Treatment of essential hypertension.
APROVASC® is indicated in the treatment of hypertension in adult patients in whom
blood pressure is not adequately controlled on irbesartan or amlodipine monotherapy.

The usual initial and maintenance dose of APROVASC® is one tablet per day. APROVASC®
can be administered with or without food.
APROVASC® should be administered in patients whose blood pressure is not adequately

controlled on monotherapy with irbesartan or amlodipine or for continuation of therapy for
patients receiving irbesartan and amlodipine as separate tablets. Dose should be determined on a
case-by-case basis, based on patient response to therapy with the individual components and the
desired antihypertensive response. The maximum recommended dose with APROVASC® is 300
mg/10 mg per day.
Treatment should be adjusted based on blood pressure response.
Pediatric patients: The safety and efficacy of APROVASC® has not been established in this
population.
Elderly patients and patients with impaired renal function: In general, no dosage reduction is
necessary in elderly patients or patients with impaired renal function (regardless of the degree of
impairment).
Patients with impaired hepatic function: As the medicinal product contains amlodipine,
APROVASC® should be administered with caution in these patients (see Section 6, Warnings).
Medicinal product for oral administration.
APROVASC® can be administered with or without food.

As the drug contains both irbesartan and amlodipine, APROVASC® is contraindicated in: - patients allergic to either or both of the active substances or to any of the ingredients of the drug - patients allergic to dihydropyridines - patients with cardiogenic shock, clinically significant aortic stenosis, unstable angina (excluding Prinzmetal’s angina) - pregnancy and lactation (see Section 4.6 Fertility, Pregnancy and lactation). APROVASC® should not be co-administered with medicinal products containing aliskiren in patients with diabetes or moderate to severe renal insufficiency (glomerular filtration rate [GFR] < 60 mL/min/1.73 m2). APROVASC® should not be co-administered with angiotensin-converting enzyme (ACE) inhibitors in patients with diabetic nephropathy.

Hypotension: volume-depleted patients: Irbesartan has been rarely associated with hypotension
in hypertensive patients without other co-morbid conditions. As with ACE inhibitors,
symptomatic hypotension may be expected to occur in sodium/volume-depleted patients and in
those undergoing intensive diuretic treatment and/or salt restriction, or on hemodialysis. Volume
and/or and sodium depletion should be corrected before therapy with APROVASC® is initiated
or the lowest possible starting dose should be considered.

Fetal/neonatal morbidity and mortality: Although there is no experience with irbesartan in
pregnant women, in utero exposure to ACE inhibitors given to pregnant women during the
second and third trimesters of gestation has been reported to cause injury to and death of the
developing fetus. Thus, as for any drug that acts directly on the renin-angiotensin-aldosterone
system, APROVASC® should not be used during pregnancy. If pregnancy is detected during
treatment, APROVASC® should be discontinued as soon as possible.
Patients with heart failure: In a long-term, placebo controlled study (PRAISE-2) of amlodipine
in patients with NYHA III and IV heart failure of nonischemic etiology, amlodipine was
associated with increased reports of pulmonary edema despite no significant difference in the
incidence of worsening of heart failure compared to placebo (see Pharmacodynamics).
Hepatic impairment: As with other calcium antagonists, amlodipine half-life is prolonged in
patients with impaired liver function and no dosage recommendations have been established in
this population. APROVASC® should therefore be administered with caution in these patients.
Hypertensive crisis: The safety and efficacy of APROVASC® in the treatment of hypertensive
crisis have not been established.
GENERAL PRECAUTIONS FOR USE:
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): the dual blockade of the
renin- angiotensin-aldosterone system induced by administration of a combination of
APROVASC® and angiotensin- converting enzyme (ACE) inhibitors or aliskiren is not
recommended as there is an increased risk of hypotension, hyperkalemia and impairment of renal
function, in comparison to monotherapy. Use of the APROVASC® + aliskiren combination is
contraindicated in patients with diabetes mellitus or with renal insufficiency (glomerular filtration
rate [GFR] <60 mL/min/1.73 m2).
The use of APROVASC® in combination with ACE inhibitors is contraindicated in patients
with diabetic nephropathy.
As a consequence of blocking the renin-angiotensin-aldosterone system, changes in renal
function may be anticipated in susceptible individuals. In patients whose renal function is
dependent on renin-angiotensin- aldosterone system activity (hypertensive patients with renal
artery stenosis in one or both kidneys, or patients with severe congestive heart failure), treatment
with other drugs that affect this system has been associated with oliguria and/or progressive
azotemia and rarely with acute renal failure and/or death. The possibility of a similar effect
occurring with the use of an angiotensin II receptor antagonist, including irbesartan, cannot be
ruled out.
Geriatric use: In patients who received irbesartan in clinical studies, no overall differences
in efficacy or safety were observed between older patients (65 years or older) and younger
patients.
Pediatric use: The safety and efficacy of APROVASC® have not been established in pediatric
patients.

