in the therapeutic effects of cilazapril is unknown.

The antihypertensive effect of cilazapril is usually apparent within the first hour after administration, with maximum effect observed between 3 and 7 hours after dosing. Supine and standing heart rates remain unchanged. Reflex tachycardia has not been observed. Small, clinically insignificant alterations of heart rate may occur.

At recommended doses, the effect of cilazapril in hypertensive patients and in patients with congestive heart failure is maintained for up to 24 hours. In some patients, blood pressure reduction may diminish toward the end of the dosage interval. Blood pressure should be assessed after 2 to 4 weeks of therapy, and dosage adjusted if required. The antihypertensive effect of cilazapril is maintained during long-term therapy. No rapid increase in blood pressure has been observed after abrupt withdrawal of cilazapril.

The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in black patients than in non-blacks.

In hypertensive patients with moderate to severe renal impairment, the glomerular filtration rate and renal blood flow remained in general unchanged with cilazapril.

In patients with congestive heart failure the renin-angiotensin-aldosterone and the sympathetic nervous systems are generally activated leading to enhanced systemic vasoconstriction and to the promotion of sodium and water retention. By suppressing the renin-angiotensin-aldosterone system, cilazapril improves loading conditions in the failing heart by reducing systemic vascular resistance (afterload) and pulmonary capillary wedge pressure (preload) in patients on diuretics and/or digitalis. The onset of action of cilazapril occurs within 1 to 2 hours, reaching its maximum effect within 2 to 4 hours after the first dose. The exercise tolerance of these patients was increased and was associated with an improvement of clinical symptomatology. Patients studied belonged primarily to New York Heart Association Class II and III. The effect of cilazapril on survival in patients with heart failure has not been evaluated.

Pharmacokinetics: Cilazapril is well absorbed and rapidly converted to the active form, cilazaprilat.

Maximum plasma concentrations of cilazaprilat are reached within 2 hours after administration of cilazapril.

Maximum ACE inhibition is greater than 90% after 1 to 5 mg cilazapril. Maximum ACE inhibition is 70 to 80% after 0.5 mg cilazapril. Dose proportionality is observed following the administration of 1 to 5 mg cilazapril. Apparent non-proportionality is observed at 0.5 mg reflective of the binding to ACE. The higher doses of cilazapril are associated with longer duration of maximum ACE inhibition.

The absolute bioavailability of cilazaprilat after oral administration of cilazapril is 57% based on urinary recovery data. (The absolute bioavailability of cilazaprilat after oral administration of cilazaprilat is 19%.) Ingestion of food immediately before the administration of cilazapril reduces the average peak plasma concentration of cilazaprilat by 29%, delays the peak by 1 hour and reduces the bioavailability of cilazaprilat by 14%. These pharmacokinetic changes have little influence on plasma ACE inhibition.

Cilazaprilat is eliminated unchanged by the kidneys. The total urinary recovery of cilazaprilat after i.v. administration of 2.5 mg is 91%. Total clearance is 12.3 L/hour and renal clearance is 10.8 L/hour. The total urinary recovery of cilazaprilat following the oral administration of 2.5 mg cilazapril is 52.6%.

Half-lives for the periods 1 to 4 hours and 1 to 7 days after the i.v. administration of 2.5 mg cilazaprilat are 0.90 and 46.2 hours respectively. These data suggest the saturable binding of cilazaprilat to ACE. The early elimination phase corresponds to the clearance of free drug. During the terminal elimination phase, almost all of the drug is bound to enzyme. Following the oral administration of 0.5, 1, 2.5 and 5 mg cilazapril, terminal elimination phase half-lives for cilazaprilat are 48.9, 39.8, 38.5 and 35.8 hours respectively.

After multiple dose, daily administration of 2.5 mg cilazapril for 8 days, pharmacokinetic parameter values for intact cilazapril after the last dose are similar to the first dose. For cilazaprilat, peak plasma concentrations are achieved at the same time but are 30% higher after the last dose. Trough plasma concentrations and areas under the curve are 20% higher. The terminal elimination phase half-life after the last dose is 53.8 hours. The effective half-life of accumulation for cilazaprilat is 8.9 hours.

