Mechanism Of Action
Angiotensin II is a potent vasoconstrictor formed from
angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE,
kininase II). Angiotensin II is the principal pressor agent of the RAS and also
stimulates aldosterone synthesis and secretion by adrenal cortex, cardiac
contraction, renal resorption of sodium, activity of the sympathetic nervous
system, and smooth muscle cell growth. Irbesartan blocks the vasoconstrictor
and aldosterone-secreting effects of angiotensin II by selectively binding to
the AT1 angiotensin II receptor. There is also an AT2
receptor in many tissues, but it is not involved in cardiovascular homeostasis.
Irbesartan is a specific competitive antagonist of AT1
receptors with a much greater affinity (more than 8500-fold) for the AT1
receptor than for the AT2 receptor, and no agonist activity.
Blockade of the AT1 receptor removes the
negative feedback of angiotensin II on renin secretion, but the resulting
increased plasma renin activity and circulating angiotensin II do not overcome
the effects of irbesartan on blood pressure.
Irbesartan does not inhibit ACE or renin or affect other
hormone receptors or ion channels known to be involved in the cardiovascular
regulation of blood pressure and sodium homeostasis. Because irbesartan does
not inhibit ACE, it does not affect the response to bradykinin; whether this
has clinical relevance is not known.
Hydrochlorothiazide is a thiazide diuretic. Thiazides
affect the renal tubular mechanisms of electrolyte reabsorption, directly
increasing excretion of sodium and chloride in approximately equivalent
amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma
volume, with consequent increases in plasma renin activity, increases in
aldosterone secretion, increases in urinary potassium loss, and decreases in
serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration
of an angiotensin II receptor antagonist tends to reverse the potassium loss
associated with these diuretics.
The mechanism of the antihypertensive effect of thiazides
is not fully understood.
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
After oral administration of hydrochlorothiazide,
diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12
Alcohol, barbiturates, or narcotics: Potentiation
of orthostatic hypotension may occur.
Skeletal muscle relaxants: Possible increased
responsiveness to muscle relaxants such as curare derivatives.
Corticosteroids, ACTH – intensified electrolyte
depletion, particularly hypokalemia.
Pressor amines (e.g., norepinephrine) – possible
decreased response to pressor amines but not sufficient to preclude their use.
Irbesartan is an orally active agent that does not
require biotransformation into an active form. The oral absorption of
irbesartan is rapid and complete with an average absolute bioavailability of
60% to 80%. Following oral administration of irbesartan, 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.
The terminal elimination half-life of irbesartan averaged
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
When plasma levels have been followed for at least 24
hours, the plasma half-life has been observed to vary between 5.6 and 14.8
Metabolism And Elimination
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.
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
In vitro studies of irbesartan oxidation by cytochrome
P450 isoenzymes indicated irbesartan was oxidized primarily by 2C9; metabolism
by 3A4 was negligible. Irbesartan was neither metabolized by, nor did it
substantially induce or inhibit, isoenzymes commonly associated with drug
metabolism (1A1, 1A2, 2A6, 2B6, 2D6, 2E1). There was no induction or inhibition
Hydrochlorothiazide is not metabolized but is eliminated
rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged
within 24 hours.
Irbesartan is 90% bound to serum proteins (primarily
albumin and α -acid glycoprotein) with negligible binding to cellular
components of blood. The average volume of distribution is 53 to 93 liters.
Total plasma and renal clearances are in the range of 157 to 176 mL/min and 3.0
to 3.5 mL/min, respectively. With repetitive dosing, irbesartan accumulates to
no clinically relevant extent.
Studies in animals indicate that radiolabeled irbesartan
weakly crosses the blood-brain barrier and placenta. Irbesartan is excreted in
the milk of lactating rats.
Hydrochlorothiazide crosses the placental but not the
blood-brain barrier and is excreted in breast milk.
Irbesartan-hydrochlorothiazide pharmacokinetics have not
been investigated in patients <18 years of age.
No gender-related differences in pharmacokinetics were
observed in healthy elderly (age 65 to 80 years) or in healthy young (age 18 to
40 years) subjects. In studies of hypertensive patients, there was no gender
difference in half-life or accumulation, but somewhat higher plasma
concentrations of irbesartan were observed in females (11% to 44%). No
gender-related dosage adjustment is necessary.
In elderly subjects (age 65 to 80 years), irbesartan
elimination half-life was not significantly altered, but AUC and Cmax values
were about 20% to 50% greater than those of young subjects (age 18 to 40 years).