For the irbesartan and amlodipine combination: Based on a pharmacokinetic study where
irbesartan and amlodipine were administered alone or in combination, there is no
pharmacokinetic interaction between irbesartan and amlodipine.
No drug interaction studies have been performed with APROVASC® and other medicinal
products.
Irbesartan: Based on in vitro data, no interactions would be expected to occur with drugs for
which metabolism depends on cytochrome P450 isoenzymes CYP1A1, CYP1A2, CYP2A6,
CYP2B6, CYP2D6, CYP2E1 or CYP3A4.
Irbesartan is primarily metabolized by CYP2C9, however, during clinical interaction studies no
significant interactions were observed when irbesartan was co-administered with warfarin
(metabolized by CYP2C9).
Co-administration with nifedipine or hydrochlorothiazide has no effect on the pharmacokinetic
profile of irbesartan.
Irbesartan has no effect on the pharmacokinetics of simvastatin (metabolized by CYP3A4) or
digoxin (substrate of P-glycoprotein efflux transporter).
Based on experience with the use of other drugs with an effect on the renin-angiotensin system,
concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes
containing potassium may increase serum potassium levels.
Use of APROVASC® concomitantly with medicinal products containing aliskiren is
contraindicated in patients with diabetes mellitus or moderate to severe renal insufficiency
(glomerular filtration rate [GFR] <60 mL/min/1.73 m2), and is not recommended in other
patients.
Angiotensin-converting enzyme (ACE) inhibitors: The use of APROVASC® in combination
with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not
recommended in other patients.
In elderly patients, volume-depleted patients (including those treated with diruetics), or in
patients with impaired renal function, co-administration of irbesartan with NSAIDs, including
selective COX-2 inhibitors, or with angiotenisin II receptor antagonists, including irbesartan, can
cause deterioration of renal function, including possible acute renal failure. These effects are
usually reversible. Renal function should be monitored periodically in patients receiving
occasional treatment with irbesartan and NSAIDs. The antihypertensive effect of angiotenisin II
receptor antagonists, including irbesartan, may be attenuated by NSAIDs including selective
COX-2 inhibitors.
Amlodipine: Amlodipine has been safely co-administered with thiazide diuretics, beta blockers,
alpha blockers, ACE inhibitors, long-acting nitrates, sublingual glyceryl trinitrate, NSAIDs,
antibiotics, and oral hypoglycemic drugs.

Data from in vitro studies with human plasma indicate that amlodipine has no effect on the
protein binding of the medicinal products studied (digoxin, phenytoin, warfarin or indomethacin).
 Cimetidine: Co-administration of amlodipine with cimetidine had no effect on the
pharmacokinetic profile of amlodipine.
 Grapefruit juice: Co-administration of 240 mL of grapefruit juice with a single 10 mg oral
dose of amlodipine in 20 healthy subjects had no significant effect on the pharmacokinetics
of amlodipine.
 Aluminum/magnesium (antacids): Concomitant administration of an antacid containing
aluminum/magnesium with a single dose of amlodipine had no significant effect on the
pharmacokinetic profile of amlodipine.
 Sildenafil: When amlodipine and sildenafil were used in combination, each agent
independently exerted a blood pressure lowering effect.
 Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine with 80 mg of
atorvastatin resulted in no significant change in the steady-state pharmacokinetic
parameters of atorvastatin.
 Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin
levels or digoxin renal clearance in healthy subjects.
 Warfarin: Co-administration of amlodipine did not significantly change the effect of
warfarin on prothrombin time.
 Cyclosporine: Pharmacokinetic studies with cyclosporine have demonstrated that
amlodipine has no significant effect on cyclosporine pharmacokinetics.
LABORATORY TEST ABNORMALITIES:
No clinically significant changes in laboratory test parameters were observed in controlled
clinical studies with irbesartan in hypertensive patients. No special monitoring of laboratory
parameters is required in patients with essential hypertension receiving treatment with irbesartan.
SPECIAL PRECAUTIONS RELATED TO THE CARCINOGENIC, MUTAGENIC AND
TERATOGENIC EFFECTS, AND EFFECTS ON FERTILITY:
Irbesartan:
No carcinogenic evidence was observed with administration of irbesartan at doses of up to
500/1000 mg/kg/day in rats (male/female, respectively) and 1000 mg/kg/day in mice for 2
years. These doses provided a systemic exposure 4-25 times (rats) and 4-6 times (mice) the
exposure in humans receiving 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).