Following the administration of 1 mg cilazapril to healthy elderly and young volunteers, the elderly group experienced greater peak plasma concentrations of cilazaprilat and areas under the curve (39% and 25%, respectively) and lower total clearance and renal clearance (20% and 28%, respectively) than the younger volunteers.

In patients with renal impairment, peak plasma concentrations of cilazaprilat, times to peak plasma concentrations, early elimination phase half-lives, areas under the curve and 24 hour plasma concentrations all increase as creatinine clearance decreases. The changes in these parameters are small for patients with creatinine clearances of 40 mL/min or more. Cilazaprilat clearance (total and renal) decreases in parallel with creatinine clearance. Cilazaprilat is not eliminated in patients with complete renal failure. Hemodialysis reduces concentrations of both cilazapril and cilazaprilat to a limited extent.

Following the administration of 1 mg cilazapril in patients with moderate to severe compensated liver cirrhosis, peak plasma concentrations of cilazapril and cilazaprilat are increased (57% and 28% respectively), attained 30 minutes and 45 minutes earlier, and total clearances are decreased (51% and 31% respectively), in comparison to healthy subjects. The renal clearance and early and terminal elimination phase half-lives of cilazaprilat are decreased 52%, 42% and 62% respectively.

In patients with congestive heart failure the clearance of cilazaprilat is correlated with the creatinine clearance. Thus, dosage adjustments beyond those recommended for patients with impaired renal functions (see Dosage, Congestive Heart Failure) should not be necessary.

Indications And Clinical Uses: The treatment of mild to moderate essential hypertension. Cilazapril may be used alone or in combination with thiazide-type diuretics. Cilazapril is also indicated in the treatment of congestive heart failure as an adjunctive therapy with digitalis and/or diuretics.

In using cilazapril consideration should be given to the risk of angioedema (see Warnings).

Hypertension: Cilazapril should normally be used in those patients in whom treatment with a diuretic or a beta-blocker was found ineffective or has been associated with unacceptable adverse effects.

Cilazapril can also be tried as an initial agent in those patients in whom use of diuretics and/or beta-blockers is contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects.

The safety and efficacy of cilazapril in renovascular hypertension has not been established and therefore, its use in this condition is not recommended.

The safety and efficacy of concomitant use of cilazapril with antihypertensive agents other than thiazide diuretics have not been established.

Congestive Heart Failure: Cilazapril is indicated in the treatment of congestive heart failure as adjunctive therapy in patients who have not responded adequately to digitalis and/or diuretics. There is limited data on New York Heart Association Class IV patients (see Pharmacology). Treatment with cilazapril should be initiated in patients with congestive heart failure under close medical supervision.

When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected, cilazapril should be discontinued as soon as possible (see Warnings, Pregnancy and Precautions, Information for the Patient).

Contra-Indications: In patients who are hypersensitive to cilazapril, in patients with a history of angioedema related to previous treatment with an ACE inhibitor and in patients with ascites.

Manufacturers’ Warnings In Clinical States: Angioedema: Angioedema has been reported in patients treated with cilazapril. Angioedema associated with laryngeal edema and/or shock may be fatal. If angioedema occurs, cilazapril should be promptly discontinued and appropriate therapy instituted without delay. The patient should be followed carefully until the swelling has resolved. Swelling confined to the face, lips and mouth usually resolves without treatment, although antihistamines may provide symptomatic relief. Swelling of the tongue, glottis or larynx, may cause airway obstruction; therefore, s.c. epinephrine (0.5 mL 1:1 000) should be administered promptly when indicated.

The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in non-black patients.

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).

Hypotension: Occasionally, symptomatic hypotension has occurred after administration of cilazapril usually after the first dose or when the dose had been increased. It is more likely to occur in patients with sodium or volume depletion in connection with diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting. 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 2 weeks of treatment and whenever the dose of cilazapril 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 Effects).

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 cilazapril, may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.

If hypotension occurs, the patient should be placed in supine position and, if necessary, receive an i.v. infusion of normal saline. A transient hypotensive response does not necessitate discontinuation of cilazapril. Once the blood pressure has increased after volume expansion, cilazapril therapy may be continued. If symptoms persist, the dosage should be reduced or the drug discontinued.

