Irbesartan Hydrochlorothiazide Zentiva

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 150 mg of irbesartan and 12.5 mg of hydrochlorothiazide. 
 
Excipient with known effect: 
Each tablet contains 26.65 mg of lactose (as lactose monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Tablet. 
Peach, biconvex, oval-shaped, with a heart debossed on one side and the number 2775 engraved on the 
other side. 
 
 
4. CLINICAL PARTICULARS 
 
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). 
 
4.2 Posology and method of administration 
 
Posology 
 
Irbesartan Hydrochlorothiazide Zentiva can be taken once daily, with or without food.  
Dose titration with the individual components (i.e. irbesartan and hydrochlorothiazide) may be 
recommended. 
 
When clinically appropriate direct change from monotherapy to the fixed combinations may be 
considered: 
• Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg may be administered in patients whose 

blood pressure is not adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone; 
• Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg may be administered in patients 

insufficiently controlled by irbesartan 300 mg or by Irbesartan Hydrochlorothiazide 
Zentiva 150 mg/12.5 mg. 

• Irbesartan Hydrochlorothiazide Zentiva 300 mg/25 mg may be administered in patients 
insufficiently controlled by Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg. 

 
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended. 
When necessary, Irbesartan Hydrochlorothiazide Zentiva may be administered with another 
antihypertensive medicinal product (see sections 4.3, 4.4, 4.5 and 5.1). 
 
Special Populations 
 
Renal impairment 

 



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Due to the hydrochlorothiazide component, Irbesartan Hydrochlorothiazide Zentiva is not 
recommended for patients with severe renal dysfunction (creatinine clearance <30 ml/min). Loop 
diuretics are preferred to thiazides in this population. No dosage adjustment is necessary in patients 
with renal impairment whose renal creatinine clearance is ≥30 ml/min (see sections 4.3 and 4.4). 
 
Hepatic impairment 

 

Irbesartan Hydrochlorothiazide Zentiva is not indicated in patients with severe hepatic impairment. 
Thiazides should be used with caution in patients with impaired hepatic function. No dosage 
adjustment of Irbesartan Hydrochlorothiazide Zentiva is necessary in patients with mild to moderate 
hepatic impairment (see section 4.3). 
 
Older people 

 

No dosage adjustment of Irbesartan Hydrochlorothiazide Zentiva is necessary inolder people. 
 
Paediatric population 

 

Irbesartan Hydrochlorothiazide Zentiva 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. 
 
4.3 Contraindications 
 
▪ Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or to 

other sulfonamide-derived substances (hydrochlorothiazide is a sulfonamide-derived substance) 
▪ Second and third trimesters of pregnancy (see sections 4.4 and 4.6) 
▪ Severe renal impairment (creatinine clearance <30 ml/min) 
▪ Refractory hypokalaemia, hypercalcaemia 
▪ Severe hepatic impairment, biliary cirrhosis and cholestasis 
▪ The concomitant use of Irbesartan Hydrochlorothiazide Zentiva with aliskiren-containing products 

is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate 
(GFR) <60 ml/min/1.73 m²) (see sections 4.5 and 5.1). 

 
4.4 Special warnings and precautions for use 
 
Hypotension - Volume-depleted patients: Irbesartan Hydrochlorothiazide Zentiva has been rarely 
associated with symptomatic hypotension in hypertensive patients without other risk factors for 
hypotension. Symptomatic hypotension may be expected to occur in patients who are volume and/or 
sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such 
conditions should be corrected before initiating therapy with Irbesartan Hydrochlorothiazide Zentiva. 
 
Renal artery stenosis - Renovascular hypertension: there is an increased risk of severe hypotension and 
renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single 
functioning kidney are treated with angiotensin converting enzyme inhibitors or angiotensin-II 
receptor antagonists. While this is not documented with Irbesartan Hydrochlorothiazide Zentiva, a 
similar effect should be anticipated. 
 
Renal impairment and kidney transplantation: when Irbesartan Hydrochlorothiazide Zentiva is used in 
patients with impaired renal function, a periodic monitoring of potassium, creatinine and uric acid 
serum levels is recommended. There is no experience regarding the administration of Irbesartan 
Hydrochlorothiazide Zentiva in patients with a recent kidney transplantation. Irbesartan 
Hydrochlorothiazide Zentiva 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 



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with impaired renal function. No dosage adjustment is necessary in patients with renal impairment 
whose creatinine clearance is ≥30 ml/min. However, in patients with mild to moderate renal 
impairment (creatinine clearance ≥30 ml/min but <60 ml/min) this fixed dose combination should be 
administered with caution. 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the 
concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of 
hypotension, hyperkalaemia and decreased renal function (including acute renal failure). 
Dual blockade of RAAS  through the combined use of ACE-inhibitors, angiotensin II receptor 
blockers or aliskirenis therefore not recommended ( see sections 4.5 and 5.1).  If dual blockade therapy 
is considered absolutely necessary, this should only occur under specialist supervision and subject to 
frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and 
angiotensin II receptor blockers should not be used concomitantly in patients with diabetic 
nephropathy. 
 
 
Hepatic impairment: thiazides should be used with caution in patients with impaired hepatic function 
or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate 
hepatic coma. There is no clinical experience with Irbesartan Hydrochlorothiazide Zentiva in patients 
with hepatic impairment. 
 
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, 
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive 
hypertrophic cardiomyopathy. 
 
Primary aldosteronism: patients with primary aldosteronism generally will not respond to 
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. 
Therefore, the use of Irbesartan Hydrochlorothiazide Zentiva is not recommended. 
 
Metabolic and endocrine effects: thiazide therapy may impair glucose tolerance. In diabetic patients 
dosage adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes mellitus 
may become manifest during thiazide therapy. 
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; 
however at the 12.5 mg dose contained in Irbesartan Hydrochlorothiazide Zentiva, minimal or no 
effects were reported. 
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide 
therapy. 
 
