Source: Health Products and Food Branch (CA) Revision Year: 2020
INHIBACE (cilazapril) is an angiotensin-converting enzyme (ACE) inhibitor, which is used in the treatment of hypertension and congestive heart failure.
INHIBACE 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 angiotensin-converting enzyme (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 hydrolysed to cilazaprilat, the active metabolite, which prevents the conversion of angiotensin I to angiotensin II by inhibition of ACE. Following the administration of INHIBACE, plasma ACE activity is inhibited more than 90% within two 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 INHIBACE 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, INHIBACE may interfere with the degradation of the vasodepressor peptide bradykinin. The role that this plays in the therapeutic effects of INHIBACE is unknown.
The antihypertensive effect of INHIBACE 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 INHIBACE 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 INHIBACE is maintained during long-term therapy. No rapid increase in blood pressure has been observed after abrupt withdrawal of INHIBACE.
The antihypertensive effect of angiotensin-converting enzyme inhibitors, including INHIBACE is generally lower in black patients than in non-blacks. Racial differences in response are no longer evident when cilazapril is administered in combination with hydrochlorothiazide.
In hypertensive patients with moderate to severe renal impairment, the glomerular filtration rate and renal blood flow remained in general unchanged with INHIBACE.
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, INHIBACE 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 INHIBACE occurs within 1-2 hours, reaching its maximum effect within 2-4 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 INHIBACE on survival in patients with heart failure has not been evaluated.
Cilazapril is well absorbed and rapidly converted to the active form, cilazaprilat. Peak plasma concentrations, and times to peak plasma concentrations for cilazapril and cilazaprilat following the oral administration of 0.5 to 5 mg cilazapril are given below.
Table 4. Peak Plasma Concentrations and Times to Peak Plasma Concentrations for Cilazapril and Cilazaprilat:
| Oral Dose (mg) | Cilazapril | Cilazaprilat | ||
|---|---|---|---|---|
| Cmax (ng/mL) | tmax (h) | Cmax (ng/mL) | tmax (h) | |
| 0.5 | 17.0 | 1.1 | 5.4 | 1.8 |
| 1.0 | 33.9 | 1.1 | 12.4 | 1.8 |
| 2.5 | 82.7 | 1.1 | 37.7 | 1.9 |
| 5.0 | 182.0 | 1.0 | 94.2 | 1.6 |
Maximum plasma concentrations of cilazaprilat are reached within two 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 one 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 intravenous administration of 2.5 mg is 91%. Total clearance is 12.3 L/h and renal clearance is 10.8 L/h. 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 intravenous 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 h 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 h. The effective half-life of accumulation for cilazaprilat is 8.9 h.
Congestive Heart Failure: 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 AND ADMINISTRATION, Congestive Heart Failure) should not be necessary.
Geriatrics: 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.
Hepatic Insufficiency: 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.
Renal Insufficiency: 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.
In in vitro studies, using hippuryl-histidyl-leucine as substrate, cilazaprilat, the active metabolite of cilazapril, inhibited the activity of ACE from rabbit lung (IC50 0.97-1.93 nM), hog lung (IC50 2.83 nM), human lung (IC50 1.39 nM), and human plasma (IC50 0.61 nM). Cilazaprilat (20 µM) did not have any effect on a number of other porcine, bovine, or human enzymes except E. coli dipeptidyl carboxypeptidase.
In ex vivo studies, oral administration of 0.1 and 0.25 mg/kg cilazapril to rats inhibited plasma ACE activity by 76% and 96% respectively and 0.3-3 mg/kg significantly inhibited tissue ACE activity in a number of arteries and veins.
In vivo, the dose of cilazapril and/or cilazaprilat required to reduce the angiotensin pressor response by 50% are summarized in Table 5 below.
Table 5. ED50 Values for Cilazapril and/or Cilazaprilat:
| Animal Model | Cilazapril Activity | Cilazaprilat Activity |
|---|---|---|
| Conscious normotensive rats | ED50 0.02 mg/kg p.o. (at 60 min) | - |
| Anesthetised SHAD (unilaterally adrenalectomised and contralaterally adrenal demedulated SHR) rats | ED50 0.44 µmol/kg i.v. | ED50 0.06 µmol/kg i.v. |
| 2-kidney-1-clip Goldblatt renal hypertensive rats | ED50 0.043 mg/kg i.v. | ED50 0.006 mg/kg i.v. |
| Anesthetized normotensive dogs | ED50 0.035 mg/kg i.v. (0.084 µmol/kg) | - |
In the anesthetized SHAD rats 0.06 µmol/kg i.v. cilazaprilat potentiated the bradykinin induced vasodepressor response.