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.

Neutropenia/Agranulocytosis: Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Cases of leukopenia and neutropenia have rarely been reported in patients treated with cilazapril. However, in no patient could a causal relationship to cilazapril be established. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and renal disease.

Pregnancy: ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, cilazapril should be discontinued as soon as possible.

In rare cases (probably less than 0.01% of pregnancies) in which no alternative to ACE inhibitors therapy will be found, the mother should be apprised of the potential hazards to the fetus. Serial ultrasound examinations should be performed to assess fetal development and well-being and the volume of amniotic fluid.

If oligohydramnios is observed, cilazapril should be discontinued unless it is considered life-saving for the mother. A non-stress test (NST), and/or a biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. If concerns regarding fetal well-being still persist, a contraction stress testing (CST) should be considered. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

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/hour for cilazapril and 2.2 to 2.8 L/hour for cilazaprilat.

Human Data: It is not known whether exposure limited to the first trimester of pregnancy can adversely affect fetal outcome. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure.

Animal Data: 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 peri- and 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 4-cilazapril to pregnant mice, rats and monkeys, radioactivity was measured in the fetuses.

Precautions: Impaired Renal Function: 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, 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.

Use of cilazapril should include appropriate assessment of renal function.

Anaphylactoid Reactions during Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (e.g., polyacrylonitrile [PAN]) 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.

Anaphylactoid Reactions during LDL Apheresis: Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL) apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.

Anaphylactoid Reactions during Desensitization: There have been isolated 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 therefore be interrupted before the start of desensitization therapy. In this situation, cilazapril must not be replaced by a beta-blocker.

Hyperkalemia: 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 and Adverse Effects).

Valvular Stenosis: 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.

Surgery/Anesthesia: 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.

Patients With Impaired Liver Function: Hepatitis (hepatocellular and/or cholestatic), jaundice, elevations of liver enzymes and/or serum bilirubin have occurred during therapy with other ACE inhibitors in patients with or without pre-existing liver abnormalities. In most cases the changes were reversed on discontinuation of the drug.

Elevations of liver enzymes and/or serum bilirubin have been reported for cilazapril (see Adverse Effects). Jaundice was also spontaneously reported in 1 patient worldwide. Should the patient receiving cilazapril experience any unexplained symptoms particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigation be carried out. Discontinuation of cilazapril should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. Cilazapril 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.

Cough: A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of cilazapril, has been reported.

Such possibility should be considered as part of the differential diagnosis of the cough.

Lactation: In rats, it has been shown that after the oral administration of cilazapril, cilazaprilat is excreted in milk.

It is not known whether cilazapril and/or cilazaprilat are excreted in human breast milk. Caution should be exercised when cilazapril is administered to nursing mothers.

Children: The safety and effectiveness of the use of cilazapril in children have not been established. Therefore, use in this age group is not recommended.

Geriatrics: 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 cilazapril 0.5 mg must be strictly followed (see Warnings, Hypotension and Dosage).

Drug Interactions: Diuretic Therapy: 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 cilazapril can be minimized by either discontinuing the diuretic, or increasing the salt intake prior to initiation of treatment with cilazapril. If it is not possible to discontinue the diuretic, the starting dose of cilazapril should be reduced and the patient should be closely observed for several hours following initial dose and until blood pressure has stabilized (see Warnings and Dosage).

Agents Increasing Serum Potassium: Since cilazapril decreases aldosterone production, elevation of serum potassium may occur. Potassium sparing diuretics such as spironolactone, triamterene or amiloride, or potassium supplements should be given only for documented hypokalemia and with caution since they may lead to a significant increase in serum potassium particularly in patients with renal impairment. Therefore, if concomitant use for such agents is indicated, their dosage should be reduced when cilazapril is initiated and serum potassium and renal function should be monitored carefully. Salt substitutes containing potassium should also be used with caution.

Agents Causing Renin Release: The antihypertensive effect of cilazapril is augmented by antihypertensive agents that cause renin release (e.g., diuretics).

