Treatment of essential hypertension.
This fixed dose combination is indicated in adult patients whose blood pressure is not adequately
controlled on Irbesartan or hydrochlorothiazide alone (see section 5.1).

Posology
Irbesartan and Hydrochlorothiazide can be taken once daily, with or without food.
Dose titration with the individual components (i.e. Irbesartan and hydrochlorothiazide) may be
recommended.
When clinically appropriate direct change from monotherapy to the fixed combinations may be
considered:
 Irbesartan and Hydrochlorothiazide 150 mg/12.5 mg may be administered in patients whose blood
pressure is not adequately controlled with hydrochlorothiazide or Irbesartan 150 mg alone;

 Irbesartan and Hydrochlorothiazide300 mg/12.5 mg may be administered in patients insufficiently
controlled by Irbesartan 300 mg or by Irbesartan and Hydrochlorothiazide150 mg/12.5 mg.
 Irbesartan and Hydrochlorothiazide300 mg/25 mg may be administered in patients insufficiently
controlled by Irbesartan and Hydrochlorothiazide300 mg/12.5 mg.
Doses higher than 300 mg Irbesartan/25 mg hydrochlorothiazide once daily are not recommended.
When necessary, Irbesartan and Hydrochlorothiazide may be administered with another antihypertensive
medicinal product (see sections 4.3, 4.4, 4.5 and 5.1).
Special Populations
Renal impairment: due to the hydrochlorothiazide component, Irbesartan and Hydrochlorothiazide is not
recommended for patients with severe renal dysfunction (creatinine clearance < 30 ml/min). Loop
diuretics are preferred to thiazides in this population. No dosage adjustment is necessary in patients with
renal impairment whose renal creatinine clearance is ≥ 30 ml/min (see sections 4.3 and 4.4).
Hepatic impairment: Irbesartan and Hydrochlorothiazide is not indicated in patients with severe hepatic
impairment. Thiazides should be used with caution in patients with impaired hepatic function. No dosage
adjustment of Irbesartan and Hydrochlorothiazide is necessary in patients with mild to moderate hepatic
impairment (see section 4.3).
Older people: no dosage adjustment of Irbesartan and Hydrochlorothiazide is necessary in older people.
Paediatric population: Irbesartan and Hydrochlorothiazide is not recommended for use in children and
adolescents because the safety and efficacy have not been established. No data are available.
Method of Administration
For oral use.

 Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or to other sulfonamide-derived substances (hydrochlorothiazide is a sulfonamide-derived substance)  Second and third trimesters of pregnancy (see sections 4.4 and 4.6)  Severe renal impairment (creatinine clearance < 30 ml/min)  Refractory hypokalaemia, hypercalcaemia  Severe hepatic impairment, biliary cirrhosis and cholestasis  The concomitant use of Irbesartan and Hydrochlorothiazide with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