Fertility and reproductive performance were not affected in studies of male and female rats,
even at doses causing some parental toxicity (up to 650 mg/kg/day). No significant effects on
the number of corpora lutea, implants, or live fetuses were observed. Irbesartan had no effect on
survival, development, or reproduction of offspring.
Transient toxic effects (increased renal pelvic cavitation, hydroureter or subcutaneous edema)
were observed in rat fetuses at doses of 50 mg/kg/day or higher, which resolved after birth. In
rabbits, maternal mortality, abortion and early resorption were observed at doses of 30
mg/kg/day. No other teratogenic effects were observed in rats or rabbits.
Amlodipine:
Carcinogenesis: Rats and mice treated with amlodipine in the diet for two years, at
concentrations calculated to provide daily dosage levels of 0.5, 1.25 and 2.5 mg/kg/day showed
no evidence of carcinogenicity. The highest dose (similar to the maximum recommended
human dose of 10 mg on a mg/m2 basis for mice, and about twice* this maximum dose for rats)
was close to the maximum tolerated dose for mice but not for rats.
Mutagenesis: Mutagenesis studies revealed no amlodipine-related effects at either the gene or
chromosome levels.
Infertility: There was no effect on fertility in rats treated with amlodipine (males for 64 days
and females for 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum
recommended human dose of 10 mg on a mg/m2 basis).
* Based on a 50 kg patient.

Pregnancy: There are no adequate and well-controlled studies in pregnant women.
APROVASC® is contraindicated during pregnancy. APROVASC® must not be administered
to women of childbearing potential unless effective contraception is used. When pregnancy is
detected during treatment, APROVASC® should be discontinued as soon as possible.
Lactating mothers: APROVASC® is contraindicated during lactation

ADVERSE EVENTS:
Because clinical trials are conducted under widely varying conditions, the incidence of adverse
reaction observed in the clinical trials of one drug cannot be directly compared to that observed
in the clinical trials of other drugs and may not reflect that observed in practice.
Irbesartan has been evaluated for safety in approximately 5000 subjects in clinical studies,
including 1300 hypertensive patients treated for 6 months and more than 400 patients treated
for 1 year or more. Adverse events in patients receiving irbesartan were generally mild and
transient with no relationship to the dose administered. The incidence of adverse events was not
related to age, gender or race.

In placebo-controlled clinical studies, including 1965 patients treated with irbesartan (usual
treatment duration: 1 to 3 months), treatment discontinuation due to any clinical or laboratory
adverse event was 3.3 percent for irbesartan-treated patients and 4.5 percent for placebo-treated
patients (p=0.029).
Adverse events that have been reported in clinical trials or postmarketing experience with
irbesartan are categorized below according to system organ class and frequency (see Table 3).
The frequency of adverse events is defined using the following convention:
Very common: (≥ 1/10); common: (≥ 1/100 to < 1/10); uncommon: (≥ 1/1 000 to < 1/100);
rare: (≥ 1/10 000 to
< 1/1 000); very rare: (< 1/10 000), unknown: no incidence data available.
Frequencies of adverse reactions from postmarketing experience are unknown, as these
reactions are reported voluntarily from a population of uncertain size.

b . possible or unlikely, irrespective of incidence in the placebo-treated patients  Includes all adverse events, whether causal relationship to therapy is probable, possible or unlikely, occurring with an incidence of 0.5% to <1% and at similar or slightly increased incidence in irbesartan- treated patients compared to placebotreated patients (no statistically significant differences between the 2 treatment groups)

For amlodipine:
Adverse events that have been reported in amlodipine trials are categorized below according to
system organ class and frequency (see Table 4).
The frequency of adverse events is defined using the following convention:
Very common: (≥ 1/10); common: (≥ 1/100 to < 1/10); uncommon: (≥ 1/1 000 to < 1/100);
rare: (≥ 1/10 000 to
< 1/1 000); very rare: (< 1/10 000), unknown: no incidence data available.