The antihypertensive activity of cilazapril was assessed in a number of experimental animal models. In spontaneously hypertensive rats (SHR), single oral doses of 10 and 30 mg/kg cilazapril reduced systolic blood pressure for longer than six hours. Repeated daily dosing with oral doses of 10 and 30 mg/kg cilazapril demonstrated 24-hour activity and at the higher dose, antihypertensive effect became maximum after one week. When administered twice daily, the lowest oral dose of cilazapril that reduced systolic blood pressure was 1 mg/kg. Dose dependent decreases in systolic blood pressure were observed between oral doses of 1 and 10 mg/kg twice daily. No further increase in effect was observed with an oral dose of 30 mg/kg twice daily. Intravenous administration of up to 10 mg/kg of either cilazapril or cilazaprilat to conscious SHR evoked only small reductions in blood pressure. The reason for this disparity with the oral dosing data in the same animal model is unclear.
Following the oral administration of 10 mg/kg cilazapril, the maximum decrease in systolic arterial pressure observed in conscious renal hypertensive hypovolemic dogs was approximately double that observed in normovolemic dogs. In the hypovolemic dogs, the systolic blood pressure fell significantly within 30 minutes of the first dose. The effect persisted for 6 hours. Maximum decrease in systolic arterial pressure in conscious normotensive hypovolemic dogs was similar to that observed in renal hypotensive normovolemic dogs.
Heart rate changes accompanying the antihypertensive action of cilazapril in the rat and the dog were minimal.
Total peripheral resistance and regional vascular resistance were reduced in all vascular beds except in the heart in SHR administered multiple, oral, daily doses of 10 mg/kg cilazapril. Regional blood flow to the kidneys, intestine and skin increased. Regional blood flow to the heart decreased. No changes were observed in cardiac output, cardiac index, stroke volume or heart rate. Hemodynamic and blood flow changes were similar after acute or repeated (twice daily for two weeks) administration of 1 mg/kg cilazapril. Additional increases in blood flow to the lungs, stomach, small intestine, pancreas and thymus were observed, however.
In conscious dogs, cilazapril had no effect on left ventricular pressure and on force of cardiac contraction at 3 mg/kg p.o. and marginal effects at 10 mg/kg p.o. At these doses, slight decreases were noted in abdominal aortic blood flow and heart rate. In anesthetized dogs, intravenous cilazapril doses of 0.03-1 mg/kg evoked dose dependent decreases in blood pressure and left ventricular pressure. At 1 mg/kg, left ventricular end diastolic pressure was decreased 15%, myocardial contractile force was reduced, and heart rate was unchanged. At 0.3 mg/kg, cardiac output, coronary blood flow, left ventricular minute work, left ventricular stroke work, and cardiac index were decreased 15%, 12%, 31%, 40%, and 12% respectively. In the anesthetized dog with ischemic heart failure, intravenous doses of cilazaprilat (0.1-1 mg/kg) reduced total peripheral resistance, left ventricular end diastolic pressure, dp/dt, and mean aortic blood pressure. Cardiac output, heart rate, pulmonary arterial pressure and right arterial pressure remained unchanged.
Oral administration of 3 mg/kg cilazapril did not have an effect on the increase in blood pressure and heart rate accompanying exercise in conscious cats. In anesthetized cats, cilazapril (10 mg/kg i.v.) increased right ventricular force of contraction (28%) and cardiac output (19%). Heart rate changes were minor.
The pharmacokinetics of cilazapril and cilazaprilat have been examined in mice, rats, dogs, monkeys, marmosets and baboons. The oral absorption of cilazapril is rapid and peak plasma concentrations of cilazapril occur in less than 1 hour. Absorption is 70-89%. Cilazapril plasma concentrations decline rapidly with a half-life of 0.7-2.7 hours. Plasma concentrations are less than dose proportional in baboons, and in rats and marmoset levels are too low for reliable quantitation.