Hypotension - Volume-depleted patients: Irbesartan and Hydrochlorothiazide has been rarely associated
with symptomatic hypotension in hypertensive patients without other risk factors for hypotension.
Symptomatic hypotension may be expected to occur in patients who are volume and/or sodium depleted
by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be
corrected before initiating therapy with Irbesartan and Hydrochlorothiazide.
Renal artery stenosis - Renovascular hypertension: there is an increased risk of severe hypotension and
renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single
functioning kidney are treated with angiotensin converting enzyme inhibitors or angiotensin-II receptor
antagonists. While this is not documented with Irbesartan and Hydrochlorothiazide, a similar effect
should be anticipated.
Renal impairment and kidney transplantation: when Irbesartan and Hydrochlorothiazide is used in
patients with impaired renal function, a periodic monitoring of potassium, creatinine and uric acid serum
levels is recommended. There is no experience regarding the administration of Irbesartan and
Hydrochlorothiazide in patients with a recent kidney transplantation. Irbesartan and Hydrochlorothiazide
should not be used in patients with severe renal impairment (creatinine clearance < 30 ml/min) (see
section 4.3). Thiazide diuretic-associated azotemia may occur in patients with impaired renal function.
No dosage adjustment is necessary in patients with renal impairment whose creatinine clearance is ≥ 30
ml/min. However, in patients with mild to moderate renal impairment (creatinine clearance ≥ 30 ml/min
but < 60 ml/min) this fixed dose combination should be administered with caution.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS):
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or
aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II
receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade
therapy is considered absolutely necessary, this should only occur under specialist supervision and
subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors
and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic
nephropathy.
Hepatic impairment: thiazides should be used with caution in patients with impaired hepatic function or
progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic
coma. There is no clinical experience with Irbesartan and Hydrochlorothiazide in patients with hepatic
impairment.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators,
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic
cardiomyopathy.
Primary aldosteronism: patients with primary aldosteronism generally will not respond to
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore,
the use of Irbesartan and Hydrochlorothiazide is not recommended.
Metabolic and endocrine effects: thiazide therapy may impair glucose tolerance. In diabetic patients
dosage adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes mellitus may
become manifest during thiazide therapy.
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy;
however at the 12.5 mg dose contained in Irbesartan and Hydrochlorothiazide, minimal or no effects
were reported.
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide
therapy.
Electrolyte imbalance: as for any patient receiving diuretic therapy, periodic determination of serum
electrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia,
hyponatraemia, and hypochloremic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular
fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with
Irbesartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patients
with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving
inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids
or ACTH. Conversely, due to the Irbesartan component of Irbesartan and Hydrochlorothiazide
hyperkalaemia might occur, especially in the presence of renal impairment and/or heart failure, and
diabetes mellitus. Adequate monitoring of serum potassium in patients at risk is recommended.
Potassium-sparing diuretics, potassium supplements or potassium-containing salts substitutes should be
co-administered cautiously with Irbesartan and Hydrochlorothiazide (see section 4.5).
There is no evidence that Irbesartan would reduce or prevent diuretic-induced hyponatraemia. Chloride
deficit is generally mild and usually does not require treatment.
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum
calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be
evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for
parathyroid function.
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in
hypomagnaesemia.
Lithium: the combination of lithium and Irbesartan and Hydrochlorothiazide is not recommended (see
section 4.5).
Anti-doping test: hydrochlorothiazide contained in this medicinal product could produce a positive
analytic result in an anti-doping test.
General: in patients whose vascular tone and renal function depend predominantly on the activity of the
renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying
renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or
angiotensin-II receptor antagonists that affect this system has been associated with acute hypotension,
azotemia, oliguria, or rarely acute renal failure (see section 4.5). As with any antihypertensive agent,excessive blood pressure decrease in patients with ischemic cardiopathy or ischemic cardiovascular
disease could result in a myocardial infarction or stroke.
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of
allergy or bronchial asthma, but are more likely in patients with such a history.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide
diuretics.
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If
photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a readministration
of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun
or to artificial UVA.
Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy.
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed
to alternative antihypertensive treatments which have an established safety profile for use in pregnancy.
When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if
appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Lactose: this medicinal product contains lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicinal product.
Acute Myopia and Secondary Acute Angle-Closure Glaucoma: sulfonamide drugs or sulfonamide
derivative drugs can cause an idiosyncratic reaction, resulting in transient myopia and acute angle-closure
glaucoma. While hydrochlorothiazide is a sulfonamide, only isolated cases of acute angle-closure
glaucoma have been reported so far with hydrochlorothiazide. Symptoms include acute onset of
decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation.
Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to
discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be
considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angleclosure
glaucoma may include a history of sulfonamide or penicillin allergy (see section 4.8).

Other antihypertensive agents: the antihypertensive effect of Irbesartan and Hydrochlorothiazide may be
increased with the concomitant use of other antihypertensive agents. Irbesartan and hydrochlorothiazide
(at doses up to 300 mg Irbesartan/25 mg hydrochlorothiazide) have been safely administered with other
antihypertensive agents including calcium channel blockers and beta-adrenergic blockers. Prior treatment
with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy
with Irbesartan with or without thiazide diuretics unless the volume depletion is corrected first (see
section 4.4).
Aliskiren-containing products or ACE-inhibitors: Clinical trial data has shown that dual blockade of the
renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE-inhibitors, angiotensin
II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as
hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the
use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects
have been very rarely reported with Irbesartan so far. Furthermore, renal clearance of lithium is reduced
by thiazides so the risk of lithium toxicity could be increased with Irbesartan and Hydrochlorothiazide.
Therefore, the combination of lithium and Irbesartan and Hydrochlorothiazide is not recommended (see
section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is
recommended.
Medicinal products affecting potassium: the potassium-depleting effect of hydrochlorothiazide is
attenuated by the potassium-sparing effect of Irbesartan. However, this effect of hydrochlorothiazide on
serum potassium would be expected to be potentiated by other medicinal products associated with
potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone,
penicillin G sodium). Conversely, based on the experience with the use of other medicinal products that
blunt the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium
supplements, salt substitutes containing potassium or other medicinal products that may increase serum
potassium levels (e.g. heparin sodium) may lead to increases in serum potassium. Adequate monitoring
of serum potassium in patients at risk is recommended (see section 4.4).