No dosage adjustment is necessary in the elderly.
In healthy black subjects, irbesartan AUC values were
approximately 25% greater than whites; there were no differences in Cmax
The pharmacokinetics of irbesartan were 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]
The pharmacokinetics of irbesartan following repeated
oral administration were not significantly affected in patients with mild to
moderate cirrhosis of the liver. No dosage adjustment is necessary in patients
with hepatic insufficiency.
No significant drug-drug pharmacokinetic (or
pharmacodynamic) interactions have been found in interaction studies with
hydrochlorothiazide, digoxin, warfarin, and nifedipine.
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. Concomitant nifedipine or
hydrochlorothiazide had no effect on irbesartan pharmacokinetics. 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 had no effect on the pharmacodynamics of warfarin (prothrombin time)
or the pharmacokinetics of digoxin. The pharmacokinetics of irbesartan were not
affected by coadministration of nifedipine or hydrochlorothiazide.
Animal Toxicology And/Or Pharmacology
Reproductive Toxicology Studies
When pregnant rats were treated with irbesartan from Day
0 to Day 20 of gestation (oral doses of 50, 180, and 650 mg/kg/day), increased
incidences of renal pelvic cavitation, hydroureter, and/or absence of renal
papilla were observed in fetuses at doses ≥50 mg/kg/day (approximately
equivalent to the MRHD, 300 mg/day, on a body surface area basis). Subcutaneous
edema was observed in fetuses at doses ≥180 mg/kg/day (about 4 times the
MRHD on a body surface area basis). As these anomalies were not observed in
rats in which irbesartan exposure (oral doses of 50, 150, and 450 mg/kg/day)
was limited to gestation days 6 to 15, they appear to reflect late gestational
effects of the drug. In pregnant rabbits, oral doses of 30 mg irbesartan/kg/day
were associated with maternal mortality and abortion. Surviving females
receiving this dose (about 1.5 times the MRHD on a body surface area basis) had
a slight increase in early resorptions and a corresponding decrease in live fetuses.
Irbesartan was found to cross the placental barrier in rats and rabbits.
The antihypertensive effects of irbesartan were examined
in 7 major 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 a comparison of once or twice-daily regimens at 150 mg/day,
comparisons of peak and trough effects, and comparisons of response by gender,
age, and race. Two of the 7 placebo-controlled trials identified above and 2
additional placebo-controlled studies 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 to 900 mg) and 611 patients
randomized to placebo. Once-daily doses of 150 to 300 mg provided statistically
and clinically significant decreases in systolic and diastolic blood pressure
with trough (24-hour post dose) effects after 6 to 12 weeks of treatment
compared to placebo, of about 8 to 10/5 to 6 mmHg and 8 to 12/5 to 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 3 and 4.
Figure 3: Placebo-subtracted reduction in trough
SeSBP; integrated analysis
Figure 4: Placebo-subtracted 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 continuous
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.
Analysis of age, gender, 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). Black patients typically show an improved response with
the addition of a low dose diuretic (e.g., 12.5 mg hydrochlorothiazide).
The effect of irbesartan is apparent after the first dose
and is close to the full observed effect at 2 weeks. At the end of the 8-week
exposure, about 2/3 of the antihypertensive effect was still present 1 week
after the last dose. Rebound hypertension was not observed. There was
essentially no change in average heart rate in irbesartan-treated patients in
The antihypertensive effects of AVALIDE
(irbesartan-hydrochlorothiazide) tablets were examined in 4 placebo-controlled
studies in patients with mild-moderate hypertension (mean seated diastolic
blood pressure [SeDBP] between 90 and 110 mmHg), one study in patients with
moderate hypertension (mean seated systolic blood pressure [SeSBP] 160 to 179
mmHg or SeDBP 100 to 109 mmHg), and one study in patients with severe
hypertension (mean SeDBP ≥110 mmHg) of 8 to 12 weeks. These trials
included 3149 patients randomized to fixed doses of irbesartan (37.5 to 300 mg)
and concomitant hydrochlorothiazide (6.25 to 25 mg).
Study I was a factorial study that compared all
combinations of irbesartan (37.5 mg, 100 mg, and 300 mg or placebo) and
hydrochlorothiazide (6.25 mg, 12.5 mg, and 25 mg or placebo).