Cilazaprilat is produced rapidly in all species and peak concentrations occur in less than 1.5 hours. Bioavailability from oral cilazapril is 70-89%. Cilazaprilat plasma concentrations decline in a biphasic manner with half-lives of 0.5-3.5 hours and 12-68 hours. Plasma concentrations are less than dose proportional and show a low order of dose dependence during the terminal phase. This is consistent with saturable binding to ACE.
The distribution of drug related material is largely confined to excretory organs, but all major tissues are exposed, including the fetus of pregnant animals. There is no evidence of tissue retention, and more than 95% of the dose is recovered within three days. Repeat administration leads to some accumulation, but only in a limited number of tissues, notably the liver and kidney.
Excretion is rapid in all species. More than 90% of the total recovery in urine is achieved within 24 hours. Excretion is predominantly hepatic in rats and baboons, and renal in marmosets.
Table 6. Acute Toxicity:
| Species | Sex | Route | Approximate LD50 (mg/kg) |
|---|---|---|---|
| Mouse | M | p.o. | 4,600 |
| F | p.o. | 2,500 - <5,000 | |
| M + F | i.v. | >250 | |
| M | i.p. | 1,600 | |
| F | i.p. | 1,300 | |
| M + F | s.c. | >1,000 | |
| Rat | M + F | p.o. | >4,000 - <5,000 |
| M + F | i.p. | 830 | |
| Monkey | M + F | p.o. | >4,000 - <5,000 |
The signs of toxicity include: ataxia, reduced motor activity, diarrhea, respiratory depression, tremors, piloerection, prostration, hunched appearance, salivation, emesis and facial fur-staining.
Table 7. Long-Term Toxicity:
| SPECIES (#/group) | STUDY DURATION | DOSE ADMINISTRATION (mg/kg/day) | ROUTE | FINDINGS |
|---|---|---|---|---|
| Rat (8M + 8F) | 2 Weeks | 0, 2, 6, 20 | i.v. | All dose groups: Swollen tails in individual rats after 8-10 days; slight increase in urine volume (males). |
| Monkey Marmoset (3M + 3F) | 2 Weeks | 0, 2, 6, 20 | i.v. | All dose groups: Slightly depressed heart rates. |
| Rat (5M + 5F) | 4 Weeks | 0, 5, 15, 50 | p.o. | All dose groups: Increased water consumption. 15 and 50 mg/kg/day: Minimal decreases in RBC, Hb and PCV values (females); increase in plasma urea (2-3x). 50 mg/kg/day: Salivation (6/10) from week 2; decrease body weight gain (20%); slight reduction in food consumption; increased incidence of kidney tubule cells in urine (females). |
| Rat (16M + 16F) | 4 Weeks | 25, 125, 625 | p.o. | All dose groups: Salivation; slight reduction in motor activity; increased urine volumes and minimal decreases in specific gravity (males). 125 and 625 mg/kg/day: Decreased body weight gain and food consumption (males only at 125 mg/kg/day); slight decreases in RBC, Hb and PCV (males); very slight thickening of glomerular afferent arteriolar wall in the kidney (males) (1/10 – 125 mg/kg/day, 6/10 – 625 mg/kg/day). 625 mg/kg/day: Increased BUN values (1.5x) (males); decreased BMC1 (males); slight decrease in heart and liver (males) weight. |
| Monkey Marmoset (3/6M + 3F) | 4 Weeks | 0, 5, 15, 50 | p.o. | 15 and 50 mg/kg/day: Marginal decreases in RBC, Hb and PCV values. 50 mg/kg/day: Increase in plasma urea (2x), K+ and cholesterol values; increased incidence of kidney tubule cells in urine. |
| Rat (16M + 16F) | 13 Weeks | 0, 10, 50, 250 | p.o. | All dose groups: Very slight increases in urine volume and decreased SG values (males). 50 and 250 mg/kg/day: Dose-related decrease in body weight gain (males only at 50 mg/kg/day); increased BUN levels (2x) (males); slight thickening of glomerular afferent arterioles in the kidneys (10/30). 250 mg/kg/day: Slight decrease in spontaneous activity and salivation; inhibition of food consumption; small decreases in RBC and BMC (males), and in RBC, PCV and Hb (females). |