Electrolyte imbalance: as for any patient receiving diuretic therapy, periodic determination of serum 
electrolytes should be performed at appropriate intervals. 
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia, 
hyponatraemia, and hypochloremic alkalosis). Warning signs of fluid or electrolyte imbalance are 
dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, 
muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea 
or vomiting. 
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with 
irbesartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patients 
with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving 
inadequate oral intake of electrolytes and in patients receiving concomitant therapy with 
corticosteroids or ACTH. Conversely, due to the irbesartan component of Irbesartan 
Hydrochlorothiazide Zentiva hyperkalaemia might occur, especially in the presence of renal 
impairment and/or heart failure, and diabetes mellitus. Adequate monitoring of serum potassium in 
patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-
containing salts substitutes should be co-administered cautiously with Irbesartan Hydrochlorothiazide 
Zentiva (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. 



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Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of 
serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia 
may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out 
tests for parathyroid function. 
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in 
hypomagnaesemia. 
 
Lithium: the combination of lithium and Irbesartan Hydrochlorothiazide Zentiva is not recommended 
(see section 4.5). 
 
Anti-doping test: hydrochlorothiazide contained in this medicinal product could produce a positive 
analytic result in an anti-doping test. 
 
General: in patients whose vascular tone and renal function depend predominantly on the activity of 
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or 
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting 
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated 
with acute hypotension, azotemia, oliguria, or rarely acute renal failure (see Section 4.5). As with any 
antihypertensive agent, excessive blood pressure decrease in patients with ischemic cardiopathy or 
ischemic cardiovascular disease could result in a myocardial infarction or stroke. 
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of 
allergy or bronchial asthma, but are more likely in patients with such a history. 
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide 
diuretics. 
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If 
photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-
administration 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). 
 
 
Acute Myopia and Secondary Acute Angle-Closure Glaucoma: sulfonamide drugs or sulfonamide 
derivative drugs can cause an idiosyncratic reaction, resulting in transient myopia and acute angle-
closure glaucoma. While hydrochlorothiazide is a sulfonamide, only isolated cases of acute angle-
closure glaucoma have been reported so far with hydrochlorothiazide. Symptoms include acute onset 
of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. 
Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to 
discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be 
considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-
closure glaucoma may include a history of sulfonamide or penicillin allergy (see section 4.8). 
 
Lactose: patients with rare hereditary problems of galactose intolerance, total lactase deficiency or 
glucose-galactose malabsorption should not take this medicine. 
 
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 



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



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Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan 
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser 
extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were 
observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by 
CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan 
have not been evaluated. The pharmacokinetic of digoxin was not altered by co-administration of 
irbesartan. 
 
Additional information on hydrochlorothiazide interactions: when administered concurrently, the 
following medicinal products may interact with thiazide diuretics: 
 
Alcohol: potentiation of orthostatic hypotension may occur; 
 
Antidiabetic medicinal products (oral agents and insulins): dosage adjustment of the antidiabetic 
medicinal product may be required (see section 4.4); 
 
Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is impaired in the presence of 
anionic exchange resins. Irbesartan Hydrochlorothiazide Zentiva should be taken at least one hour 
before or four hours after these medications; 
 
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be increased; 
 
Digitalis glycosides: thiazide induced hypokalaemia or hypomagnaesemia favour the onset of 
digitalis-induced cardiac arrhythmias (see section 4.4); 
 
Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory drug 
may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients; 
 
Pressor amines (e.g. noradrenaline): the effect of pressor amines may be decreased, but not 
sufficiently to preclude their use; 
 
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): the effect of nondepolarizing skeletal 
muscle relaxants may be potentiated by hydrochlorothiazide; 
 
Antigout medicinal products: dosage adjustments of antigout medicinal products may be necessary as 
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or 
sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence 
of hypersensitivity reactions to allopurinol; 
 
Calcium salts: thiazide diuretics may increase serum calcium levels due to decreased excretion. If 
calcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be 
prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly; 
 
Carbamazepine: concomitant use of carbamazepine and hydrochlorothiazide has been associated with 
the risk of symptomatic hyponatraemia. Electrolytes should be monitored during concomitant use. If 
possible, another class of diuretics should be used; 
 

Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by 
thiazides. Anticholinergic agents (e.g. atropine, beperiden) may increase the bioavailability of 
thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides 
may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal 
excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their 
myelosuppressive effects. 
 



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4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
Angiotensin II Receptor Antagonists (AIIRAs): 

 
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The 
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 
and 4.4). 
 
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors 
during the first trimester of pregnancy has not been conclusive; however a small increase in risk 
cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II 
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued 
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative 
antihypertensive treatments which have an established safety profile for use in pregnancy. When 
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, 
alternative therapy should be started. 
 
Exposure to AIIRA therapy during the second and third trimesters is known to induce human 
foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal 
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see 
sections 4.3 and 4.4). 
 
Hydrochlorothiazide: 

 
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first 
trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the 
pharmacological mechanism of action of hydrochlorothiazide its use during the second and third 
trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like 
icterus, disturbance of electrolyte balance and thrombocytopenia. 
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or 
preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a 
beneficial effect on the course of the disease. 
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare 
situations where no other treatment could be used. 
 
Since Irbesartan Hydrochlorothiazide Zentiva contains hydrochlorothiazide, it is not recommended 
during the first trimester of pregnancy. A switch to a suitable alternative treatment should be carried 
out in advance of a planned pregnancy. 
 
Breast-feeding 
 
Angiotensin II Receptor Antagonists (AIIRAs): 

 
Because no information is available regarding the use of Irbesartan Hydrochlorothiazide Zentiva 
during breast-feeding, Irbesartan Hydrochlorothiazide Zentiva is not recommended and alternative 
treatments with better established safety profiles during breast-feeding are preferable, especially while 
nursing a newborn or preterm infant. 
 
It is unknown whether irbesartan or its metabolites are excreted in human milk.  
Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its 
metabolites in milk (for details see 5.3). 
 



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Hydrochlorothiazide: 

 
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing 
intense diuresis can inhibit the milk production. The use of Irbesartan Hydrochlorothiazide Zentiva 
during breast feeding is not recommended. If Irbesartan Hydrochlorothiazide Zentiva 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).  
 