Medicinal products affected by serum potassium disturbances: periodic monitoring of serum potassium is
recommended when Irbesartan and Hydrochlorothiazide is administered with medicinal products affected
by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered simultaneously
with non-steroidal anti- inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3
g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect may occur.
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an
increased risk of worsening of renal function, including possible acute renal failure, and an increase in
serum potassium, especially in patients with poor pre-existing renal function. The combination should be
administered with caution, especially in the elderly. Patients should be adequately hydrated and
consideration should be given to monitoring renal function after initiation of concomitant therapy, and
periodically thereafter.
Additional information on Irbesartan interactions: in clinical studies, the pharmacokinetic of Irbesartan is
not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent
by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed
when Irbesartan was coadministered with warfarin, a medicinal product metabolised by CYP2C9. The
effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of Irbesartan have not been
evaluated. The pharmacokinetic of digoxin was not altered by co-administration of Irbesartan.
Additional information on hydrochlorothiazide interactions: when administered concurrently, the
following medicinal products may interact with thiazide diuretics:
Alcohol: potentiation of orthostatic hypotension may occur;
Antidiabetic medicinal products (oral agents and insulins): dosage adjustment of the antidiabetic
medicinal product may be required (see section 4.4);
Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is impaired in the presence of
anionic exchange resins. Irbesartan and Hydrochlorothiazide should be taken at least one hour before or
four hours after these medications;
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be increased;
Digitalis glycosides: thiazide induced hypokalaemia or hypomagnaesemia favour the onset of digitalisinduced
cardiac arrhythmias (see section 4.4);

Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory drug may
reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients;
Pressor amines (e.g. noradrenaline): the effect of pressor amines may be decreased, but not sufficiently
to preclude their use;
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): the effect of nondepolarizing skeletal
muscle relaxants may be potentiated by hydrochlorothiazide;
Antigout medicinal products: dosage adjustments of antigout medicinal products may be necessary as
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or
sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence of
hypersensitivity reactions to allopurinol;
Calcium salts: thiazide diuretics may increase serum calcium levels due to decreased excretion. If
calcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be prescribed,
serum calcium levels should be monitored and calcium dosage adjusted accordingly;
Carbamazepine: concomitant use of carbamazepine and hydrochlorothiazide has been associated with the
risk of symptomatic hyponatraemia. Electrolytes should be monitored during concomitant use. If
possible, another class of diuretics should be used;
Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by
thiazides. Anticholinergic agents (e.g. atropine, beperiden) may increase the bioavailability of thiazidetype
diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides may increase
the risk of adverse effects caused by amantadine. Thiazides may reduce the renal excretion of cytotoxic
medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects

Pregnancy:
Angiotensin II Receptor Antagonists (AIIRAs):
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The use of
AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors
during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor
Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is
considered essential, patients planning pregnancy should be changed to alternative antihypertensive
treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed,
treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be
started.
Exposure to AIIRA therapy during the second and third trimesters is known to induce human fetotoxicity
(decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal
failure, hypotension, hyperkalaemia). (See section 5.3).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of
renal function and skull is recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3
and 4.4).
Hydrochlorothiazide:
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first
trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the
pharmacological mechanism of action of hydrochlorothiazide its use during the second and third
trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like
icterus, disturbance of electrolyte balance and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia
due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on
the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare
situations where no other treatment could be used.
Since Irbesartan and Hydrochlorothiazide contains hydrochlorothiazide, it is not recommended during the
first trimester of pregnancy. A switch to a suitable alternative treatment should be carried out in advance
of a planned pregnancy.
Breast-feeding:
Angiotensin II Receptor Antagonists (AIIRAs):