| Monkey Cynomolgus (4M + 4F) | 13 weeks | 0, 2.5, 25, 50 | p.o. | 25 and 50 mg/kg/day: Slight decreases in RBC, Hb and PCV. Slight to moderate hyperplasia of the juxtaglomerular apparatus; dose-related decreased body weight gains. 50 mg/kg/day: Two deaths; salivation; emesis; decreased spontaneous activity. Slight decrease in BMC, total protein and inorganic phosphate; increase in BUN (4x), blood creatinine; enlargement of kidney (1 female); reduction in heart weight; kidney tubular dilatation. |
| Monkey Baboon (2M + 2F) | 13 Weeks | 0, 2, 10, 20, 40 | p.o. | All dose groups: Emesis; slight reductions in heart rate, body weight gain and heart weight; hypertrophy and hyperplasia of the juxtaglomerular cells (¼ - 10 mg/kg, ¾ - 20 mg/kg, 4/4 – 40 mg/kg). 20 and 40 mg/kg/day: Slight decrease in RBC, PCV and Hb; kidney tubular basophilia/ dilatation (¼ - 20 mg/kg; ¾ - 40 mg/kg). Increased urea (2x) in 40 mg/kg only. |
| Rat (30M + 30F) | 26 Weeks | 0, 5, 30, 200; 0, 2, 12, 75 – from Week 6; 0, 2, 12, 50 from Week 14 | p.o. | All dose groups: Slight decrease in heart rate; weight loss; lethargy; hunched posture. Piloerection; facial fur-staining; dose-related increases in kidney weights (male). 12 and 50 mg/kg/day: Hypertrophy of afferent glomerular arterioles in the kidneys (13 weeks). 50 mg/kg/day: Body weight gain decrease (14%) (males); increased water intake. Increased BUN levels (3x) (males), ALP activity, and liver weights (males); prominent kidney tubular regeneration; kidney tubular dilatation; minimal kidney tubular necrosis (2 animals at 13 weeks). Sclerosis (2 animals at 26 weeks). |
| Monkey Marmoset (9, 7, 7, 11M+ 9, 7, 7, 11F) | 26 Weeks | 0, 5, 30, 200; 0, 2, 15, 100 from Week 9; 0, 2, 15, 50 from Week 14 | p.o. | 200 mg/kg/day: Depression in heart rate; body weight loss (females). 15 mg/kg/day: Two deaths (unrelated to treatment) of minor glomerular arteriolar hypertrophy (13 and 26 weeks). 50 mg/kg/day: Six deaths (two unrelated to treatment); unsteadiness; inactivity; salivation; emesis; diarrhea; slight decrease in RBC, PCV, Hb and bone marrow, myeloid/erythroid ratio (26 weeks). Increase in plasma urea (2x); small reductions in urine osmolality; slight kidney tubular dilatation and tubular epithelium regeneration (4/5 at 13 weeks – 100 mg/kg) (4/10 after 26 weeks). |
| Monkey Baboon (7M + 7F) | 52 Weeks | 0, 0.5, 4, 40 | p.o. | 4 and 40 mg/kg/day: Hyperplasia and hypertrophy of juxtaglomerular apparatus with hypertrophy of muscle cells of glomerular arterioles (1/10 – 4 mg/kg; 8/10 – 40 mg/kg/day). 40 mg/kg/day: Emesis; body weight gain reduction; slight reduction in RBC, PCV and Hb; increase in urea values (2x) and creatinine; osmolality reductions; increased incidence in proteinous casts (Week 52); small increase in adrenal and thyroid weights. |
| Rat (35M + 35F) | 78 Weeks | 0, 0.5, 4, 40 | p.o. | All dose levels: Small reductions in body weight gain. 4 and 40 mg/kg/day: Slight decrease in RBC, PCV and Hb; minimal reduction in food intake; increase in BUN (2x) (males). 40 mg/kg/day: Increased water consumption; slight increase in total WBC count (males); increased urine volumes (males); irregular surface ocysts in the kidneys (7/40 at 76 weeks); increased kidney weights (males); slight decrease in heart and liver weight (females); vascular hypertrophy (20/20 males, 17/20 females) consisting of glomerular afferent arteriolar wall thickening; similar but less frequent and less severe changes were observed in the mid dose group. |