4.7 Effects on ability to drive and use machines 
 
Based on its pharmacodynamic properties, Irbesartan Hydrochlorothiazide Zentiva is unlikely to affect 
the ability to drive and use machines. When driving vehicles or operating machines, it should be taken 
into account that occasionally dizziness or weariness may occur during treatment of hypertension. 
 
4.8 Undesirable effects 
 
Irbesartan/hydrochlorothiazide combination: 
Among 898 hypertensive patients who received various doses of irbesartan/hydrochlorothiazide 
(range: 37.5 mg/6.25 mg to 300 mg/25 mg) in placebo-controlled trials, 29.5% of the patients 
experienced adverse reactions. The most commonly reported ADRs were dizziness (5.6%), fatigue 
(4.9%), nausea/vomiting (1.8%), and abnormal urination (1.4%). In addition, increases in blood urea 
nitrogen (BUN) (2.3%), creatine kinase (1.7%) and creatinine (1.1%) were also commonly observed in 
the trials. 
 
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled 
trials. 
 
The frequency of adverse reactions listed below is defined using the following convention: 
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare 
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects 
are presented in order of decreasing seriousness. 
 
Table 1: Adverse Reactions in Placebo-Controlled Trials and Spontaneous Reports 
Investigations: Common: increases in blood urea nitrogen (BUN), 

creatinine and creatine kinase 
Uncommon: decreases in serum potassium and sodium 

Cardiac disorders: Uncommon: syncope, hypotension, tachycardia, oedema 
Nervous system disorders: Common: dizziness 

Uncommon: orthostatic dizziness 
Not known: headache 

Ear and labyrinth disorders: Not known: tinnitus 
Respiratory, thoracic and 

mediastinal disorders: 

Not known: cough 

Gastrointestinal disorders: Common: nausea/vomiting 
Uncommon: diarrhoea 
Not known: dyspepsia, dysgeusia 

Renal and urinary disorders: Common: abnormal urination 
Not known: impaired renal function including isolated 

cases of renal failure in patients at risk (see 
section 4.4) 

Musculoskeletal and connective 

tissue disorders: 
Uncommon: swelling extremity 
Not known: arthralgia, myalgia 



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Metabolism and nutrition 

disorders: 

Not known: hyperkalaemia 

Vascular disorders: Uncommon: flushing 
General disorders and 

administration site conditions: 
Common: fatigue 

Immune system disorders: Not known: cases of hypersensitivity reactions such as 
angioedema, rash, urticaria 

Hepatobiliary disorders: Uncommon: 
Not known: 

jaundice 
hepatitis, abnormal liver function 

Reproductive system and breast 

disorders: 
Uncommon: sexual dysfunction, libido changes 

 
Additional information on individual components: in addition to the adverse reactions listed above for 
the combination product, other adverse reactions previously reported with one of the individual 
components may be potential adverse reactions with Irbesartan Hydrochlorothiazide Zentiva. Tables 2 
and 3 below detail the adverse reactions reported with the individual components of Irbesartan 
Hydrochlorothiazide Zentiva. 
 
Table 2: Adverse reactions reported with the use of irbesartan alone 
Blood and lymphatic system 

disorders: 

Not known: thrombocytopenia  

General disorders and 

administration site conditions: 

Uncommon: chest pain 

Immune system disorders: Not known: Anaphylactic reaction including 
anaphylactic shock 

 
Table 3: Adverse reactions reported with the use of hydrochlorothiazide alone 
Investigations: Not known: electrolyte imbalance (including hypokalaemia 

and hyponatraemia, see section 4.4), 
hyperuricaemia, glycosuria, hyperglycaemia, 
increases in cholesterol and triglycerides 

Cardiac disorders: Not known: cardiac arrhythmias 
Blood and lymphatic system 

disorders: 
Not known: aplastic anaemia, bone marrow depression, 

neutropenia/agranulocytosis, haemolytic 
anaemia, leucopenia, thrombocytopenia 

Nervous system disorders: Not known: vertigo, paraesthesia, light-headedness, 
restlessness 

Eye disorders: Not known: transient blurred vision, xanthopsia, acute 
myopia and secondary acute angle-closure 
glaucoma 

Respiratory, thoracic and 

mediastinal disorders: 

Not known: respiratory distress (including pneumonitis and 
pulmonary oedema) 

Gastrointestinal disorders: Not known: pancreatitis, anorexia, diarrhoea, constipation, 
gastric irritation, sialadenitis, loss of appetite 

Renal and urinary disorders: Not known: interstitial nephritis, renal dysfunction 
Skin and subcutaneous tissue 

disorders: 

Not known: anaphylactic reactions, toxic epidermal 
necrolysis, necrotizing angitis (vasculitis, 
cutaneous vasculitis), cutaneous lupus 
erythematosus-like reactions, reactivation of 
cutaneous lupus erythematosus, 
photosensitivity reactions, rash, urticaria 

Musculoskeletal and connective 

tissue disorders: 

Not known: weakness, muscle spasm 

Vascular disorders: Not known: postural hypotension 
General disorders and 

administration site conditions: 

Not known: fever 



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Hepatobiliary disorders: Not known: jaundice (intrahepatic cholestatic jaundice) 
Psychiatric disorders: Not known: depression, sleep disturbances 
Neoplasms benign, malignant 

and unspecified (incl cysts and 

polyps) 

Not known: non-melanoma skin cancer (basal cell 
carcinoma and squamous cell carcinoma) 

 
Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose 
dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1). 
 
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may 
increase when titrating the hydrochlorothiazide. 
 
Reporting of suspected adverse reactions  
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 in Appendix V.  
 
4.9 Overdose 
 
No specific information is available on the treatment of overdose with Irbesartan Hydrochlorothiazide 
Zentiva. 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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: angiotensin-II antagonists, combinations 
ATC code: C09DA04. 
 
Mechanism of action 
 
Irbesartan Hydrochlorothiazide Zentiva 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 



 12 

or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors 
results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma 
aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at 
the recommended doses in patients without risk of electrolyte imbalance (see sections 4.4 and 4.5). 
Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also 
degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its 
activity. 
 
Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive effect of thiazide 
diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, 
directly increasing excretion of sodium and chloride in approximately equivalent amounts. The 
diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, 
increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, 
and decreases in serum potassium. Presumably through blockade of the renin-angiotensin-aldosterone 
system, co-administration of irbesartan tends to reverse the potassium loss associated with these 
diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at 
about 4 hours, while the action persists for approximately 6-12 hours. 
 
The combination of hydrochlorothiazide and irbesartan produces dose-related additive reductions in 
blood pressure across their therapeutic dose ranges. The addition of 12.5 mg hydrochlorothiazide to 
300 mg irbesartan once daily in patients not adequately controlled on 300 mg irbesartan alone resulted 
in further placebo-corrected diastolic blood pressure reductions at trough (24 hours post-dosing) of 
6.1 mm Hg. The combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide resulted in an 
overall placebo-subtracted systolic/diastolic reductions of up to 13.6/11.5 mm Hg. 
 
Limited clinical data (7 out of 22 patients) suggest that patients not controlled with the 
300 mg/12.5 mg combination may respond when uptitrated to 300 mg/25 mg. In these patients, an 
incremental blood pressure lowering effect was observed for both systolic blood pressure (SBP) and 
diastolic blood pressure (DBP) (13.3 and 8.3 mm Hg, respectively). 
 
Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide gave systolic/diastolic 
mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of 12.9/6.9 mm Hg 
in patients with mild-to-moderate hypertension. Peak effects occurred at 3-6 hours. When assessed by 
ambulatory blood pressure monitoring, the combination 150 mg irbesartan and 12.5 mg 
hydrochlorothiazide once daily produced consistent reduction in blood pressure over the 24 hours 
period with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mm Hg. When 
measured by ambulatory blood pressure monitoring, the trough to peak effects of Irbesartan 
Hydrochlorothiazide Zentiva 150 mg/12.5 mg were 100%. The trough to peak effects measured by 
cuff during office visits were 68% and 76% for Irbesartan Hydrochlorothiazide 
Zentiva 150 mg/12.5 mg and Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg, respectively. 
These 24-hour effects were observed without excessive blood pressure lowering at peak and are 
consistent with safe and effective blood-pressure lowering over the once-daily dosing interval. 
 
In patients not adequately controlled on 25 mg hydrochlorothiazide alone, the addition of irbesartan 
gave an added placebo-subtracted systolic/diastolic mean reduction of 11.1/7.2 mm Hg. 
 
The blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide is apparent 
after the first dose and substantially present within 1-2 weeks, with the maximal effect occurring by 
6-8 weeks. In long-term follow-up studies, the effect of irbesartan/hydrochlorothiazide was maintained 
for over one year. Although not specifically studied with the Irbesartan Hydrochlorothiazide Zentiva, 
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. 
 



 13 

There is no difference in response to Irbesartan Hydrochlorothiazide Zentiva, 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. 
 
Clinical efficacy and safety 
 
Efficacy and safety of Irbesartan Hydrochlorothiazide Zentiva as initial therapy for severe 
hypertension (defined as SeDBP ≥ 110 mmHg) was evaluated in a multicentre, 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 force-titrated (before assessing the response to the lower dose) after one week to 
irbesartan/hydrochlorothiazide 300 mg/25 mg or irbesartan 300 mg, respectively. 
 
The study recruited 58% males. The mean age of patients was 52.5 years, 13% were ≥ 65 years of age, 
and just 2% were ≥ 75 years of age. Twelve percent (12%) of patients were diabetic, 34% were 
hyperlipidemic and the most frequent cardiovascular condition was stable angina pectoris in 3.5% of 
the participants. 
 
The primary objective of this study was to compare the proportion of patients whose SeDBP was 
controlled (SeDBP < 90 mmHg) at Week 5 of treatment. Forty-seven percent (47.2%) of patients on 
the combination achieved trough SeDBP < 90 mmHg compared to 33.2% of patients on irbesartan 
(p = 0.0005). The mean baseline blood pressure was approximately 172/113 mmHg in each treatment 
group and decreases of SeSBP/SeDBP at five weeks were 30.8/24.0 mmHg and 21.1/19.3 mmHg for 
irbesartan/hydrochlorothiazide and irbesartan, respectively (p < 0.0001). 
 
The types and incidences of adverse events reported for patients treated with the combination were 
similar to the adverse event profile for patients on monotherapy. During the 8-week treatment period, 
there were no reported cases of syncope in either treatment group. There were 0.6% and 0% of patients 
with hypotension and 2.8% and 3.1% of patients with dizziness as adverse reactions reported in the 
combination and monotherapy groups, respectively. 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) 
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in 
combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs 
Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an 
angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of 
cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of 
end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and 
diabetic nephropathy. 
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and 
mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as 
compared to monotherapy was observed. Given their similar pharmacodynamic properties, these 
results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. 
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in 
patients with diabetic nephropathy. 
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) 
was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor 
or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney 
disease, cardiovascular disease, or both. The study was terminated early because of an increased risk 
of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the 
aliskiren group than in the placebo group and adverse events and serious adverse events of interest 
(hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren 
group than in the placebo group. 
 
Non-melanoma skin cancer:  



 14 

Based on available data from epidemiological studies, cumulative dosedependent 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 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). 
 
5.2 Pharmacokinetic properties 
 
Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the 
pharmacokinetics of either medicinal product. 
 
Absorption 
 
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for 
their activity. Following oral administration of Irbesartan Hydrochlorothiazide Zentiva, the absolute 
oral bioavailability is 60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food 
does not affect the bioavailability of Irbesartan Hydrochlorothiazide Zentiva. Peak plasma 
concentration occurs at 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for 
hydrochlorothiazide. 
 
Distribution 
 
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. 
 
Linearity / non-linearity 
 
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 oldersubjects (≥ 65 years) than those of young subjects (18-40 years). However the terminal 
half-life was not significantly altered. No dosage adjustment is necessary inolder people. The mean 
plasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hours. 
 
Biotransformation 
 
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.  
 
Elimination 
 



 15 

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. 
 