In the clinical trials comparing the fixed-dose combination irbesartan/amlodipine to either
irbesartan or amlodipine monotherapy, the types and incidences of treatment-emergent adverse
events (TEAEs) possibly related to study treatment were similar to those observed in earlier
monotherapy clinical trials and postmarketing reports. The most frequently reported adverse
event was peripheral edema, mainly associated with amlodipine.
The following CIOMS frequency rating is used, when applicable:
Very common ≥ 10 %; Common ≥ 1 and <10 %; Uncommon ≥ 0.1 and < 1 %; Rare ≥ 0.01 and
< 0.1 %; Very rare < 0.01 %, Unknown (cannot be estimated from available data).

To report any side effect(s):
Saudi Arabia:
National Pharmacovigilance & Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc

Experience in adults exposed to doses of up to 900 mg/day irbesartan for 8 weeks revealed no
toxicity. No specific information is available on the treatment of overdose with irbesartan.
Available data for amlodipine suggest that overdose could result in excessive peripheral
vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic
hypotension and shock with fatal outcome have been reported. The patient should be closely
monitored and symptomatic and supportive treatment administered.
Suggested measures include gastric lavage. Administration of activated charcoal to healthy
subjects immediately or up to two hours after ingestion of amlodipine 10 mg has been shown to
significantly decrease amlodipine absorption.
As amlodipine is highly protein bound and irbesartan is not removed from the body by
hemodialysis, hemodialysis does not appear to be useful.
If massive overdose should occur, active cardiac and respiratory monitoring should be initiated.
Frequent blood pressure measurement is essential. Clinically significant hypotension due to
amlodipine overdose calls for active cardiovascular support including elevation of the
extremities and attention to circulating fluid volume and urine output. A vasoconstrictor may be
helpful in restoring vascular tone and blood pressure, provided that there is no contraindication
to its use.
Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel
blockade.

NA

The pharmacodynamic properties of each drug, irbesartan and amlodipine, provide an additive
antihypertensive effect when administered in combination compared to the effect of each drug
administered separately. Both AT1 receptor antagonists and calcium channel blockers lower
blood pressure by reducing peripheral resistance, but calcium influx blockade and reduction of
angiotensin II vasoconstriction are complementary mechanisms.

Irbesartan:
Mechanism of action: Irbesartan is a specific angiotensin II receptor antagonist (AT1 subtype).
Angiotensin II is an important component of the renin-angiotensin system involved in the
pathophysiology of hypertension and sodium homeostasis. Irbesartan does not require
metabolic activation to exert its effect.
Irbesartan blocks the potent vasoconstrictor and aldosterone-secreting effects of angiotensin II
by selective antagonism of angiotensin II receptors (AT1 subtype) located on vascular smooth
muscle cells and the adrenal cortex. Irbesartan has no agonist activity at the AT1 receptor and
has a much greater affinity (more than 8500- fold) for the AT1 receptor than for the AT2
receptor (receptor that has not been shown to be associated with cardiovascular homeostasis).
Irbesartan does not inhibit enzymes involved in the renin-angiotensin system (i.e., angiotensin
converting enzyme [ACE]) or have an effect on other hormone receptors or ion channels
involved in the cardiovascular regulation of blood pressure and sodium homeostasis. Irbesartan
AT1 receptor blockade disrupts the renin- angiotensin feedback loop, increasing plasma renin
and angiotensin II levels. Following irbesartan administration, aldosterone plasma
concentrations decrease; however, no significant effect on serum potassium levels can be
observed at the recommended doses (mean increase <0.1 mEq/L). Irbesartan has no notable
effect on serum triglycerides, cholesterol or glucose concentrations; it has no effect on serum
uric acid levels or on urinary uric acid excretion.
Pharmacokinetic Properties: Irbesartan is an orally active agent that does not require
biotransformation to exert its effect. Following oral administration, irbesartan is rapidly and
completely absorbed. Peak plasma concentrations are reached 1.5-2 hours after oral
administration. The absolute oral bioavailability of irbesartan is 60-80%. Food has no effect
on irbesartan bioavailability.
Irbesartan is approximately 96% plasma protein bound, and has negligible binding to cellular
components of blood. The volume of distribution is 53-93 L/Kg.
In plasma, unchanged irbesartan accounts for 80-85% of the circulating radioactivity following
oral or intravenous administration of 14C-labeled irbesartan. Irbesartan is metabolized by the
liver via glucuronide conjugation and oxidation. The main circulating metabolite is irbesartan
glucuronide (approximately 6%). Irbesartan undergoes oxidation primarily by the cytochrome
P450 isoenzyme CYP2C9; the isoenzyme CYP3A4 has a negligible effect. Irbesartan is not
metabolized by most isoenzymes commonly involved in drug metabolism (i.e., CYP1A1,
CYP1A2, CYP2A6, CYP2B6, CYP2D6, or CYP2E1), and it does not significantly induce or
inhibit these enzymes. Irbesartan does not induce or inhibit the isoenzyme CYP3A4.
Irbesartan and its metabolites are eliminated by both the biliary and renal routes. About 20% of
the administered radioactivity after administration of either an oral or intravenous dose of 14Clabeled
irbesartan is recovered in urine, with the remainder recovered in the feces. Less than
2% of the dose is excreted in the urine as unchanged irbesartan.
The terminal elimination half-life (t1/2) of irbesartan is 11-15 hours. The total body clearance
of intravenously administered irbesartan is 157-176 mL/min, of which 3.0-3.5 mL/min is renal
clearance. Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range. Steadystate
plasma concentrations are reached within three days after initiation of a once-daily dosing
regimen. Limited accumulation (<20%) is observed in plasma after repeated once-daily dosing.

