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).

CoIrbetel 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:

• CoIrbetel 150 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone;
• CoIrbetel 300 mg/12.5 mg may be administered in patients insufficiently controlled by irbesartan 300 mg or by CoIrbetel 150 mg/12.5 mg.
• CoIrbetel 300 mg/25 mg may be administered in patients insufficiently controlled by CoIrbetel 300 mg/12.5 mg.

Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended.
When necessary, CoIrbetel may be administered with another antihypertensive medicinal product
(see section 4.5).

Renal impairment: due to the hydrochlorothiazide component, CoIrbetel 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: CoIrbetel 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
CoIrbetel is necessary in patients with mild to moderate hepatic impairment (see section 4.3).
Elderly patients: no dosage adjustment of CoIrbetel is necessary in elderly patients.
Paediatric patients: CoIrbetel is not recommended for use in children and adolescents due to a lack
of data on safety and efficacy.

Hypotension - Volume-depleted patients: CoIrbetel 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 CoIrbetel.

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 CoIrbetel, a similar effect
should be anticipated

Renal impairment and kidney transplantation: when CoIrbetel 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 CoIrbetel in patients with a recent kidney
transplantation. CoIrbetel 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.

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 CoIrbetel 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 CoIrbetel 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 CoIrbetel, 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 CoIrbetel 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. Potassiumsparing
diuretics, potassium supplements or potassium-containing salts substitutes should be coadministered
cautiously with CoIrbetel (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 CoIrbetel 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. 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.

Choroidal effusion, acute myopia and secondary angle-closure glaucoma:
Sulfonamide or sulfonamide derivative drugs can cause an idiosyncratic reaction resulting in
choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma.
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.

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).

Other antihypertensive agents: the antihypertensive effect of CoIrbetel 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).

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 CoIrbetel.
Therefore, the combination of lithium and CoIrbetel 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 CoIrbetel 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. CoIrbetel 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;

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.

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;

Pregnancy:
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).

Pregnancy category D
Thiazides cross the placental barrier and appear in cord blood. They may cause a decrease in
placental perfusion, foetal electrolyte disturbances and possibly other reactions that have occurred
in the adults. Cases of neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported
with maternal thiazide therapy. Since CoIrbetel 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. with the following:

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 CoIrbetel 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.

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).

Thiazides cross the placental barrier and appear in cord blood. They may cause a decrease in
placental perfusion, foetal electrolyte disturbances and possibly other reactions that have occurred
in the adults. Cases of neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported
with maternal thiazide therapy. Since CoIrbetel 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.

Lactation:
Because no information is available regarding the use of CoIrbetel during breast-feeding, CoIrbetel
is not recommended and alternative treatments with better established safety profiles during breastfeeding
are preferable, especially while nursing a newborn or preterm infant.

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 CoIrbetel during breast feeding is not
recommended. If CoIrbetel 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, CoIrbetel 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.

* Frequency for adverse reactions detected by spontaneous reports is described as “not known”

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 CoIrbetel. Tables 2 and 3 below

detail the adverse reactions reported with the individual components of CoIrbetel.

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

may increase when titrating the hydrochlorothiazide.

Description of selected adverse reactions

• 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.

• 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).

To report any side effect(s):

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

rbesartan 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 reninangiotensin-
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 postdosing)
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 CoIrbetel
150 mg/12.5 mg were 100%. The trough to peak effects measured by cuff during office visits were
68% and 76% for CoIrbetel 150 mg/12.5 mg and CoIrbetel 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 CoIrbetel, 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 CoIrbetel, 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 CoIrbetel as initial therapy for severe hypertension (defined as SeDBP ≥ 110
mmHg) was evaluated in a multicenter, randomized, double-blind, active-controlled, 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 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.
Non-melanoma skin cancer
Based on available data from epidemiological studies, cumulative dose-dependent association
between HCTZ and NMSC has been observed. One study included a population comprised of
71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population
controls, respectively. High HCTZ use (≥50,000 mg cumulative) was associated with an adjusted
OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative
dose response relationship was observed for both BCC and SCC. Another study showed a possible

massociation between lip cancer (SCC) and exposure to HCTZ: 633 cases of lip-cancer were matched
with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response
relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-
4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000
mg) (see also section 4.4).

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 CoIrbetel, the absolute oral bioavailability is 60-80%
and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect the
bioavailability of CoIrbetel. 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 elderly 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
elderly patients. 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 reninproducing
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.
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.

Tablet core:
Lactose monohydrate
Microcrystalline cellulose
Croscarmellose sodium
Hypromellose
Silicon dioxide
Magnesium stearate
Film-coating:
Lactose monohydrate
Hypromellose Titanium
dioxide Macrogol 3000
Red and yellow ferric oxides
Carnauba wax

Not applicable.

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

Cartons of 14 film-coated tablets; 1 blister card of 14 film-coated tablets in
PVC/PVDC/Aluminium blisters.
Cartons of 28 film-coated tablets; 2 blister cards of 14 film-coated tablets in
PVC/PVDC/Aluminium blisters.
Cartons of 30 film-coated tablets; 2 blister cards of 15 film-coated tablets in
PVC/PVDC/Aluminium blisters.
Cartons of 56 film-coated tablets; 4 blister cards of 14 film-coated tablets in
PVC/PVDC/Aluminium blisters.
Cartons of 84 film-coated tablets; 6 blister cards of 14 film-coated tablets in
PVC/PVDC/Aluminium blisters.
Cartons of 90 film-coated tablets; 6 blister cards of 15 film-coated tablets in
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Cartons of 98 film-coated tablets; 7 blister cards of 14 film-coated tablets in
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Cartons of 56 x 1 film-coated tablets; 7 blister cards of 8 x 1 film-coated tablets each in
PVC/PVDC/Aluminium perforated unit dose blisters.
Not all pack sizes may be marketed.

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