Because no information is available regarding the use of Irbesartan and Hydrochlorothiazide during
breast-feeding, Irbesartan and Hydrochlorothiazide is not recommended and alternative treatments with
better established safety profiles during breast-feeding are preferable, especially while nursing a newborn
or preterm infant.
It is unknown whether Irbesartan or its metabolites are excreted in human milk.
Available pharmacodynamic/toxicological data in rats have shown excretion of Irbesartan or its
metabolites in milk (for details see 5.3).
Hydrochlorothiazide:
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense
diuresis can inhibit the milk production. The use of Irbesartan and Hydrochlorothiazide during breast
feeding is not recommended. If Irbesartan and Hydrochlorothiazide is used during breast feeding, doses
should be kept as low as possible.
Fertility:
Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducing the
first signs of parental toxicity (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed. Based on its
pharmacodynamic properties, Irbesartan and Hydrochlorothiazide is unlikely to affect this ability. When
driving vehicles or operating machines, it should be taken into account that occasionally dizziness or
weariness may occur during treatment of hypertension.

Irbesartan/hydrochlorothiazide combination:
Among 898 hypertensive patients who received various doses of Irbesartan/hydrochlorothiazide (range:
37.5 mg/6.25 mg to 300 mg/25 mg) in placebo-controlled trials, 29.5% of the patients experienced
adverse reactions. The most commonly reported ADRs were dizziness (5.6%), fatigue (4.9%),
nausea/vomiting (1.8%), and abnormal urination (1.4%). In addition, increases in blood urea nitrogen
(BUN) (2.3%), creatine kinase (1.7%) and creatinine (1.1%) were also commonly observed in the trials.
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled trials.

The frequency of adverse reactions listed below 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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

 

Table 1: Adverse Reactions in Placebo-Controlled Trials and Spontaneous Reports
Investigations:	Common:	increases in blood urea nitrogen (BUN), creatinine and creatine kinase
	Uncommon:	decreases in serum potassium and sodium
Cardiac disorders:	Uncommon:	syncope, hypotension, tachycardia, oedema
Nervous system disorders:	Common:	dizziness
	Uncommon:	orthostatic dizziness
	Not known:	headache
Ear and labyrinth disorders:	Not known:	tinnitus
Respiratory, thoracic and mediastinal disorders:	Not known:	cough
Gastrointestinal disorders:	Common:	nausea/vomiting
	Uncommon:	diarrhoea
	Not known:	dyspepsia, dysgeusia
Renal and urinary disorders:	Common:	abnormal urination
	Not known:	impaired renal function including isolated cases of renal failure in patients at risk (see section 4.4)
Musculoskeletal and connective tissue disorders:	Uncommon:	swelling extremity
	Not known:	arthralgia, myalgia
Metabolism and nutrition disorders:	Not known:	hyperkalaemia
Vascular disorders:	Uncommon:	flushing
General disorders and administration site conditions:	Common:	fatigue
Immune system disorders:	Not known:	cases of hypersensitivity reactions such as angioedema, rash, urticaria
Hepatobiliary disorders:	Uncommon: Not known:	jaundice hepatitis, abnormal liver function
Reproductive system and breast disorders:	Uncommon:	sexual dysfunction, libido changes

Additional information on individual components: in addition to the adverse reactions listed above for the combination product, other adverse reactions previously reported with one of the individual components may be potential adverse reactions with CoAprovel. Tables 2 and 3 below detail the adverse reactions reported with the individual components of CoAprovel.