Study II compared the irbesartan-hydrochlorothiazide
combinations of 75/12.5 mg and 150/12.5 mg to their individual components and
Study III investigated the ambulatory blood pressure
responses to irbesartan-hydrochlorothiazide (75/12.5 mg and 150/12.5 mg) and
placebo after 8 weeks of dosing.
Study IV investigated the effects of the addition of
irbesartan (75 or 150 mg) in patients not controlled (SeDBP 93 – 120 mmHg) on
hydrochlorothiazide (25 mg) alone. In Studies I – III, the addition of irbesartan
150 to 300 mg to hydrochlorothiazide doses of 6.25, 12.5, or 25 mg produced
further doserelated reductions in blood pressure at trough of 8 to 10 mmHg/3 to
6 mmHg, similar to those achieved with the same monotherapy dose of irbesartan.
The addition of hydrochlorothiazide to irbesartan produced further dose-related
reductions in blood pressure at trough (24 hours post dose) of 5 to 6/2 to 3
mmHg (12.5 mg) and 7 to 11/4 to 5 mmHg (25 mg), also similar to effects
achieved with hydrochlorothiazide alone. Once-daily dosing with 150 mg
irbesartan and 12.5 mg hydrochlorothiazide, 300 mg irbesartan and 12.5 mg
hydrochlorothiazide, or 300 mg irbesartan and 25 mg hydrochlorothiazide
produced mean placebo-adjusted blood pressure reductions at trough (24 hours post
dosing) of about 13 to 15/7 to 9 mmHg, 14/9 to 12 mmHg, and 19 to 21/11 to 12
mmHg, respectively. Peak effects occurred at 3 to 6 hours, with the
trough-to-peak ratios >65%.
In Study IV, the addition of irbesartan (75 – 150 mg) gave
an additive effect (systolic/diastolic) at trough (24 hours post dosing) of
Studies V and VI had no placebo group, so effects
described below are not all attributable to irbesartan or HCTZ.
Study V was conducted in patients with a mean baseline
blood pressure of 162/98 mmHg and compared the change from baseline in SeSBP at
8 weeks between the combination group (irbesartan and HCTZ 150/12.5 mg), to
irbesartan (150 mg) and to HCTZ (12.5 mg). These initial study regimens were increased
at 2 weeks to AVALIDE 300/25 mg, irbesartan 300 mg, or to HCTZ 25 mg,
Mean reductions from baseline for SeDBP and SeSBP at
trough were 14.6 mmHg and 27.1 mmHg for patients treated with AVALIDE, 11.6
mmHg and 22.1 mmHg for patients treated with irbesartan, and 7.3 mmHg and 15.7
mmHg for patients treated with HCTZ at 8 weeks, respectively. For patients
treated with AVALIDE, the mean change from baseline in SeDBP was 3.0 mmHg lower
(p=0.0013) and the mean change from baseline in SeSBP was 5.0 mmHg lower
(p=0.0016) compared to patients treated with irbesartan, and 7.4 mmHg lower
(p<0.0001) and 11.3 mmHg lower (p<0.0001) compared to patients treated
with HCTZ, respectively. Withdrawal rates were 3.8% on irbesartan, 4.8% on
HCTZ, and 6.7% on AVALIDE.
Study VI was conducted in patients with a mean baseline
blood pressure of 172/113 mmHg and compared trough SeDBP at 5 weeks between the
combination group (irbesartan and HCTZ 150/12.5 mg) and irbesartan (150 mg).
These initial study regimens were increased at 1 week to AVALIDE 300/25 mg or
to irbesartan 300 mg, respectively.
At 5 weeks, mean reductions from baseline for SeDBP and
SeSBP at trough were 24.0 mmHg and 30.8 mmHg for patients treated with AVALIDE
and 19.3 mmHg and 21.1 mmHg for patients treated with irbesartan, respectively.
The mean SeDBP was 4.7 mmHg lower (p<0.0001) and the mean SeSBP was 9.7 mmHg
lower (p<0.0001) in the group treated with AVALIDE than in the group treated
with irbesartan. Patients treated with AVALIDE achieved more rapid blood
pressure control with significantly lower SeDBP and SeSBP and greater blood
pressure control at every assessment (Week 1, Week 3, Week 5, and Week 7).
Maximum effects were seen at Week 7.
Withdrawal rates were 2.2% on irbesartan and 2.1% on
In Studies I – VI, there was no difference in response for
men and women or in patients over or under 65 years of age. Black patients had
a larger response to hydrochlorothiazide than non-black patients and a smaller
response to irbesartan. The overall response to the combination was similar for
black and nonblack patients.