5.3 Preclinical safety data 
 
Irbesartan/hydrochlorothiazide 
 
The potential toxicity of the irbesartan/hydrochlorothiazide combination after oral administration was 
evaluated in rats and macaques in studies lasting up to 6 months. There were no toxicological findings 
observed of relevance to human therapeutic use. 
The following changes, observed in rats and macaques receiving the irbesartan/hydrochlorothiazide 
combination at 10/10 and 90/90 mg/kg/day, were also seen with one of the two medicinal products 
alone and/or were secondary to decreases in blood pressure (no significant toxicologic interactions 
were observed): 
• kidney changes, characterized by slight increases in serum urea and creatinine, and 

hyperplasia/hypertrophy of the juxtaglomerular apparatus, which are a direct consequence of the 
interaction of irbesartan with the renin-angiotensin system; 

• slight decreases in erythrocyte parameters (erythrocytes, haemoglobin, haematocrit); 
• stomach discoloration, ulcers and focal necrosis of gastric mucosa were observed in few rats in 

a 6 months toxicity study at irbesartan 90 mg/kg/day, hydrochlorothiazide 90 mg/kg/day, and 
irbesartan/hydrochlorothiazide 10/10 mg/kg/day. These lesions were not observed in macaques; 

• decreases in serum potassium due to hydrochlorothiazide and partly prevented when 
hydrochlorothiazide was given in combination with irbesartan. 
 

Most of the above mentioned effects appear to be due to the pharmacological activity of irbesartan 
(blockade of angiotensin-II-induced inhibition of renin release, with stimulation of the renin-producing 
cells) and occur also with angiotensin converting enzyme inhibitors. These findings appear to have no 
relevance to the use of therapeutic doses of irbesartan/hydrochlorothiazide in humans. 
 
No teratogenic effects were seen in rats given irbesartan and hydrochlorothiazide in combination at 
doses that produced maternal toxicity. The effects of the irbesartan/hydrochlorothiazide combination 
on fertility have not been evaluated in animal studies, as there is no evidence of adverse effect on 
fertility in animals or humans with either irbesartan or hydrochlorothiazide when administered alone. 
However, another angiotensin-II antagonist affected fertility parameters in animal studies when given 
alone. These findings were also observed with lower doses of this other angiotensin-II antagonist when 
given in combination with hydrochlorothiazide. 
 
There was no evidence of mutagenicity or clastogenicity with the irbesartan/hydrochlorothiazide 
combination. The carcinogenic potential of irbesartan and hydrochlorothiazide in combination has not 
been evaluated in animal studies. 
 



 16 

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 
foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. 
Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. 
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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Microcrystalline cellulose 
Croscarmellose sodium 
Lactose monohydrate 
Magnesium stearate 
Colloidal hydrated silica 
Pregelatinised maize starch 
Red and yellow ferric oxides (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 



 17 

6.4 Special precautions for storage 
 
Do not store above 30°C. 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
Cartons of 14 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 28 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 98 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 x 1 tablets in PVC/PVDC/Aluminium perforated unit dose blisters. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/377/001-005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 January 2007 
Date of latest renewal: 19 January 2012 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/ 



 18 

1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 300 mg of irbesartan and 12.5 mg of hydrochlorothiazide. 
 
Excipient with known effect: 
Each tablet contains 65.8 mg of lactose (as lactose monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Tablet. 
Peach, biconvex, oval-shaped, with a heart debossed on one side and the number 2776 engraved on the 
other side. 
 
 
4. CLINICAL PARTICULARS 
 
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). 
 
4.2 Posology and method of administration 
 
Posology 
 
Irbesartan Hydrochlorothiazide Zentiva can be taken once daily, with or without food.  
Dose titration with the individual components (i.e. irbesartan and hydrochlorothiazide) may be 
recommended. 
 
When clinically appropriate direct change from monotherapy to the fixed combinations may be 
considered: 

•  Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg may be administered in patients 
whose blood pressure is not adequately controlled with hydrochlorothiazide or 
irbesartan 150 mg alone; 

•  Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg may be administered in patients 
insufficiently controlled by irbesartan 300 mg or by Irbesartan Hydrochlorothiazide 
Zentiva 150 mg/12.5 mg. 

•  Irbesartan Hydrochlorothiazide Zentiva 300 mg/25 mg may be administered in patients 
insufficiently controlled by Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg. 

 
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended. 
When necessary, Irbesartan Hydrochlorothiazide Zentiva may be administered with another 
antihypertensive medicinal product (see sections 4.3, 4.4, 4.5 and 5.1). 
 
Special populations 
 
Renal impairment 

 



 19 

Due to the hydrochlorothiazide component, Irbesartan Hydrochlorothiazide Zentiva is not 
recommended for patients with severe renal dysfunction (creatinine clearance <30 ml/min). Loop 
diuretics are preferred to thiazides in this population. No dosage adjustment is necessary in patients 
with renal impairment whose renal creatinine clearance is ≥30 ml/min (see sections 4.3 and 4.4). 
 
Hepatic impairment 

 

Irbesartan Hydrochlorothiazide Zentiva is not indicated in patients with severe hepatic impairment. 
Thiazides should be used with caution in patients with impaired hepatic function. No dosage 
adjustment of Irbesartan Hydrochlorothiazide Zentiva is necessary in patients with mild to moderate 
hepatic impairment (see section 4.3). 
 
Older people 

 

No dosage adjustment of Irbesartan Hydrochlorothiazide Zentiva is necessary inolder people. 
 
Paediatric population  
 
Irbesartan Hydrochlorothiazide Zentiva 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. 
 
4.3 Contraindications 
 
▪ Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or to 

other sulfonamide-derived substances (hydrochlorothiazide is a sulfonamide-derived substance) 
▪ Second and third trimesters of pregnancy (see sections 4.4 and 4.6) 
▪ Severe renal impairment (creatinine clearance <30 ml/min) 
▪ Refractory hypokalaemia, hypercalcaemia 
▪ Severe hepatic impairment, biliary cirrhosis and cholestasis 
▪ The concomitant use of Irbesartan Hydrochlorothiazide Zentiva with aliskiren-containing products 

is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate 
(GFR) <60 ml/min/1.73 m²) (see sections4.5 and 5.1). 