 

 

Table 2: Adverse reactions reported with the use of irbesartan alone
Blood and lymphatic system disorders:	Not known:	thrombocytopenia
General disorders and administration site conditions:	Uncommon:	chest pain
Immune system disorders:	Not known:	Anaphylactic reaction including anaphylactic shock

 

 

Table 3: Adverse reactions reported with the use of hydrochlorothiazide alone
Investigations:	Not known:	electrolyte imbalance (including hypokalaemia and hyponatraemia, see section 4.4), hyperuricaemia, glycosuria, hyperglycaemia, increases in cholesterol and triglycerides
Cardiac disorders:	Not known:	cardiac arrhythmias
Blood and lymphatic system disorders:	Not known:	aplastic anaemia, bone marrow depression, neutropenia/agranulocytosis, haemolytic anaemia, leucopenia, thrombocytopenia
Nervous system disorders:	Not known:	vertigo, paraesthesia, light-headedness, restlessness
Eye disorders:	Not known:	transient blurred vision, xanthopsia, acute myopia and secondary acute angle-closure glaucoma
Respiratory, thoracic and mediastinal disorders:	Not known:	respiratory distress (including pneumonitis and pulmonary oedema)
Gastrointestinal disorders:	Not known:	pancreatitis, anorexia, diarrhoea, constipation, gastric irritation, sialadenitis, loss of appetite
Renal and urinary disorders:	Not known:	interstitial nephritis, renal dysfunction
Skin and subcutaneous tissue disorders:	Not known:	anaphylactic reactions, toxic epidermal necrolysis, necrotizing angitis (vasculitis, cutaneous vasculitis), cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, photosensitivity reactions, rash, urticaria
Musculoskeletal and connective tissue disorders:	Not known:	weakness, muscle spasm
Vascular disorders:	Not known:	postural hypotension
General disorders and administration site conditions:	Not known:	fever
Hepatobiliary disorders:	Not known:	jaundice (intrahepatic cholestatic jaundice)
Psychiatric disorders:	Not known:	depression, sleep disturbances
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Not known:	non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).

The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may increase when titrating the hydrochlorothiazide.

Reporting of suspected adverse reactions
To report any side effect(s):
Saudi Arabia:
The National Pharmacovigilance and 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
Other GCC States:
Please contact the relevant competent authority.

No specific information is available on the treatment of overdose with Irbesartan and
Hydrochlorothiazide. The patient should be closely monitored, and the treatment should be symptomatic
and supportive. Management depends on the time since ingestion and the severity of the symptoms.

Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful
in the treatment of overdose. Serum electrolytes and creatinine should be monitored frequently. If
hypotension occurs, the patient should be placed in a supine position, with salt and volume replacements
given quickly.
The most likely manifestations of Irbesartan overdose are expected to be hypotension and tachycardia;
bradycardia might also occur.
Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia,
hypochloremia, hyponatraemia) and dehydration resulting from excessive diuresis. The most common
signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasms
and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or
certain anti-arrhythmic medicinal products.
Irbesartan is not removed by haemodialysis. The degree to which hydrochlorothiazide is removed by
haemodialysis has not been established.

Pharmacotherapeutic group: angiotensin-II antagonists, combinations
ATC code: C09DA04.
Irbesartan and Hydrochlorothiazide is a combination of an angiotensin-II receptor antagonist, Irbesartan,
and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an additive
antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Irbesartan is a potent, orally active, selective angiotensin-II receptor (AT1 subtype) antagonist. It is
expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source or
route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors
results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma aldosterone
concentration. Serum potassium levels are not significantly affected by Irbesartan alone at the
recommended doses in patients without risk of electrolyte imbalance (see sections 4.4 and 4.5). Irbesartan
does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also degrades
bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its activity.

Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive effect of thiazide diuretics
is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly
increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of
hydrochlorothiazide reduces plasma volume, increases plasma renin activity, increases aldosterone
secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum
potassium. Presumably through blockade of the renin-angiotensin-aldosterone system, co-administration
of Irbesartan tends to reverse the potassium loss associated with these diuretics. With
hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at about 4 hours, while
the action persists for approximately 6-12 hours.
The combination of hydrochlorothiazide and Irbesartan produces dose-related additive reductions in
blood pressure across their therapeutic dose ranges. The addition of 12.5 mg hydrochlorothiazide to 300
mg Irbesartan once daily in patients not adequately controlled on 300 mg Irbesartan alone resulted in
further placebo-corrected diastolic blood pressure reductions at trough (24 hours post-dosing) of 6.1 mm
Hg. The combination of 300 mg Irbesartan and 12.5 mg hydrochlorothiazide resulted in an overall
placebo-subtracted systolic/diastolic reductions of up to 13.6/11.5 mm Hg.
Limited clinical data (7 out of 22 patients) suggest that patients not controlled with the 300 mg/12.5 mg
combination may respond when uptitrated to 300 mg/25 mg. In these patients, an incremental blood
pressure lowering effect was observed for both systolic blood pressure (SBP) and diastolic blood pressure
(DBP) (13.3 and 8.3 mm Hg, respectively).
Once daily dosing with 150 mg Irbesartan and 12.5 mg hydrochlorothiazide gave systolic/diastolic mean
placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of 12.9/6.9 mm Hg in
patients with mild-to-moderate hypertension. Peak effects occurred at 3-6 hours. When assessed by
ambulatory blood pressure monitoring, the combination 150 mg Irbesartan and 12.5 mg
hydrochlorothiazide once daily produced consistent reduction in blood pressure over the 24 hours period
with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mm Hg. When measured
by ambulatory blood pressure monitoring, the trough to peak effects of Irbesartan and
Hydrochlorothiazide 150 mg/12.5 mg were 100%. The trough to peak effects measured by cuff during
office visits were 68% and 76% for Irbesartan and Hydrochlorothiazide 150 mg/12.5 mg and Irbesartan
and Hydrochlorothiazide 300 mg/12.5 mg, respectively. These 24-hour effects were observed without excessive blood pressure lowering at peak and are consistent with safe and effective blood-pressure
lowering over the once-daily dosing interval.
In patients not adequately controlled on 25 mg hydrochlorothiazide alone, the addition of Irbesartan gave
an added placebo-subtracted systolic/diastolic mean reduction of 11.1/7.2 mm Hg.
The blood pressure lowering effect of Irbesartan in combination with hydrochlorothiazide is apparent
after the first dose and substantially present within 1-2 weeks, with the maximal effect occurring by 6-8
weeks. In long-term follow-up studies, the effect of Irbesartan/hydrochlorothiazide was maintained for
over one year. Although not specifically studied with the Irbesartan and Hydrochlorothiazide, rebound
hypertension has not been seen with either Irbesartan or hydrochlorothiazide.
The effect of the combination of Irbesartan and hydrochlorothiazide on morbidity and mortality has not
been studied. Epidemiological studies have shown that long term treatment with hydrochlorothiazide
reduces the risk of cardiovascular mortality and morbidity.
There is no difference in response to Irbesartan and Hydrochlorothiazide, regardless of age or gender. As
is the case with other medicinal products that affect the renin-angiotensin system, black hypertensive
patients have notably less response to Irbesartan monotherapy. When Irbesartan is administered
concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response
in black patients approaches that of non-black patients.
Efficacy and safety of Irbesartan and Hydrochlorothiazide as initial therapy for severe hypertension
(defined as SeDBP ≥ 110 mmHg) was evaluated in a multicenter, randomized, double-blind, activecontrolled,
8-week, parallel-arm study. A total of 697 patients were randomized in a 2:1 ratio to either
Irbesartan/hydrochlorothiazide 150 mg/12.5 mg or to Irbesartan 150 mg and systematically force-titrated
(before assessing the response to the lower dose) after one week to Irbesartan/hydrochlorothiazide 300
mg/25 mg or Irbesartan 300 mg, respectively.
The study recruited 58% males. The mean age of patients was 52.5 years, 13% were ≥ 65 years of age,
and just 2% were ≥ 75 years of age. Twelve percent (12%) of patients were diabetic, 34% were
hyperlipidemic and the most frequent cardiovascular condition was stable angina pectoris in 3.5% of the
participants.
The primary objective of this study was to compare the proportion of patients whose SeDBP was
controlled (SeDBP < 90 mmHg) at Week 5 of treatment. Forty-seven percent (47.2%) of patients on the combination achieved trough SeDBP < 90 mmHg compared to 33.2% of patients on Irbesartan (p =
0.0005). The mean baseline blood pressure was approximately 172/113 mmHg in each treatment group
and decreases of SeSBP/SeDBP at five weeks were 30.8/24.0 mmHg and 21.1/19.3 mmHg for
Irbesartan/hydrochlorothiazide and Irbesartan, respectively (p < 0.0001).
The types and incidences of adverse events reported for patients treated with the combination were
similar to the adverse event profile for patients on monotherapy. During the 8-week treatment period,
there were no reported cases of syncope in either treatment group. There were 0.6% and 0% of patients
with hypotension and 2.8% and 3.1% of patients with dizziness as adverse reactions reported in the
combination and monotherapy groups, respectively.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination
with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in
Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor
blocker. ONTARGET was a study conducted in patients with a history of cardiovascular or
cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA
NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and
mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared
to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also
relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in
patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was
a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an
angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease,
cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse
outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group
than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the
placebo group.

