4.1 Therapeutic indications
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
CO-RIBEX 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:

CO-RIBEX 150 mg/12.5 mg may be administered in patients whose blood pressure is not
adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone;

CO-RIBEX 300 mg/12.5 mg may be administered in patients insufficiently controlled by
irbesartan 300 mg or by CO-RIBEX 150 mg/12.5 mg.

CO-RIBEX 300 mg/25 mg may be administered in patients insufficiently controlled by CORIBEX
300 mg/12.5 mg.

Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended.
When necessary, CO-RIBEX may be administered with another antihypertensive medicinal
product(see sections 4.3, 4.4, 4.5 and 5.1).
Special Populations
Renal impairment: due to the hydrochlorothiazide component, CO-RIBEX 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
impairmen twhose renal creatinine clearance is ≥30 ml/min (see sections 4.3 and 4.4).
Hepatic impairment: CO-RIBEX 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 CO-RIBEX is necessary in patients with mild to moderate hepatic impairment (see
section 4.3).
Older people: no dosage adjustment of CO-RIBEX is necessary in older people.

Paediatric population: CO-RIBEX 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.

Hypotension - Volume-depleted patients: CO-RIBEX 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 CO-RIBEX.
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 CO-RIBEX, a similar effect should be
anticipated.
Renal impairment and kidney transplantation: when CO-RIBEX is used in patients with impaired
renalfunction, a periodic monitoring of potassium, creatinine and uric acid serum levels is
recommended. There is no experience regarding the administration of CO-RIBEX in patients with a
recent kidney transplantation. CO-RIBEX should not be used in patients with severe renal
impairment (creatinine clearance < 30 ml/min) (see section 4.3). Thiazide diuretic-associated
azotemia may occur in patients with impaired renal function. No dosage adjustment is necessary in
patients with renal impairment whose creatinine clearance is ≥30 ml/min. However, in patients with
mild to moderate renal impairment (creatinine clearance ≥ 30 ml/min but < 60 ml/min) this fixed
dose combination should be administered with caution.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS):
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers oral
iskiren 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,
angiotensinII receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).
If dualblockade 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 CO-RIBEX 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 CO-RIBEX is not recommended.

Metabolic and endocrine effects: thiazide therapy may impair glucose tolerance. In diabetic
patientsdosage adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes
mellitusmay 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 CO-RIBEX, minimal or no effects were reported.
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving
thiazidetherapy.

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).

Electrolyte imbalance: as for any patient receiving diuretic therapy, periodic determination of
serumelectrolytes 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 aredryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or
cramps,muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such
as nauseaor vomiting.
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy
withirbesartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in
patientswith cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are
receivinginadequate oral intake of electrolytes and in patients receiving concomitant therapy
withcorticosteroids or ACTH. Conversely, due to the irbesartan component of CORIBEXhyperkalaemiamight
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-sparingdiuretics, potassium supplements or potassium-containing salts
substitutes should be co-administeredcautiously with CO-RIBEX (see section 4.5).
There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatraemia.
Chloridedeficit is generally mild and usually does not require treatment.
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation
ofserum calcium in the absence of known disorders of calcium metabolism. Marked
hypercalcaemiamay be evidence of hidden hyperparathyroidism. Thiazides should be discontinued
before carrying outtests for parathyroid function.
Thiazides have been shown to increase the urinary excretion of magnesium, which may result
inhypomagnaesemia.

Lithium: the combination of lithium and CO-RIBEX is not recommended (see section 4.5).
Anti-doping test: hydrochlorothiazide contained in this medicinal product could produce a
positiveanalytic result in an anti-doping test.

