AVAPRO Film-coated tablet Ref.[10541] Active ingredients: Irbesartan

In healthy subjects, single oral irbesartan doses of up to 300 mg produced dose-dependent inhibition of the pressor effect of angiotensin II infusions. Inhibition was complete (100%) 4 hours following oral doses of 150 mg or 300 mg and partial inhibition was sustained for 24 hours (60% and 40% at 300 mg and 150 mg, respectively).

In hypertensive patients, angiotensin II receptor inhibition following chronic administration of irbesartan causes a 1.5-fold to 2-fold rise in angiotensin II plasma concentration and a 2-fold to 3-fold increase in plasma renin levels. Aldosterone plasma concentrations generally decline following irbesartan administration, but serum potassium levels are not significantly affected at recommended doses.

In hypertensive patients, chronic oral doses of irbesartan (up to 300 mg) had no effect on glomerular filtration rate, renal plasma flow, or filtration fraction. In multiple dose studies in hypertensive patients, there were no clinically important effects on fasting triglycerides, total cholesterol, HDL-cholesterol, or fasting glucose concentrations. There was no effect on serum uric acid during chronic oral administration, and no uricosuric effect.

Absorption

The oral absorption of irbesartan is rapid and complete with an average absolute bioavailability of 60% to 80%. Following oral administration of AVAPRO, peak plasma concentrations of irbesartan are attained at 1.5 to 2 hours after dosing. Food does not affect the bioavailability of irbesartan.

Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range.

Distribution

Irbesartan is 90% bound to serum proteins (primarily albumin and α₁-acid glycoprotein) with negligible binding to cellular components of blood. The average volume of distribution is 53 to 93 liters.

Studies in animals indicate that radiolabeled irbesartan weakly crosses the blood-brain barrier and placenta. Irbesartan is excreted in the milk of lactating rats.

Elimination

Total plasma and renal clearances are in the range of 157 to 176 mL/min and 3.0 to 3.5 mL/min, respectively. The terminal elimination half-life of irbesartan averages 11 to 15 hours. Steady-state concentrations are achieved within 3 days. Limited accumulation of irbesartan (<20%) is observed in plasma upon repeated once-daily dosing and is not clinically relevant.

Metabolism

Irbesartan is an orally active agent that does not require biotransformation into an active form. Irbesartan is metabolized via glucuronide conjugation and oxidation. Following oral or intravenous administration of ¹⁴C-labeled irbesartan, more than 80% of the circulating plasma radioactivity is attributable to unchanged irbesartan. The primary circulating metabolite is the inactive irbesartan glucuronide conjugate (approximately 6%). The remaining oxidative metabolites do not add appreciably to irbesartan’s pharmacologic activity.

In vitro studies indicate irbesartan is oxidized primarily by CYP2C9; metabolism by CYP3A4 is negligible.

Excretion

Irbesartan and its metabolites are excreted by both biliary and renal routes. Following either oral or intravenous administration of ¹⁴C-labeled irbesartan, about 20% of radioactivity is recovered in the urine and the remainder in the feces, as irbesartan or irbesartan glucuronide.

Specific Populations

Sex

No sex-related differences in pharmacokinetics are observed in healthy elderly (age 65–80 years) or in healthy young (age 18–40 years) subjects. In studies of hypertensive patients, there is no sex difference in half-life or accumulation, but somewhat higher plasma concentrations of irbesartan are observed in females (11%–44%). No sex-related dosage adjustment is necessary.

Geriatrics

In elderly subjects (age 65–80 years), irbesartan elimination half-life is not significantly altered, but AUC and C_max values are about 20% to 50% greater than those of young subjects (age 18–40 years). No dosage adjustment is necessary in the elderly.

Race/ethnicity

In healthy black subjects, irbesartan AUC values are approximately 25% greater than whites; there is no difference in C_max values.

Renal impairment

The pharmacokinetics of irbesartan is not altered in patients with renal impairment or in patients on hemodialysis. Irbesartan is not removed by hemodialysis. No dosage adjustment is necessary in patients with mild to severe renal impairment unless a patient with renal impairment is also volume depleted [see Warnings and Precautions (5.2) and Dosage and Administration (2.4)].