Concomitant administration of hydrochlorothiazide and Irbesartan has no effect on the pharmacokinetics
of either medicinal product.
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for their
activity. Following oral administration of Irbesartan and Hydrochlorothiazide, the absolute oral
bioavailability is 60-80% and 50-80% for Irbesartan and hydrochlorothiazide, respectively. Food does
not affect the bioavailability of Irbesartan and Hydrochlorothiazide. Peak plasma concentration occurs at
1.5-2 hours after oral administration for Irbesartan and 1-2.5 hours for hydrochlorothiazide.
Plasma protein binding of Irbesartan is approximately 96%, with negligible binding to cellular blood
components. The volume of distribution for Irbesartan is 53-93 litres. Hydrochlorothiazide is 68%
protein-bound in the plasma, and its apparent volume of distribution is 0.83-1.14 l/kg.
Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. A
less than proportional increase in oral absorption at doses beyond 600 mg was observed; the mechanism
for this is unknown. The total body and renal clearance are 157-176 and 3.0-3.5 ml/min, respectively.
The terminal elimination half-life of Irbesartan is 11-15 hours. Steady-state plasma concentrations are
attained within 3 days after initiation of a once-daily dosing regimen. Limited accumulation of Irbesartan
(< 20%) is observed in plasma upon repeated once-daily dosing. In a study, somewhat higher plasma
concentrations of Irbesartan were observed in female hypertensive patients. However, there was no
difference in the half-life and accumulation of Irbesartan. No dosage adjustment is necessary in female
patients. Irbesartan AUC and Cmax values were also somewhat greater in older subjects (≥ 65 years) than
those of young subjects (18-40 years). However the terminal half-life was not significantly altered. No
dosage adjustment is necessary in older people. The mean plasma half-life of hydrochlorothiazide
reportedly ranges from 5-15 hours.
Following oral or intravenous administration of 14C Irbesartan, 80-85% of the circulating plasma
radioactivity is attributable to unchanged Irbesartan. Irbesartan is metabolised by the liver via
glucuronide conjugation and oxidation. The major circulating metabolite is Irbesartan glucuronide
(approximately 6%). In vitro studies indicate that Irbesartan is primarily oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. Irbesartan and its metabolites are
eliminated by both biliary and renal pathways. After either oral or intravenous administration of 14C
Irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the faeces. Less
than 2% of the dose is excreted in the urine as unchanged Irbesartan. Hydrochlorothiazide is not
metabolized but is eliminated rapidly by the kidneys. At least 61% of the oral dose is eliminated
unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier,
and is excreted in breast milk.
Renal impairment: in patients with renal impairment or those undergoing haemodialysis, the
pharmacokinetic parameters of Irbesartan are not significantly altered. Irbesartan is not removed by
haemodialysis. In patients with creatinine clearance < 20 ml/min, the elimination half-life of
hydrochlorothiazide was reported to increase to 21 hours.
Hepatic impairment: in patients with mild to moderate cirrhosis, the pharmacokinetic parameters of
Irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic
impairment.

Irbesartan/hydrochlorothiazide: the potential toxicity of the Irbesartan/hydrochlorothiazide combination
after oral administration was evaluated in rats and macaques in studies lasting up to 6 months. There
were no toxicological findings observed of relevance to human therapeutic use.
The following changes, observed in rats and macaques receiving the Irbesartan/hydrochlorothiazide
combination at 10/10 and 90/90 mg/kg/day, were also seen with one of the two medicinal products alone
and/or were secondary to decreases in blood pressure (no significant toxicologic interactions were
observed):
• kidney changes, characterized by slight increases in serum urea and creatinine, and
hyperplasia/hypertrophy of the juxtaglomerular apparatus, which are a direct consequence of the
interaction of Irbesartan with the renin-angiotensin system;
• slight decreases in erythrocyte parameters (erythrocytes, haemoglobin, haematocrit);
• stomach discoloration, ulcers and focal necrosis of gastric mucosa were observed in few rats in a 6
months toxicity study at Irbesartan 90 mg/kg/day, hydrochlorothiazide 90 mg/kg/day, and
Irbesartan/hydrochlorothiazide 10/10 mg/kg/day. These lesions were not observed in macaques;