General: in patients whose vascular tone and renal function depend predominantly on the activity
ofthe renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure
orunderlying renal disease, including renal artery stenosis), treatment with angiotensin
convertingenzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been
associatedwith acute hypotension, azotemia, oliguria, or rarely acute renal failure (see section 4.5).
As with anyantihypertensive agent, excessive blood pressure decrease in patients with ischemic
cardiopathy orischemic cardiovascular disease could result in a myocardial infarction or stroke.
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history
ofallergy 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
thiazidediuretics.
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8).
Ifphotosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a
readministrationof the diuretic is deemed necessary, it is recommended to protect exposed areas to
thesun 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 bechanged to alternative antihypertensive treatments which have an established safety
profile for use inpregnancy. 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
galactoseintolerance, the Lapp lactase deficiency or glucose-galactosemalabsorption should not take
thismedicinal product.
Acute Myopia and Secondary Acute Angle-Closure Glaucoma: sulfonamide drugs or
sulfonamidederivative drugs can cause an idiosyncratic reaction, resulting in transient myopia and
acute angleclosureglaucoma. While hydrochlorothiazide is a sulfonamide, only isolated cases of
acute angleclosureglaucoma have been reported so far with hydrochlorothiazide. Symptoms include
acute onsetof 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 todiscontinue drug intake as rapidly as possible. Prompt medical or surgical
treatments may need to beconsidered if the intraocular pressure remains uncontrolled. Risk factors
for developing acute angleclosureglaucoma may include a history of sulfonamide or penicillin
allergy (see section 4.8).

Other antihypertensive agents: the antihypertensive effect of CO-RIBEX may be increased with
theconcomitant use of other antihypertensive agents. Irbesartan and hydrochlorothiazide (at doses
up to300 mg irbesartan/25 mg hydrochlorothiazide) have been safely administered with
otherantihypertensive agents including calcium channel blockers and beta-adrenergic blockers.
Priortreatment with high dose diuretics may result in volume depletion and a risk of hypotension
wheninitiating therapy with irbesartan with or without thiazide diuretics unless the volume
depletion iscorrected first (see section 4.4).
Aliskiren-containing products or ACE-inhibitors:
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone system
(RAAS)through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is
associatedwith a higher frequency of adverse events such as hypotension, hyperkalaemia and

decreased renalfunction (including acute renal failure) compared to the use of a single RAAS-acting
agent (seesections 4.3, 4.4 and 5.1).
Lithium: reversible increases in serum lithium concentrations and toxicity have been reported
duringconcomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar
effectshave been very rarely reported with irbesartan so far. Furthermore, renal clearance of lithium
isreduced by thiazides so the risk of lithium toxicity could be increased with CO-RIBEX. Therefore,
thecombination of lithium and CO-RIBEX is not recommended (see section 4.4). If the
combinationproves necessary, careful monitoring of serum lithium levels is recommended.
Medicinal products affecting potassium: the potassium-depleting effect of hydrochlorothiazide
isattenuated by the potassium-sparing effect of irbesartan. However, this effect of
hydrochlorothiazideon serum potassium would be expected to be potentiated by other medicinal
products associated withpotassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives,
amphotericin,carbenoxolone, penicillin G sodium). Conversely, based on the experience with the
use of othermedicinal products that blunt the renin-angiotensin system, concomitant use of
potassium-sparingdiuretics, potassium supplements, salt substitutes containing potassium or other
medicinal productsthat may increase serum potassium levels (e.g. heparin sodium) may lead to
increases in serumpotassium. Adequate monitoring of serum potassium in patients at risk is
recommended (seesection 4.4).

Medicinal products affected by serum potassium disturbances: periodic monitoring of
serumpotassium is recommended when CO-RIBEX is administered with medicinal products
affected byserum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).

Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are
administeredsimultaneously 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 effectmay occur.
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to
anincreased risk of worsening of renal function, including possible acute renal failure, and an
increase inserum potassium, especially in patients with poor pre-existing renal function. The
combination shouldbe administered with caution, especially in the elderly. Patients should be
adequately hydrated andconsideration should be given to monitoring renal function after initiation
of concomitant therapy, andperiodically thereafter.
Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of
irbesartanis not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and
to a lesserextent by glucuronidation. No significant pharmacokinetic or pharmacodynamic
interactions wereobserved when irbesartan was coadministered with warfarin, a medicinal product
metabolised byCYP2C9. The effects of CYP2C9 inducers such as rifampicin on the
pharmacokinetic of irbesartanhave not been evaluated. The pharmacokinetic of digoxin was not
altered by co-administration ofirbesartan.
Additional information on hydrochlorothiazide interactions: when administered concurrently,
thefollowing 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
antidiabeticmedicinal product may be required (see section 4.4);

Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is impaired in the presence
ofanionic exchange resins. CO-RIBEX should be taken at least one hour before or four hours after
thesemedications;
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be increased;
Digitalis glycosides: thiazide induced hypokalaemia or hypomagnaesemiafavour the onset
ofdigitalis-induced cardiac arrhythmias (see section 4.4);
Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory
drugmay 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:
Angiotensin II Receptor Antagonists (AIIRAs):
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4).
The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see
sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE
inhibitorsduring the first trimester of pregnancy has not been conclusive; however a small increase
in riskcannot be excluded. Whilst there is no controlled epidemiological data on the risk with

Angiotensin IIReceptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless
continuedAIIRA therapy is considered essential, patients planning pregnancy should be changed to
alternativeantihypertensive treatments which have an established safety profile for use in
pregnancy. Whenpregnancy 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
humanfetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and
neonataltoxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound
checkof renal function and skull is recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (seesections
4.3 and 4.4).

Hydrochlorothiazide:
There is limited experience with hydrochlorothiazide during pregnancy, especially during the
firsttrimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on
thepharmacological mechanism of action of hydrochlorothiazide its use during the second and
thirdtrimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects
likeicterus, disturbance of electrolyte balance and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension
orpreeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without
abeneficial effect on the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in
raresituations where no other treatment could be used.
Since CO-RIBEX contains hydrochlorothiazide, it is not recommended during the first trimester
ofpregnancy. A switch to a suitable alternative treatment should be carried out in advance of a
plannedpregnancy.
Breast-feeding:

Angiotensin II Receptor Antagonists (AIIRAs):
Because no information is available regarding the use of CO-RIBEX during breast-feeding, CO
RIBEXis not recommended and alternative treatments with better established safety profiles during
breastfeedingare 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
itsmetabolites in milk (for details see 5.3).
Hydrochlorothiazide:
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses
causingintense diuresis can inhibit the milk production. The use of CO-RIBEX during breast
feeding is notrecommended. If CO-RIBEX 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
inducingthe 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
itspharmacodynamic properties, CO-RIBEX is unlikely to affect this ability. When driving vehicles
oroperating machines, it should be taken into account that occasionally dizziness or weariness may
occurduring treatment of hypertension.

Irbesartan/hydrochlorothiazide combination:
Among 898 hypertensive patients who received various doses ofirbesartan/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
Cardiacdisorders: Uncommon: syncope, hypotension, tachycardia, oedema
Nervous system disorders: Common: dizziness
Uncommon: orthostaticdizziness
Not known: headache
Ear and labyrinthdisorders: Not known: tinnitus
Respiratory, thoracic and
mediastinal disorders:
Not known: cough
Gastrointestinaldisorders: Common: nausea/vomiting
Uncommon: diarrhoea
Not known: dyspepsia, dysgeusia
Renal and urinarydisorders: Common: abnormal urination
Not known: impaired renal function including isolated
casesof renal failure in patients at risk (see
section 4.4)
Musculoskeletal and connective
tissue disorders:
Uncommon:
Not known:
swellingextremity
arthralgia, myalgia
Metabolism and nutrition
disorders:
Not known: hyperkalaemia
Vasculardisorders: Uncommon: flushing
General disorders and Common: fatigue

administration site conditions:
Immune system disorders: Not known: cases of hypersensitivity reactions such as
angioedema, rash, urticaria
Hepatobiliarydisorders: Uncommon: jaundice
Not known: hepatitis, abnormalliverfunction
Reproductive system and breast
disorders:
Uncommon: sexualdysfunction, libido changes

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

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

Table 3: Adverse reactions reported with the use of hydrochlorothiazide alone
Investigations: Not known: electrolyte imbalance (including
hypokalaemiaand hyponatraemia, see section
4.4),hyperuricaemia, glycosuria,
hyperglycaemia,increases in cholesterol and
triglycerides
Cardiacdisorders: Not known: cardiacarrhythmias
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
Eyedisorders: Not known: transient blurred vision, xanthopsia, acute
myopia and secondary acute angle-closure
glaucoma
Respiratory, thoracic and
mediastinal disorders:
Not known: respiratory distress (including pneumonitis
andpulmonary oedema)
Gastrointestinaldisorders: Not known: pancreatitis, anorexia, diarrhoea, constipation,
gastric irritation, sialadenitis, loss of appetite
Renal and urinarydisorders: Not known: interstitialnephritis, renaldysfunction
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,
photosensitivityreactions, rash, urticaria
Musculoskeletal and connective
tissue disorders:
Not known: weakness, muscle spasm
Vasculardisorders: Not known: postural hypotension