Pharmacokinetic Properties: Irbesartan is an orally active agent that does not require
biotransformation to exert its effect. Following oral administration, irbesartan is rapidly and
completely absorbed. Peak plasma concentrations are reached 1.5-2 hours after oral
administration. The absolute oral bioavailability of irbesartan is 60-80%. Food has no effect
on irbesartan bioavailability.
Irbesartan is approximately 96% plasma protein bound, and has negligible binding to cellular
components of blood. The volume of distribution is 53-93 L/Kg.
In plasma, unchanged irbesartan accounts for 80-85% of the circulating radioactivity following
oral or intravenous administration of 14C-labeled irbesartan. Irbesartan is metabolized by the
liver via glucuronide conjugation and oxidation. The main circulating metabolite is irbesartan
glucuronide (approximately 6%). Irbesartan undergoes oxidation primarily by the cytochrome
P450 isoenzyme CYP2C9; the isoenzyme CYP3A4 has a negligible effect. Irbesartan is not
metabolized by most isoenzymes commonly involved in drug metabolism (i.e., CYP1A1,
CYP1A2, CYP2A6, CYP2B6, CYP2D6, or CYP2E1), and it does not significantly induce or
inhibit these enzymes. Irbesartan does not induce or inhibit the isoenzyme CYP3A4.
Irbesartan and its metabolites are eliminated by both the biliary and renal routes. About 20% of
the administered radioactivity after administration of either an oral or intravenous dose of 14Clabeled
irbesartan is recovered in urine, with the remainder recovered in the feces. Less than
2% of the dose is excreted in the urine as unchanged irbesartan.
The terminal elimination half-life (t1/2) of irbesartan is 11-15 hours. The total body clearance
of intravenously administered irbesartan is 157-176 mL/min, of which 3.0-3.5 mL/min is renal
clearance. Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range. Steadystate
plasma concentrations are reached within three days after initiation of a once-daily dosing
regimen. Limited accumulation (<20%) is observed in plasma after repeated once-daily dosing.