Hepatic insufficiency

The pharmacokinetics of irbesartan following repeated oral administration are not significantly affected in patients with mild to moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency.

Drug-Drug Interactions

In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites with the known cytochrome CYP2C9 substrates/inhibitors sulphenazole, tolbutamide and nifedipine. However, in clinical studies the consequences of concomitant irbesartan on the pharmacodynamics of warfarin were negligible. Based on in vitro data, no interaction would be expected with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes 1A1, 1A2, 2A6, 2B6, 2D6, 2E1, or 3A4.

In separate studies of patients receiving maintenance doses of warfarin, hydrochlorothiazide, or digoxin, irbesartan administration for 7 days has no effect on the pharmacodynamics of warfarin (prothrombin time) or pharmacokinetics of digoxin. The pharmacokinetics of irbesartan are not affected by coadministration of nifedipine or hydrochlorothiazide.

No evidence of carcinogenicity was observed when irbesartan was administered at dosages of up to 500/1000 mg/kg/day (males/females, respectively) in rats and 1000 mg/kg/day in mice for up to 2 years. For male and female rats, 500 mg/kg/day provided an average systemic exposure to irbesartan (AUC_{0–24 hour}, bound plus unbound) about 3 and 11 times, respectively, the average systemic exposure in humans receiving the maximum recommended dose (MRHD) of 300 mg irbesartan/day, whereas 1000 mg/kg/day (administered to females only) provided an average systemic exposure about 21 times that reported for humans at the MRHD. For male and female mice, 1000 mg/kg/day provided an exposure to irbesartan about 3 and 5 times, respectively, the human exposure at 300 mg/day.

Irbesartan was not mutagenic in a battery of in vitro tests (Ames microbial test, rat hepatocyte DNA repair test, V79 mammalian-cell forward gene-mutation assay). Irbesartan was negative in several tests for induction of chromosomal aberrations (in vitro—human lymphocyte assay; in vivo—mouse micronucleus study).

Irbesartan had no adverse effects on fertility or mating of male or female rats at oral dosages ≤650 mg/kg/day, the highest dose providing a systemic exposure to irbesartan (AUC_{0–24 hour}, bound plus unbound) about 5 times that found in humans receiving the MRHD of 300 mg/day.

14.1 Hypertension

The antihypertensive effects of AVAPRO were examined in 7 placebo-controlled 8- to 12-week trials in patients with baseline diastolic blood pressures of 95 to 110 mmHg. Doses of 1 to 900 mg were included in these trials in order to fully explore the dose-range of irbesartan. These studies allowed comparison of once or twice-daily regimens at 150 mg/day, comparisons of peak and trough effects, and comparisons of response by sex, age, and race. Two of the seven placebo-controlled trials identified above examined the antihypertensive effects of irbesartan and hydrochlorothiazide in combination.

The 7 studies of irbesartan monotherapy included a total of 1915 patients randomized to irbesartan (1–900 mg) and 611 patients randomized to placebo. Once-daily doses of 150 mg and 300 mg provided statistically and clinically significant decreases in systolic and diastolic blood pressure with trough (24 hours post-dose) effects after 6 to 12 weeks of treatment compared to placebo, of about 8–10/5–6 mmHg and 8–12/5–8 mmHg, respectively. No further increase in effect was seen at dosages greater than 300 mg. The dose-response relationships for effects on systolic and diastolic pressure are shown in Figures 1 and 2.

Figure 1. Placebo-substracted reduction in trough SeSBP; integrated analysis:

Figure 2. Placebo-substracted reduction in trough SeDBP; integrated analysis:

Once-daily administration of therapeutic doses of irbesartan gave peak effects at around 3 to 6 hours and, in one ambulatory blood pressure monitoring study, again around 14 hours. This was seen with both once-daily and twice-daily dosing. Trough-to-peak ratios for systolic and diastolic response were generally between 60% and 70%. In a continuous ambulatory blood pressure monitoring study, once-daily dosing with 150 mg gave trough and mean 24-hour responses similar to those observed in patients receiving twice-daily dosing at the same total daily dose.

In controlled trials, the addition of irbesartan to hydrochlorothiazide doses of 6.25 mg, 12.5 mg, or 25 mg produced further dose-related reductions in blood pressure similar to those achieved with the same monotherapy dose of irbesartan. HCTZ also had an approximately additive effect.