 
4.4 Special warnings and precautions for use 
 
Hypotension - Volume-depleted patients: Irbesartan Hydrochlorothiazide Zentiva has been rarely 
associated with symptomatic hypotension in hypertensive patients without other risk factors for 
hypotension. Symptomatic hypotension may be expected to occur in patients who are volume and/or 
sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such 
conditions should be corrected before initiating therapy with Irbesartan Hydrochlorothiazide Zentiva. 
 
Renal artery stenosis - Renovascular hypertension: there is an increased risk of severe hypotension and 
renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single 
functioning kidney are treated with angiotensin converting enzyme inhibitors or angiotensin-II 
receptor antagonists. While this is not documented with Irbesartan Hydrochlorothiazide Zentiva, a 
similar effect should be anticipated. 
 
Renal impairment and kidney transplantation: when Irbesartan Hydrochlorothiazide Zentiva is used in 
patients with impaired renal function, a periodic monitoring of potassium, creatinine and uric acid 
serum levels is recommended. There is no experience regarding the administration of Irbesartan 
Hydrochlorothiazide Zentiva in patients with a recent kidney transplantation. Irbesartan 
Hydrochlorothiazide Zentiva 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 



 20 

with impaired renal function. No dosage adjustment is necessary in patients with renal impairment 
whose creatinine clearance is ≥ 30 ml/min. However, in patients with mild to moderate renal 
impairment (creatinine clearance ≥ 30 ml/min but <60 ml/min) this fixed dose combination should be 
administered with caution. 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the 
concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of 
hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual 
blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or 
aliskiren is therefore not recommended (see sections 4.5 and 5.1).  If dual blockade therapy is 
considered absolutely necessary, this should only occur under specialist supervision and subject to 
frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and 
angiotensin II receptor blockers should not be used concomitantly in patients with diabetic 
nephropathy. 
 
 
Hepatic impairment: thiazides should be used with caution in patients with impaired hepatic function 
or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate 
hepatic coma. There is no clinical experience with Irbesartan Hydrochlorothiazide Zentiva in patients 
with hepatic impairment. 
 
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, 
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive 
hypertrophic cardiomyopathy. 
 
Primary aldosteronism: patients with primary aldosteronism generally will not respond to 
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. 
Therefore, the use of Irbesartan Hydrochlorothiazide Zentiva is not recommended. 
 
Metabolic and endocrine effects: thiazide therapy may impair glucose tolerance. In diabetic patients 
dosage adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes mellitus 
may become manifest during thiazide therapy. 
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; 
however at the 12.5 mg dose contained in Irbesartan Hydrochlorothiazide Zentiva, minimal or no 
effects were reported. 
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide 
therapy. 
 
Electrolyte imbalance: as for any patient receiving diuretic therapy, periodic determination of serum 
electrolytes should be performed at appropriate intervals. 
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia, 
hyponatraemia, and hypochloremic alkalosis). Warning signs of fluid or electrolyte imbalance are 
dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, 
muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea 
or vomiting. 
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with 
irbesartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patients 
with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving 
inadequate oral intake of electrolytes and in patients receiving concomitant therapy with 
corticosteroids or ACTH. Conversely, due to the irbesartan component of Irbesartan 
Hydrochlorothiazide Zentiva hyperkalaemia might occur, especially in the presence of renal 
impairment and/or heart failure, and diabetes mellitus. Adequate monitoring of serum potassium in 
patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-
containing salts substitutes should be co-administered cautiously with Irbesartan Hydrochlorothiazide 
Zentiva (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. 



 21 

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of 
serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia 
may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out 
tests for parathyroid function. 
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in 
hypomagnaesemia. 
 
Lithium: the combination of lithium and Irbesartan Hydrochlorothiazide Zentiva is not recommended 
(see section 4.5). 
 
Anti-doping test: hydrochlorothiazide contained in this medicinal product could produce a positive 
analytic result in an anti-doping test. 
 
General: in patients whose vascular tone and renal function depend predominantly on the activity of 
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or 
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting 
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated 
with acute hypotension, azotemia, oliguria, or rarely acute renal failure (see Section 4.5). As with any 
antihypertensive agent, excessive blood pressure decrease in patients with ischemic cardiopathy or 
ischemic cardiovascular disease could result in a myocardial infarction or stroke. 
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of 
allergy or bronchial asthma, but are more likely in patients with such a history. 
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide 
diuretics. 
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If 
photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-
administration 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). 
 
 
Acute Myopia and Secondary Acute Angle-Closure Glaucoma: sulfonamide drugs or sulfonamide 
derivative drugs can cause an idiosyncratic reaction, resulting in transient myopia and acute angle-
closure glaucoma. While hydrochlorothiazide is a sulfonamide, only isolated cases of acute angle-
closure glaucoma have been reported so far with hydrochlorothiazide. Symptoms include acute onset 
of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. 
Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to 
discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be 
considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-
closure glaucoma may include a history of sulfonamide or penicillin allergy (see section 4.8). 
 
Lactose: patients with rare hereditary problems of galactose intolerance, total lactase deficiency or 
glucose-galactose malabsorption should not take this medicine. 
 
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 



 22 

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



 23 

Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan 
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser 
extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were 
observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by 
CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan 
have not been evaluated. The pharmacokinetic of digoxin was not altered by co-administration of 
irbesartan. 
 
Additional information on hydrochlorothiazide interactions: when administered concurrently, the 
following medicinal products may interact with thiazide diuretics: 
 
Alcohol: potentiation of orthostatic hypotension may occur; 
 
Antidiabetic medicinal products (oral agents and insulins): dosage adjustment of the antidiabetic 
medicinal product may be required (see section 4.4); 
 
Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is impaired in the presence of 
anionic exchange resins. Irbesartan Hydrochlorothiazide Zentiva should be taken at least one hour 
before or four hours after these medications; 
 
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be increased; 
 
Digitalis glycosides: thiazide induced hypokalaemia or hypomagnaesemia favour the onset of 
digitalis-induced cardiac arrhythmias (see section 4.4); 
 
Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory drug 
may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients; 
 
Pressor amines (e.g. noradrenaline): the effect of pressor amines may be decreased, but not 
sufficiently to preclude their use; 
 
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): the effect of nondepolarizing skeletal 
muscle relaxants may be potentiated by hydrochlorothiazide; 
 
Antigout medicinal products: dosage adjustments of antigout medicinal products may be necessary as 
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or 
sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence 
of hypersensitivity reactions to allopurinol; 
 
Calcium salts: thiazide diuretics may increase serum calcium levels due to decreased excretion. If 
calcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be 
prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly; 
 
Carbamazepine: concomitant use of carbamazepine and hydrochlorothiazide has been associated with 
the risk of symptomatic hyponatraemia. Electrolytes should be monitored during concomitant use. If 
possible, another class of diuretics should be used; 
 

Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by 
thiazides. Anticholinergic agents (e.g. atropine, beperiden) may increase the bioavailability of 
thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides 
may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal 
excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their 
myelosuppressive effects. 
 



 24 

4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
Angiotensin II Receptor Antagonists (AIIRAs): 

 
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The 
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 
and 4.4). 
 
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors 
during the first trimester of pregnancy has not been conclusive; however a small increase in risk 
cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II 
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued 
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative 
antihypertensive treatments which have an established safety profile for use in pregnancy. When 
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, 
alternative therapy should be started. 
 
Exposure to AIIRA therapy during the second and third trimesters is known to induce human 
foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal 
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see 
sections 4.3 and 4.4). 
 
Hydrochlorothiazide 

 
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first 
trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the 
pharmacological mechanism of action of hydrochlorothiazide its use during the second and third 
trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like 
icterus, disturbance of electrolyte balance and thrombocytopenia. 
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or 
preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a 
beneficial effect on the course of the disease. 
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare 
situations where no other treatment could be used. 
 
Since Irbesartan Hydrochlorothiazide Zentiva contains hydrochlorothiazide, it is not recommended 
during the first trimester of pregnancy. A switch to a suitable alternative treatment should be carried 
out in advance of a planned pregnancy. 
 
Breast-feeding 
 
Angiotensin II Receptor Antagonists (AIIRAs) 

 
Because no information is available regarding the use of Irbesartan Hydrochlorothiazide Zentiva 
during breast-feeding, Irbesartan Hydrochlorothiazide Zentiva is not recommended and alternative 
treatments with better established safety profiles during breast-feeding are preferable, especially while 
nursing a newborn or preterm infant. 
 
It is unknown whether irbesartan or its metabolites are excreted in human milk.  
Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its 
metabolites in milk (for details see 5.3). 
 



 25 

Hydrochlorothiazide 

 
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing 
intense diuresis can inhibit the milk production. The use of Irbesartan Hydrochlorothiazide Zentiva 
during breast feeding is not recommended. If Irbesartan Hydrochlorothiazide Zentiva 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).  
 
4.7 Effects on ability to drive and use machines 
 
Based on its pharmacodynamic properties, Irbesartan Hydrochlorothiazide Zentiva is unlikely to affect 
the ability to drive and use machines. When driving vehicles or operating machines, it should be taken 
into account that occasionally dizziness or weariness may occur during treatment of hypertension. 
 
4.8 Undesirable effects 
 
Irbesartan/hydrochlorothiazide combination 
Among 898 hypertensive patients who received various doses of irbesartan/hydrochlorothiazide 
(range: 37.5 mg/6.25 mg to 300 mg/25 mg) in placebo-controlled trials, 29.5% of the patients 
experienced adverse reactions. The most commonly reported ADRs were dizziness (5.6%), fatigue 
(4.9%), nausea/vomiting (1.8%), and abnormal urination (1.4%). In addition, increases in blood urea 
nitrogen (BUN) (2.3%), creatine kinase (1.7%) and creatinine (1.1%) were also commonly observed in 
the trials. 
 
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled 
trials. 
 
The frequency of adverse reactions listed below is defined using the following convention: 
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare 
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects 
are presented in order of decreasing seriousness. 
 
Table 1: Adverse Reactions in Placebo-Controlled Trials and Spontaneous Reports 
Investigations: Common: increases in blood urea nitrogen (BUN), 

creatinine and creatine kinase 
Uncommon: decreases in serum potassium and sodium 

Cardiac disorders: Uncommon: syncope, hypotension, tachycardia, oedema 
Nervous system disorders: Common: dizziness 

Uncommon: orthostatic dizziness 
Not known: headache 

Ear and labyrinth disorders: Not known: tinnitus 
Respiratory, thoracic and 

mediastinal disorders: 

Not known: cough 

Gastrointestinal disorders: Common: nausea/vomiting 
Uncommon: diarrhoea 
Not known: dyspepsia, dysgeusia 

Renal and urinary disorders: Common: abnormal urination 
Not known: impaired renal function including isolated 

cases of renal failure in patients at risk (see 
section 4.4) 

Musculoskeletal and connective 

tissue disorders: 
Uncommon: swelling extremity 
Not known: arthralgia, myalgia 



 26 

Metabolism and nutrition 

disorders: 

Not known: hyperkalaemia 

Vascular disorders: Uncommon: flushing 
General disorders and 

administration site conditions: 
Common: fatigue 

Immune system disorders: Not known: cases of hypersensitivity reactions such as 
angioedema, rash, urticaria 

Hepatobiliary disorders: Uncommon: 
Not known: 

jaundice 
hepatitis, abnormal liver function 

Reproductive system and breast 

disorders: 
Uncommon: sexual dysfunction, libido changes 

 
Additional information on individual components: in addition to the adverse reactions listed above for 
the combination product, other adverse reactions previously reported with one of the individual 
components may be potential adverse reactions with Irbesartan Hydrochlorothiazide Zentiva. Tables 2 
and 3 below detail the adverse reactions reported with the individual components of Irbesartan 
Hydrochlorothiazide Zentiva. 
 