In hypertensive subjects, higher irbesartan plasma concentrations were observed in females
compared to males (11-44%). Following multiple dosing, however, no differences in either
accumulation or elimination half- life were observed between males and females. No genderspecific
differences in clinical effect have been observed.
In elderly normotensive subjects (males and females, 65-80 years) with clinically normal renal
and hepatic function, irbesartan plasma AUC and peak plasma concentrations (Cmax) were
approximately 20-50% higher than in younger subjects (18-40 years). Regardless of age,
elimination half-life is comparable.
No significant age-related differences in clinical effect have been observed.
In black and white normotensive subjects, irbesartan plasma AUC and t1/2 are approximately
20-25% higher in black subjects compared to white subjects, whereas irbesartan peak plasma
concentrations (Cmax) were essentially equivalent.
In patients with renal impairment (regardless of degree) and in hemodialysis patients, the
pharmacokinetic profile of irbesartan is not significantly altered. Irbesartan is not removed by
hemodialysis.
In patients with hepatic insufficiency due to mild to moderate cirrhosis, the pharmacokinetic
profile of irbesartan is not significantly altered.
Pharmacodynamic properties: The blood pressure lowering effect of irbesartan is apparent
after the first dose and becomes substantial within 1-2 weeks, with maximal effect at 4-6
weeks. In long-term follow-up studies, the effect of irbesartan was maintained for more than
one year.
A single dose of up to 900 mg per day produced a dose-dependent decrease in blood pressure.
Once daily doses of 150-300 mg decrease trough supine or seated blood pressures (i.e., 24
hours after dosing) by an average of 8-13/5-8 mm Hg (systolic/diastolic), which is higher than
that observed with placebo. The effects measured at trough are 60-70% of the corresponding
peak diastolic and systolic effects. Optimal effects on 24- hour blood pressure are achieved
with once daily dosing.
Blood pressure is lowered to about the same extent in both standing and supine positions.
Orthostatic effects are infrequent, but as with ACE inhibitors, may be expected to occur in
sodium- and/or volume-depleted patients.
The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In
patients not adequately controlled by irbesartan alone, the addition of a low dose of
hydrochlorothiazide (12.5 mg) to irbesartan once daily results in a higher blood pressure
reduction at trough of 7-10/3-6 mm Hg (systolic/diastolic) compared to placebo.
Neither age or gender has an effect on irbesartan efficacy. As is the case with other drugs that
have an effect on the renin-angiotensin system, black patients have a notably lower response to
irbesartan monotherapy. When irbesartan is administered concomitantly with low-dose
hydrochlorothiazide (e.g., 12.5 mg daily), the antihypertensive response in black patients is
similar to that in white patients.

After withdrawal of irbesartan, blood pressure gradually returns to baseline. Rebound
hypertension has not been observed.
Amlodipine:
Mechanism of action: Amlodipine is a dihydropyridine calcium antagonist (calcium ion
antagonist or slow- channel blocker) that inhibits the transmembrane influx of calcium ions
into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of
amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise
mechanism by which amlodipine relieves angina symptoms has not been determined but
amlodipine reduces total ischemic burden in the following two ways:
1) Amlodipine dilates peripheral arterioles and thus reduces the total peripheral resistance
(afterload) against which the heart works. Since the heart rate remains stable, this unloading
of the heart reduces myocardial energy consumption and oxygen requirements;
2) The mechanism of action of amlodipine also probably involves dilatation of the main
coronary arteries and arterioles, both in normal and ischemic regions. This dilatation
increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or
variant angina).
In patients with hypertension, once daily dosing produces significant reductions of blood
pressure in both the supine and standing positions over a period of 24 hours. Due to the slow
onset of action, acute hypotension is not associated with amlodipine administration.
In patients with angina, once daily administration of amlodipine increases total exercise time,
time to angina onset, and time to 1 mm ST segment depression. In addition, it decreases both
angina attack frequency and glyceryl trinitrate tablet consumption.
Amlodipine has not been associated with any adverse metabolic effects or changes in plasma
lipids and is suitable for use in patients with asthma, diabetes, and gout.
Pharmacokinetic properties: After oral administration of therapeutic doses, amlodipine is well
absorbed, with peak blood levels reached between 6 and 12 hours post administration.
Absolute bioavailability is estimated to be between 64 and 90%. The volume of distribution of
amlodipine is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of
circulating amlodipine is bound to plasma protein. Food intake does not have an effect on
amlodipine absorption.
The terminal plasma elimination half-life is about 35–50 hours and is compatible with once
daily dosing. Amlodipine is extensively metabolized by the liver to inactive metabolites with
10% of the parent compound and 60% of metabolites excreted in the urine.
Use in elderly patients: The time to reach peak plasma concentrations of amlodipine is similar
in elderly and younger subjects. Amlodipine clearance tends to decrease, resulting in increases
in AUC and elimination half- life in elderly patients.
Increases in AUC and elimination half-life in patients with congestive heart failure were as
expected in this age group.