Analysis of age, sex, and race subgroups of patients showed that men and women, and patients over and under 65 years of age, had generally similar responses. Irbesartan was effective in reducing blood pressure regardless of race, although the effect was somewhat less in blacks (usually a low-renin population).

The effect of irbesartan is apparent after the first dose, and it is close to its full observed effect at 2 weeks. At the end of an 8-week exposure, about ⅔ of the antihypertensive effect was still present one week after the last dose. Rebound hypertension was not observed. There was essentially no change in average heart rate in irbesartan-treated patients in controlled trials.

14.2 Nephropathy in Type 2 Diabetic Patients

The Irbesartan Diabetic Nephropathy Trial (IDNT) was a randomized, placebo- and active-controlled, double-blind, multicenter study conducted worldwide in 1715 patients with type 2 diabetes, hypertension (SeSBP >135 mmHg or SeDBP >85 mmHg), and nephropathy (serum creatinine 1.0 to 3.0 mg/dL in females or 1.2 to 3.0 mg/dL in males and proteinuria ≥900 mg/day). Patients were randomized to receive AVAPRO 75 mg, amlodipine 2.5 mg, or matching placebo once-daily. Patients were titrated to a maintenance dose of AVAPRO 300 mg, or amlodipine 10 mg, as tolerated. Additional antihypertensive agents (excluding ACE inhibitors, angiotensin II receptor antagonists and calcium channel blockers) were added as needed to achieve blood pressure goal (≤135/85 or 10 mmHg reduction in systolic blood pressure if higher than 160 mmHg) for patients in all groups.

The study population was 66.5% male, 72.9% below 65 years of age, and 72% White (Asian/Pacific Islander 5.0%, Black 13.3%, Hispanic 4.8%). The mean baseline seated systolic and diastolic blood pressures were 159 mmHg and 87 mmHg, respectively. The patients entered the trial with a mean serum creatinine of 1.7 mg/dL and mean proteinuria of 4144 mg/day.

The mean blood pressure achieved was 142/77 mmHg for AVAPRO, 142/76 mmHg for amlodipine, and 145/79 mmHg for placebo. Overall, 83.0% of patients received the target dose of irbesartan more than 50% of the time. Patients were followed for a mean duration of 2.6 years.

The primary composite endpoint was the time to occurrence of any one of the following events: doubling of baseline serum creatinine, end-stage renal disease (ESRD; defined by serum creatinine ≥6 mg/dL, dialysis, or renal transplantation), or death. Treatment with AVAPRO resulted in a 20% risk reduction versus placebo (p=0.0234) (see Figure 3 and Table 1). Treatment with AVAPRO also reduced the occurrence of sustained doubling of serum creatinine as a separate endpoint (33%), but had no significant effect on ESRD alone and no effect on overall mortality (see Table 1).

Figure 3. IDNT: Kaplan-Meier Estimates of Primary Endpoint (Doubling of Serum Creatinine, End-Stage Renal Disease or All-Cause Mortality):

The percentages of patients experiencing an event during the course of the study can be seen in Table 1 below:

Table 1. IDNT: Components of Primary Composite Endpoint:

The secondary endpoint of the study was a composite of cardiovascular mortality and morbidity (myocardial infarction, hospitalization for heart failure, stroke with permanent neurological deficit, amputation). There were no statistically significant differences among treatment groups in these endpoints. Compared with placebo, AVAPRO significantly reduced proteinuria by about 27%, an effect that was evident within 3 months of starting therapy. AVAPRO significantly reduced the rate of loss of renal function (glomerular filtration rate), as measured by the reciprocal of the serum creatinine concentration, by 18.2%.

Table 2 presents results for demographic subgroups. Subgroup analyses are difficult to interpret, and it is not known whether these observations represent true differences or chance effects. For the primary endpoint, AVAPRO’s favorable effects were seen in patients also taking other antihypertensive medications (angiotensin II receptor antagonists, angiotensin-converting-enzyme inhibitors, and calcium channel blockers were not allowed), oral hypoglycemic agents, and lipid-lowering agents.

Table 2. IDNT: Primary Efficacy Outcome within Subgroups: