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

Irovel Plus 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:

• Irovel Plus 150 mg/12.5 mg may be administered in patients whose blood pressure is not adequately

controlled with hydrochlorothiazide or irbesartan 150 mg alone;

• Irovel Plus 300 mg/12.5 mg may be administered in patients insufficiently controlled by irbesartan 300

mg or by Irovel Plus 150 mg/12.5 mg.

• Irovel Plus 300 mg/25 mg may be administered in patients insufficiently controlled by Irovel Plus 300

mg/12.5 mg.

Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended.

When necessary, Irovel Plus may be administered with another antihypertensive medicinal product (see

section 4.5).

Special Populations

Renal impairment: due to the hydrochlorothiazide component, Irovel Plus 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: Irovel Plus 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 Irovel Plus

is necessary in patients with mild to moderate hepatic impairment (see section 4.3).

Older people: no dosage adjustment of Irovel Plus is necessary in older people.

Paediatric population: Irovel Plus 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 • Co-administration of Irovel Plus with aliskiren-containing medicines in patients with diabetes or with moderate to severe renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m²) (see sections 4.4 and 4.5).

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 Irovel plus.
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 Irovel plus, a 
similar effect should be anticipated.
Renal impairment and kidney transplantation: 
When Irovel plus 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. Irovel plus should not be 
used in patients with severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.3). Thiazide diuretic-associated azotaemia 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 Irovel plus is not recommended.
Metabolic and endocrine effects: 
thiazide therapy may impair glucose tolerance. Latent diabetes mellitus may become manifest during thiazide 
therapy. Irbesartan may induce hypoglycaemia, particularly in diabetic patients. In patients treated with insulin 
or antidiabetics an appropriate blood glucose monitoring should be considered; a dose adjustment of insulin or 
antidiabetics may be required when indicated (see section 4.5).
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 Irovel plus 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 Irovel plus (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 Irovel plus is not recommended (see section 4.5).
Anti-doping test: 
hydrochlorothiazide contained in this medicinal product could produce a positive analytic result in an antidoping test.

General: 
in patients whose vascular tone and renal function depend predominantly on the activity of the reninangiotensin-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, azotaemia, 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).
Choroidal effusion, Acute Myopia and Secondary Acute Angle-Closure Glaucoma: 
sulfonamide drugs or sulfonamide derivative drugs can cause an idiosyncratic reaction, resulting in choroidal 
effusion with visual field defect, 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 angle-closure glaucoma may include a history of sulfonamide or penicillin 
allergy (see section 4.8).
Excipients:
Irovel plus film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, 
total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Irovel plus film-coated tablets contain sodium. This medicine contains less than 1 mmol sodium (23 mg) per 
tablet, that is to say essentially ‘sodium-free’.

Non-melanoma skin cancer
An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell 
carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been 
observed in two epidemiological studies based on the Danish National Cancer Registry.
Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC. Patients taking HCTZ should 
be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly 
report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV 
rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the 
risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological 
examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have 
experienced previous NMSC (see also section 4.8).

Acute Respiratory Toxicity
Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS) 
have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to 
hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary 
deterioration and hypotension. If diagnosis of ARDS is suspected, irbesartan and hydrochlorothiazide should 
be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered to patients 
who previously experienced ARDS following hydrochlorothiazide intake

Other antihypertensive agents: the antihypertensive effect of Irovel Plus 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: the combination of Irovel Plus with aliskiren-containing medicinal

products is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment

(GFR <60 ml/min/1.73 mÇ) and is not recommended in other patients.

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 Irovel Plus. Therefore, the

combination of lithium and Irovel Plus 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 Irovel Plus 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 coadministration

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. Irovel Plus 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

digitalis-induced 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

thiazide-type 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:

Pregnancy category D

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).

Hydrochlorothiazide (HCTZ)-irbesartan has been assigned to pregnancy category D by the FDA.

Animal data have revealed evidence of fetotoxicity associated with the use of irbesartan (renal pelvic

cavitation, hydroureter and/or absence of renal papilla) after doses equivalent to maximum

recommended human doses (MRHD) and maternal mortality and abortion after doses equivalent to 1.5

times the MRHD after correction for body surface area. Surviving females receiving 1.5 times the

MRHD were observed to have an increased incidence of early fetal resorptions and a corresponding

decrease in live births. There are no controlled data in human pregnancy. The manufacturer states that

when used in pregnancy during the second and third trimesters, drugs that act directly on the reninangiotensin

system can cause injury and even death to the developing fetus.

Retrospective reviews have shown an increased risk of malformations associated with thiazide

diuretics. Use of HCTZ-irbesartan is considered contraindicated during pregnancy.

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 Irovel Plus 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 Irovel Plus during breast-feeding, Irovel Plus

is not recommended and alternative treatments with better established safety profiles during breastfeeding

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 Irovel Plus during breast feeding is not

recommended. If Irovel Plus 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, Irovel Plus 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 Irovel Plus. Tables 2 and 3 below detail the adverse reactions reported with the individual components of Irovel Plus.

Table 2: Adverse reactions reported with the use of irbesartan alone
General disorders and administration site conditions:	Uncommon:	chest pain
Respiratory, thoracic and mediastinal disorders:	Uncommon:	dyspnea

 

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, choroidal effusion
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

The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may

increase when titrating the hydrochlorothiazide.

Description of selected adverse reactions
Choroidal effusion
Cases of choroidal effusion with visual field defect have been reported after the use of thiazide and thiazide-like
diuretics. If cases are to be reported for these substances in the future, the appropriate procedure should be used 
to update the product information accordingly.

Please report adverse drug events to:
• Saudi Arabia
The National Pharmacovigilance Center (NPC):
Fax: +966-11-205-7662
SFDA Call Center: 19999
E-mail: npc.drug@sfda.gov.sa
Website: https://ade.sfda.gov.sa
• Other GCC States:
Please contact the relevant competent authority.

No specific information is available on the treatment of overdose with Irovel Plus. 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.

Irovel Plus 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 Irovel Plus 150

mg/12.5 mg were 100%. The trough to peak effects measured by cuff during office visits were 68% and

76% for Irovel Plus 150 mg/12.5 mg and Irovel Plus 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 Irovel Plus, 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 Irovel Plus, 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 Irovel Plus as initial therapy for severe hypertension (defined as SeDBP ≥ 110

mmHg) was evaluated in a multicenter, randomized, double-blind, active-controlled, 8-week, parallelarm

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 forcetitrated (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.

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 Irovel Plus, the absolute oral bioavailability is 60-80%

and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect the

bioavailability of Irovel Plus. 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.

LLactose Monohydrate 
Colloidal Silicon Dioxide 
Microcrystalline Cellulose
Croscarmellose Sodium
Hypromellose 6 cps
Magnesium stearate
Opadry OY 7300
Ferric Oxide Red 
Ferric Oxide Yellow
Simethicone Emulsion

Not applicable.

3 years.

Store below 30°C.

Three white PVC /PVDC aluminum foil blisters each blister contains 10 tablets packed in carton with

folded leaflet.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.