Agents Affecting Sympathetic Activity: Agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents) should be used with caution. Beta-adrenergic blocking drugs may add some further antihypertensive effect to cilazapril.

Inhibitors of Endogenous Prostaglandin Synthesis: Concomitant administration of a nonsteroidal anti-inflammatory drug (NSAID) may reduce the antihypertensive effect of cilazapril. 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.

Digoxin: 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).

Lithium Salts: As with other drugs which eliminate sodium, lithium elimination may be reduced. Therefore, the serum lithium levels should be monitored carefully if lithium salts are to be administered.

Information for the Patient: Angioedema: Angioedema, including laryngeal edema, may occur especially following the first dose of cilazapril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician. Should the tongue and/or larynx be involved, the physician should be consulted immediately.

Hypotension: Patients should be cautioned to report light-headedness, especially during the first few days of cilazapril therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician.

All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with their physician.

Neutropenia: Patients should be advised to report promptly any indication of infection (e.g., sore throat, fever) since this may be an early sign of neutropenia.

Impaired Liver Function: Patients should be advised to return to the physician if he/she experiences any symptoms possibly related to liver dysfunction. This would include “viral-like symptoms” in the first weeks to months of therapy (such as fever, malaise, muscle pain, rash or adenopathy which are possible indicators of hypersensitivity reactions), or if abdominal pain, nausea or vomiting, loss of appetite, jaundice, itching or any other unexplained symptoms occur during therapy.

Hyperkalemia: Patients should be advised not to use potassium supplements or salt substitutes containing potassium without consulting their physician.

Surgery: Patients planning to undergo surgery and/or anesthesia should be told to inform their physician that they are taking an ACE inhibitor.

Pregnancy: Since the use of cilazapril during pregnancy can cause injury and even death of the developing fetus, patients should be advised to report promptly to their physician if they become pregnant.

Adverse Reactions: Cilazapril has been evaluated for safety in 5 450 patients treated for essential hypertension and in 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 1 year or longer.

The most severe 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) (see Warnings, Hypotension).

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.

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.

Postmarketing Experience: Treatment with ACE inhibitors has been associated with, rarely, the following: hemolytic anemia, pemphigus and Stevens-Johnson syndrome.

Abnormal Laboratory Findings: Hematology: 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.

Leukopenia and neutropenia: Leukopenia 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; 1 case with 2 successive abnormalities showed no associated clinical symptoms.

Liver Function Tests: Clinically relevant changes in the values associated with liver function (AST, ALT, GGTP, LDH, total bilirubin and alkaline phosphatase) occurred in 0.1% (bilirubin) to 1.1% (ALT, GGTP) of the hypertensive patients and in 0.8% (LDH) to 2.9% (ALT) of the congestive heart failure patients. Most of these abnormalities were transient.

Renal: 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 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, 4 of the 5 had abnormal serum creatinine values at baseline.

Proteinuria (³2+ dipstick reaction or excretion of ³1 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.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Limited data are available with regard to overdosage in humans. The most likely clinical manifestation would be symptoms attributable to severe hypotension, which should be normally treated by i.v. volume expansion with normal saline.

Hemodialysis removes cilazapril and cilazaprilat from the general circulation to a limited extent.

Dosage And Administration: Dosage must be individualized.

Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction, and other pertinent clinical factors. The dosage of other antihypertensive agents being used with cilazapril may need to be adjusted.

The dose should always be taken at about the same time each day.

Hypertension: Monotherapy: The recommended initial dose is 2.5 mg once daily. Dosage should be adjusted according to blood pressure response, generally, at intervals of at least 2 weeks. The usual dose range is 2.5 to 5 mg once daily. Minimal additional blood pressure lowering effects were achieved with a dose of 10 mg once daily. A dose of 10 mg should not be exceeded.

In most patients, the antihypertensive effect of cilazapril is maintained with a once a day dosing regimen. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, either twice daily administration with the same total daily dose, or an increase in dose should be considered. If blood pressure is not adequately controlled with cilazapril alone, a non-potassium-sparing diuretic may be administered concomitantly. After the addition of a diuretic, it may be possible to reduce the dose of cilazapril.

Concomitant Diuretic Therapy: In patients receiving diuretics, cilazapril therapy should be initiated with caution, since they are usually volume depleted and more likely to experience hypotension following ACE inhibition. Whenever possible, all diuretics should be discontinued 2 to 3 days prior to the administration of cilazapril to reduce the likelihood of hypotension (see Warnings). If this is not possible because of the patient’s condition, cilazapril should be started at 0.5 mg once daily and the blood pressure closely monitored after the first dose until stabilized. Thereafter, the dose should be adjusted according to individual response.

Dosage in Geriatrics (over 65 Years): Cilazapril treatment should be initiated with 1.25 mg (half of a 2.5 mg tablet) once daily or less, depending on the patient’s volume status and general condition. Thereafter, the dose of cilazapril must be adjusted according to individual tolerability, response, and clinical status.

Dosage Adjustment in Renal Impairment: see Precautions, Anaphylactoid Reactions during Membrane Exposure. The following dose schedules are recommended in patients with hypertension.

Hemodialysis Patients: Cilazapril should be administered on days when dialysis is not performed and the dosage should be adjusted according to blood pressure response.

Dosage Adjustment in Hepatic Impairment: Should patients with liver cirrhosis require treatment with cilazapril, treatment should be initiated with caution at a dose of 0.5 mg once daily or less as significant hypotension may occur (see Precautions).

Congestive Heart Failure: Cilazapril can be used as adjunctive therapy with digitalis and/or diuretics in patients with congestive heart failure. Therapy should be initiated under close medical supervision. Blood pressure and renal function should be monitored both before and during treatment with cilazapril because severe hypotension and more rarely, renal failure have been reported (see Warnings and Precautions).

Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion. If possible, the dose of diuretic should be reduced before beginning treatment, to reduce the likelihood of hypotension. Serum potassium should also be monitored (see Warnings and Precautions, Drug Interactions).

Therapy with cilazapril should be initiated with a recommended starting dose of 0.5 mg once daily under close medical surpervision. In elderly patients with congestive heart failure on high diuretic dosage the recommended starting dose of cilazapril 0.5 mg must be strictly followed (see Warnings).

The dose should be increased to the lowest maintenance dose of 1 mg daily, usually within a 5 day period, according to tolerability and clinical status. Further titration within the usual maintenance dose of 1 mg to 2.5 mg daily should be carried out based on patient response, clinical status and tolerability.

The usual maximum dose is 2.5 mg once daily. A few patients have been titrated to 5 mg once daily with some additional benefits being achieved. However only limited data is available in congestive heart failure patients treated with 5 mg once daily.

Dosage Adjustment in Patients with Congestive Heart Failure and Renal Impairment or Hyponatremia: Reduced dosage may be required for patients with congestive heart failure and renal impairment or hyponatremia depending on the creatinine clearance. The following dosing is recommended.

SuppliedSupplied: 1 mg: Each yellow, oval-shaped, single-scored, biconvex, film-coated tablet, imprinted CIL 1, contains: cilazapril 1 mg as cilazapril monohydrate. Nonmedicinal ingredients: cornstarch, hydroxypropyl methylcellulose, iron oxide, lactose, sodium stearyl fumarate, talc and titanium dioxide. Bottles of 100.

2.5 mg: Each pinkish-brown, oval-shaped, single-scored, biconvex, film-coated tablet, imprinted CIL 2.5, contains: cilazapril 2.5 mg as cilazapril monohydrate. Nonmedicinal ingredients: cornstarch, hydroxypropyl methylcellulose, iron oxide, lactose, sodium stearyl fumarate, talc and titanium dioxide. Bottles of 100.

5 mg: Each reddish-brown, oval-shaped, single-scored, biconvex tablet, imprinted CIL 5, contains: cilazapril 5 mg as cilazapril monohydrate. Nonmedicinal ingredients: cornstarch, hydroxypropyl methylcellulose, iron oxide, lactose, sodium stearyl fumarate, talc and titanium dioxide. Bottles of 100.

Store 15 to 30°C. Keep container tightly closed.

INHIBACE® Roche Cilazapril Angiotensin Converting Enzyme Inhibitor

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