APROVASC® contains two substances called irbesartan and amlodipine. Both
of these substances help to control high blood pressure.
- Irbesartan belongs to a group of medicines known as angiotensin-II receptor
antagonists. Angiotensin-II is a substance produced in the body which binds to
receptors in blood vessels causing them to tighten. This results in an increase in

blood pressure. Irbesartan prevents the binding of angiotensin-II to these
receptors, causing the blood vessels to relax.
- Amlodipine belongs to a group of substances called “calcium channel
blockers”. Amlodipine stops calcium from moving into the blood vessel wall
which stops the blood vessels from tightening.
APROVASC® is indicated in the treatment of hypertension in adult patients in
whom blood pressure is not adequately controlled on irbesartan or amlodipine
monotherapy.

a. Do not take APROVASC®
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 e; Pregnancy and breast-feeding).
APROVASC should not be administered concomitantly 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).
b. Take special care with
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 toACE 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.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with
aliskiren-containing medicinal products: the dual blockade of the reninangiotensin-
aldosterone system induced by administration of the APROVASC
+ aliskiren combination is not recommended as there is an increased risk of
hypertension, hyperkalemia and impairment of renal function. 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).
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 anangiotensin 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.
c. Taking other medicines
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 reninangiotensin
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] <60mL/ min/
1.73m2), 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.
Grapefruitjuice: 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.
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 inrats 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)
d. APROVASC® with food and drink.
APROVASC can be administered with or without food.
e. Pregnancy and breast-feeding
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.

Always take APROVASC exactly as your doctor has told you. Check with your
doctor or pharmacist if you are not sure.
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 300mg/10mg 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 2b Take special care with).
Medicinal product for oral administration.
APROVASC can be administered with or without food.

SYMPTOMS AND TREATMENT OF OVERDOSE OR ACCIDENTAL
INGESTION:
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.

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 irbesartantreated
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 (seeTable1).
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.

For amlodipine:
Adverse events that have been reported in amlodipine trials are categorized
below according to system organ class and frequency (seeTable2).
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 (seeTable3).
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).

Keep out of the reach and sight of children.
Store below 30°C, in a dry place