1 Bone marrow nucleated cell count.
Table 8. Reproduction and Teratology:
| SPECIES#/GROUP | DOSE (mg/kg/day) | ROUTE | DURATION OF DOSING | EFFECTS |
|---|---|---|---|---|
| Fertility and General Reproduction Performance | ||||
| Rat Charles River (Crl:CD (SD) BR) (30M + 30F) | 0, 1, 7, 50 | p.o. | Males – 70 days prior to mating and up to 14 days during mating. Females – 14 days before mating, during gestation and until Day 21 post-partum. | All dose groups: No effect on mating or fertility at any dose. Retching reflex after dosing (dose-related) (males). Decreased body weight gain. Males at 50 mg/kg/day: Six deaths (due to dosing error). Females at 50 mg/kg/day: Two deaths (50 mg/kg) (due to dosing error). Increased preimplantation loss (forced delivery group at 50 mg/kg). F1 generation at 7 and 50 mg/kg/day: Reduced body weight at the end of lactation; increased incidence of dilatation of the renal pelvis. Reduction in viable fetuses due to a lower number of implantations (50 mg/kg). |
| Embryotoxicity | ||||
| Rat Charles River (CD) (35F) | 0, 2, 30, 400 | p.o. | Days 6-17 of gestation. | All dose groups: No effect on embryonic, fetal or postnatal development. Females at 400 mg/kg/day: Body weight gain and food consumption were reduced during latter half of gestation. F1 generation at 400 mg/kg/day: Slight increase in renal cavitation incidence. |
| Fertility and General Reproduction Performance | ||||
| Monkey Cynomolgus (10 or 11F) | 0, 20 | p.o. | Days 21 to 31 or Days 32 to 45 of gestation. | Control group: Reduced food consumption and diarrhea (5/10 females); 2/10 abortions between Days 51-53 of pregnancy; low incidence of skeletal variations in tail (2/8 fetuses) and ribs (2/8). 20 mg/kg/day – Days 21-31: Reduced food consumption (10/10 females); diarrhea (2/10); vomiting (2/10). Skeletal findings – ribs (2/8 fetuses), humeri (2/8), distal caudal variations (4/8), and prepuce not patent (2/8) - not treatment related. 20 mg/kg/day – Days 32-45: Decreased food consumption and/or diarrhea (11/11 females); 5/11 abortions; 2/11 maternal deaths (not treatment related). Caudal and humerus variations (1/5 fetuses) - not treatment related. |
| Peri- and Post-natal Toxicity | ||||
| Rat Charles River (CDCrl:CD(SD) BR) (25 or 30F) | 0, 1, 7, 50 | p.o. | Day 15 of gestation to Day 21 post-partum. | Females at 50 mg/kg/day: 5 deaths on Day 18 postcoitus or Days 4-16 of lactation (due to dosing error). F1 generation at 50 mg/kg/day: Increased pup mortality (4.9%); reduction in body weight gain during lactation; an associated slight delay in pinna unfolding. |
An 88-week carcinogenicity study with cilazapril was conducted in mice initially dosed at 5, 25 or 100 mg/kg/day, subsequently reduced to 1, 7 or 50 mg/kg/day from week 11 onwards. Another carcinogenicity study was conducted in rats in which dose levels of 0.5, 4 or 40 mg/kg/day were administered for 104 weeks. Hypertrophy of renal afferent glomerular arterioles and interlobular arteries, and increased cortical nephropathy were the only recorded findings and occurred in the mid- and high-dose groups in both studies. Tri-PAs staining of kidney sections from the 104-week rat carcinogenicity study indicated no hyperplastic or neoplastic oxyphilic cell response and no enhancement of the development of oncocytomas.
No evidence of mutagenicity with cilazapril was found in the Ames test with or without metabolic activation (up to 2.0 mg/plate), “Treatment and Plate” test (up to 7,000 µcg/mL), unscheduled DNA synthesis assay (up to 200 µcg/mL), mutagenic assay with Chinese hamster V79 cells with or without metabolic activation (up to 4,800 µcg/mL), chromosomal aberration test with or without metabolic activation (up to 3,500 µcg/mL), or in vivo micronucleus test in mice (2.0 g/kg).
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