• decreases in serum potassium due to hydrochlorothiazide and partly prevented when
hydrochlorothiazide was given in combination with Irbesartan.
Most of the above mentioned effects appear to be due to the pharmacological activity of Irbesartan
(blockade of angiotensin-II-induced inhibition of renin release, with stimulation of the renin-producing
cells) and occur also with angiotensin converting enzyme inhibitors. These findings appear to have no
relevance to the use of therapeutic doses of Irbesartan/hydrochlorothiazide in humans.
No teratogenic effects were seen in rats given Irbesartan and hydrochlorothiazide in combination at doses
that produced maternal toxicity. The effects of the Irbesartan/hydrochlorothiazide combination on fertility
have not been evaluated in animal studies, as there is no evidence of adverse effect on fertility in animals
or humans with either Irbesartan or hydrochlorothiazide when administered alone. However, another
angiotensin-II antagonist affected fertility parameters in animal studies when given alone. These findings
were also observed with lower doses of this other angiotensin-II antagonist when given in combination
with hydrochlorothiazide.
There was no evidence of mutagenicity or clastogenicity with the Irbesartan/hydrochlorothiazide
combination. The carcinogenic potential of Irbesartan and hydrochlorothiazide in combination has not
been evaluated in animal studies.
Irbesartan: there was no evidence of abnormal systemic or target organ toxicity at clinically relevant
doses. In non-clinical safety studies, high doses of Irbesartan (≥ 250 mg/kg/day in rats and ≥ 100
mg/kg/day in macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin,
haematocrit). At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidneys (such as
interstitial nephritis, tubular distention, basophilic tubules, increased plasma concentrations of urea and
creatinine) were induced by Irbesartan in the rat and the macaque and are considered secondary to the
hypotensive effects of the medicinal product which led to decreased renal perfusion. Furthermore,
Irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥ 90 mg/kg/day, in
macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused by the pharmacological
action of Irbesartan. For therapeutic doses of Irbesartan in humans, the hyperplasia/hypertrophy of the
renal juxtaglomerular cells does not appear to have any relevance.
There was no evidence of mutagenicity, clastogenicity or carcinogenicity.

Fertility and reproductive performance were not affected in studies of male and female rats even at oral
doses of Irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including mortality at the
highest dose. No significant effects on the number of corpora lutea, implants, or live fetuses were
observed. Irbesartan did not affect survival, development, or reproduction of offspring. Studies in animals
indicate that the radiolabeled Irbesartan is detected in rat and rabbit fetuses. Irbesartan is excreted in the
milk of lactating rats.
Animal studies with Irbesartan showed transient toxic effects (increased renal pelvic cavitation,
hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, abortion
or early resorption was noted at doses causing significant maternal toxicity, including mortality. No
teratogenic effects were observed in the rat or rabbit.
Hydrochlorothiazide: although equivocal evidence for a genotoxic or carcinogenic effect was found in
some experimental models, the extensive human experience with hydrochlorothiazide has failed to show
an association between its use and an increase in neoplasms.

Core:
 Lactose Monohydrate
 Microcrystalline Cellulose PH 101
 Pregelatinized Starch – 1500
 Croscarmellose Sodium
 Purified Water
 Microcrystalline Cellulose PH 102
 Magnesium Stearate
Coating:
 Opadry II 32F265003 Pink which is consists of HPMC 2910/Hypromellose ,Lactose
Monohydrate, Titanium Dioxide, Macrogol/Polyethylene glycol (PEG), Iron Oxide Red and
Ferrosoferric Oxide)

Not applicable

2 Years

• Do not store above 30°C.
• Store in the original package in order to protect from moisture.

Arena Plus 300/25 mg Film Coated is packed in Aluminium foil and Opaque PVC /PVDC, Blister
pack of 3x10’s.
Not all pack sizes may be marketed.

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