General disorders and
administration site conditions:
Not known: fever
Hepatobiliarydisorders: Not known: jaundice (intrahepaticcholestaticjaundice)
Psychiatricdisorders: Not known: depression, sleepdisturbances
Neoplasms benign, malignant
and unspecified (incl cysts and
polyps)
Not known melanoma skin cancer (Basal cell carcinoma
and Squamous cell carcinoma)
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances)
may increase when titrating the hydrochlorothiazide.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via the national reporting system
listed.

Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
o Toll free phone: 8002490000
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc

No specific information is available on the treatment of overdose with CO-RIBEX. 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.

CO-RIBEX 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 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 CO-RIBEX
150 mg/12.5 mg were 100%. The trough to peak effects measured by cuff during office visits were
68% and 76% for CO-RIBEX 150 mg/12.5 mg and CO-RIBEX 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
irbesartangave 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 CO-RIBEX, 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 CO-RIBEX, 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 irbesartanmonotherapy. 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 CO-RIBEX 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 troughSeDBP< 90 mmHg compared to 33.2% of patients on irbesartan(p
= 0.0005). The mean baseline blood pressure was approximately 172/113 mmHg in each treatment
group and decreases of SeSBP/SeDBP at five weeks were 30.8/24.0 mmHg and 21.1/19.3 mmHg
for irbesartan/hydrochlorothiazide and irbesartan, respectively (p < 0.0001).
The types and incidences of adverse events reported for patients treated with the combination were
similar to the adverse event profile for patients on monotherapy. During the 8-week treatment
period, there were no reported cases of syncope in either treatment group. There were 0.6% and 0%
of patients with hypotension and 2.8% and 3.1% of patients with dizziness as adverse reactions
reported in the combination and monotherapy groups, respectively.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Two large randomised, controlled trials (ONTARGET (ONgoingTelmisartan Alone and in
combination with Ramipril Global Endpoint Trial) andVA NEPHRON-D (The Veterans Affairs
Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an
angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of
cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of
end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and
diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes
and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as

compared to monotherapy was observed. Given their similar pharmacodynamic properties, these
results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in
patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease
Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an
ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and
chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of
an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more
frequent in the aliskiren group than in the placebo group and adverse events and serious adverse
events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently
reported in the aliskirengroup than in the placebo group.
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 association between lip cancer (SCC) and exposure to HCTZ: 633 cases of lipcancer
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
thepharmacokinetics of either medicinal product.
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for
their activity. Following oral administration of CO-RIBEX, the absolute oral bioavailability is 60-
80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect the
bioavailability of CO-RIBEX. 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. Irbesartanis metabolised by the liver via
glucuronide conjugation and oxidation. The major circulating metabolite is
irbesartanglucuronide(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 theirbesartan/hydrochlorothiazide
combination after oral administration was evaluated in rats and macaques in studies lasting up to6
months. There were no toxicological findings observed of relevance to human therapeutic use.
The following changes, observed in rats and macaques receiving the
irbesartan/hydrochlorothiazidecombination 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,
andhyperplasia/hypertrophy of the juxtaglomerular apparatus, which are a direct consequence of
theinteraction 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 ina
6 months toxicity study at irbesartan 90 mg/kg/day, hydrochlorothiazide 90 mg/kg/day,
andirbesartan/hydrochlorothiazide 10/10 mg/kg/day. These lesions were not observed in
macaques;

decreases in serum potassium due to hydrochlorothiazide and partly prevented
whenhydrochlorothiazide 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 theirbesartan/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.

Tablet core:
Microcrystalline cellulose
Starch pregelatinised
Lactose monohydrate
Poloxamer 188
Croscarmellose sodium
Magnesium Stearate

Film-coating:
Opadry pink 03A34089
consisting of:
Hypromellose 6cP
Titanium dioxide
Purified stearic acid
Microcrystalline cellulose
Iron oxide yellow
Iron oxide red

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 in PVC/PE/PVDC/Aluminium blisters.
Cartons of 28 film-coated tablets in PVC/PE/PVDC/Aluminium blisters.

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