Pediatric patients: A population PK study has been conducted in 74 hypertensive children aged
from 12 months to 17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17
years) receiving amlodipine doses of between 1.25 and 20 mg given either once or twice daily.
In children 6 to 12 and in adolescents 13-17 years of age the typical oral clearance (CL/F) was
22.5 and 27.4 L/h, respectively, in males and 16.4 and 21.3 L/h, respectively, in females. Large
variability in exposure between individuals was observed. Data reported in children younger
than 6 years are limited.
Patients with hepatic insufficiency: see Warnings.
Irbesartan / Amlodipine Combination:
Concomitant administration of irbesartan and amlodipine, whether in a fixed dose combination
tablet or the free combination, has no effect on the bioavailability of the individual
components.
The three fixed dose combinations of irbesartan and amlodipine (150 mg/10 mg, 300 mg/5 mg,
and 300 mg/10 mg) are bioequivalent to the free dose combinations (150 mg/10 mg, 300 mg/5
mg, and 300 mg/10 mg) both in terms of rate and extent of absorption.
When given separately or concomitantly at 300 mg and 10 mg dose levels, time to mean peak
plasma concentrations of irbesartan and amlodipine remain unchanged, i.e. 0.75-1 hour and 5
hours after administration, respectively. Similarly, Cmax and AUCs are in the same
range resulting in a relative
bioavailability of 95% for irbesartan and 98% for amlodipine whether the two drugs are
administered concomitantly.
The mean half-life values for irbesartan and amlodipine, administered alone or in combination,
are similar: 17.6 hours versus 17.7 hours for irbesartan, and 58.5 hours versus 52.1 hours for
amlodipine. Elimination of irbesartan and amlodipine is unchanged whether the drugs are
administered alone or concomitantly.
The pharmacokinetic profile of both drugs appears to be linear over the co-administered dose
range (i.e. between 150 mg and 300 mg for irbesartan, and between 5 mg and 10 mg for
amlodipine).
Pediatric patients: No information is available for the fixed dose combination.
CLINICAL EFFICACY/CLINICAL STUDIES
The clinical evidence for the efficacy of the fixed-dose combination of irbesartan and
amlodipine is derived from two studies: the I-ADD and I-COMBINE studies. Both studies
were multi-center,
prospective, randomized, open-label, parallel-group studies with blinded endpoint evaluation
design. The studies were conducted in patients with established essential hypertension, having
uncontrolled blood pressure (mean systolic blood pressure [SBP] ≥145 mmHg) after at least
four weeks of treatment with irbesartan 150 mg (I-ADD) or amlodipine 5 mg (I-COMBINE).

Both studies consisted of three treatment periods, A, B, and C. During Period A, all patients
received amlodipine 5 mg or irbesartan 150 mg, once daily, for seven to ten days. At the end of
Period A, if a patient’s mean SBP was <135 mmHg, he or she was withdrawn from the
respective study.
In I-ADD, patients (n=325) were randomized following Period A to receive either irbesartan
150 mg or fixed-dose combination irbesartan/amlodipine 150 mg/5 mg once daily for five
weeks (Period B).
At Week 5, the doses were increased (forced titration) to irbesartan 300 mg or the fixed-dose
combination irbesartan/amlodipine 300 mg/5 mg once daily and continued for five weeks.
In I-COMBINE, patients (n=290) were randomized following Period A to receive either
amlodipine 5 mg or the fixed-dose combination irbesartan/amlodipine 150 mg/5 mg once daily
for five weeks (Period B). At Week 5, the doses were increased (forced titration) to amlodipine
10 mg or fixed-dose combination irbesartan/amlodipine 150 mg/10 mg once daily and
continued for five weeks (Period C).
In I-ADD, the primary endpoint was the change in SBP measured at home at Week 10.
In I-COMBINE, the primary endpoint was the change in SBP measured at home at Week 5.
Secondary endpoints were home diastolic blood pressure (DBP) and office blood pressure
measurement (OBPM) as well as the percentage of controlled patients (mean home SBP <135
mmHg) and responder patients (mean home SBP <135 mmHg and mean home DBP <85
mmHg) at Week 10 for both studies.
Results of both studies demonstrated significantly greater efficacy of the fixed-dose
combination compared to amlodipine alone or irbesartan alone (see Tables 1 and 2).

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36 Months

Store below 30°C, in a dry place.
Information for physicians only
Keep out of the reach of children
Prescription-only medicine.
Do not use during pregnancy and breast-feeding.

Cardboard box with 28 tablets in blister packs.
Irbesartan 150 mg and amlodipine 5 mg
Irbesartan 150 mg and amlodipine 10 mg
Irbesartan 300 mg and amlodipine 5 mg
Irbesartan 300mg and amlodipine 10 mg.

NA