Table 2: Adverse reactions reported with the use of irbesartan alone 
Blood and lymphatic system 

disorders: 

Not known: thrombocytopenia  

General disorders and 

administration site conditions: 

Uncommon: chest pain 

Immune system disorders: Not known: Anaphylactic reaction including anaphylactic 
shock 

 
Table 3: Adverse reactions reported with the use of hydrochlorothiazide alone 
Investigations: Not known: electrolyte imbalance (including hypokalaemia 

and hyponatraemia, see section 4.4), 
hyperuricaemia, glycosuria, hyperglycaemia, 
increases in cholesterol and triglycerides 

Cardiac disorders: Not known: cardiac arrhythmias 
Blood and lymphatic system 

disorders: 
Not known: aplastic anaemia, bone marrow depression, 

neutropenia/agranulocytosis, haemolytic 
anaemia, leucopenia, thrombocytopenia 

Nervous system disorders: Not known: vertigo, paraesthesia, light-headedness, 
restlessness 

Eye disorders: Not known: transient blurred vision, xanthopsia, acute 
myopia and secondary acute angle-closure 
glaucoma 

Respiratory, thoracic and 

mediastinal disorders: 

Not known: respiratory distress (including pneumonitis and 
pulmonary oedema) 

Gastrointestinal disorders: Not known: pancreatitis, anorexia, diarrhoea, constipation, 
gastric irritation, sialadenitis, loss of appetite 

Renal and urinary disorders: Not known: interstitial nephritis, renal dysfunction 
Skin and subcutaneous tissue 

disorders: 

Not known: anaphylactic reactions, toxic epidermal 
necrolysis, necrotizing angitis (vasculitis, 
cutaneous vasculitis), cutaneous lupus 
erythematosus-like reactions, reactivation of 
cutaneous lupus erythematosus, 
photosensitivity reactions, rash, urticaria 

Musculoskeletal and connective 

tissue disorders: 

Not known: weakness, muscle spasm 

Vascular disorders: Not known: postural hypotension 
General disorders and 

administration site conditions: 

Not known: fever 



 27 

Hepatobiliary disorders: Not known: jaundice (intrahepatic cholestatic jaundice) 
Psychiatric disorders: Not known: depression, sleep disturbances 
Neoplasms benign, malignant 

and unspecified (incl cysts and 

polyps) 

Not known: non-melanoma skin cancer (basal cell 
carcinoma and squamous cell carcinoma) 

 
Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose 
dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1). 
 
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may 
increase when titrating the hydrochlorothiazide. 
 
Reporting of suspected adverse reactions  
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 in Appendix V.  
 
4.9 Overdose 
 
No specific information is available on the treatment of overdose with Irbesartan Hydrochlorothiazide 
Zentiva. 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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: angiotensin-II antagonists, combinations 
ATC code: C09DA04. 
 
Mechanism of action 
 
Irbesartan Hydrochlorothiazide Zentiva 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 



 28 

or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors 
results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma 
aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at 
the recommended doses in patients without risk of electrolyte imbalance (see sections 4.4 and 4.5). 
Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also 
degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its 
activity. 
 
Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive effect of thiazide 
diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, 
directly increasing excretion of sodium and chloride in approximately equivalent amounts. The 
diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, 
increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, 
and decreases in serum potassium. Presumably through blockade of the renin-angiotensin-aldosterone 
system, co-administration of irbesartan tends to reverse the potassium loss associated with these 
diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at 
about 4 hours, while the action persists for approximately 6-12 hours. 
 
The combination of hydrochlorothiazide and irbesartan produces dose-related additive reductions in 
blood pressure across their therapeutic dose ranges. The addition of 12.5 mg hydrochlorothiazide to 
300 mg irbesartan once daily in patients not adequately controlled on 300 mg irbesartan alone resulted 
in further placebo-corrected diastolic blood pressure reductions at trough (24 hours post-dosing) of 
6.1 mm Hg. The combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide resulted in an 
overall placebo-subtracted systolic/diastolic reductions of up to 13.6/11.5 mm Hg. 
 
Limited clinical data (7 out of 22 patients) suggest that patients not controlled with the 
300 mg/12.5 mg combination may respond when uptitrated to 300 mg/25 mg. In these patients, an 
incremental blood pressure lowering effect was observed for both systolic blood pressure (SBP) and 
diastolic blood pressure (DBP) (13.3 and 8.3 mm Hg, respectively). 
 
Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide gave systolic/diastolic 
mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of 12.9/6.9 mm Hg 
in patients with mild-to-moderate hypertension. Peak effects occurred at 3-6 hours. When assessed by 
ambulatory blood pressure monitoring, the combination 150 mg irbesartan and 12.5 mg 
hydrochlorothiazide once daily produced consistent reduction in blood pressure over the 24 hours 
period with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mm Hg. When 
measured by ambulatory blood pressure monitoring, the trough to peak effects of Irbesartan 
Hydrochlorothiazide Zentiva 150 mg/12.5 mg were 100%. The trough to peak effects measured by 
cuff during office visits were 68% and 76% for Irbesartan Hydrochlorothiazide 
Zentiva 150 mg/12.5 mg and Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg, respectively. 
These 24-hour effects were observed without excessive blood pressure lowering at peak and are 
consistent with safe and effective blood-pressure lowering over the once-daily dosing interval. 
 
In patients not adequately controlled on 25 mg hydrochlorothiazide alone, the addition of irbesartan 
gave an added placebo-subtracted systolic/diastolic mean reduction of 11.1/7.2 mm Hg. 
 
The blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide is apparent 
after the first dose and substantially present within 1-2 weeks, with the maximal effect occurring by 
6-8 weeks. In long-term follow-up studies, the effect of irbesartan/hydrochlorothiazide was maintained 
for over one year. Although not specifically studied with the Irbesartan Hydrochlorothiazide Zentiva, 
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. 
 



 29 

There is no difference in response to Irbesartan Hydrochlorothiazide Zentiva, 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. 
 
Clinical efficacy and safety 
 
Efficacy and safety of Irbesartan Hydrochlorothiazide Zentiva as initial therapy for severe 
hypertension (defined as SeDBP ≥ 110 mmHg) was evaluated in a multicentre, 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 force-titrated (before assessing the response to the lower dose) after one week to 
irbesartan/hydrochlorothiazide 300 mg/25 mg or irbesartan 300 mg, respectively. 
 
The study recruited 58% males. The mean age of patients was 52.5 years, 13% were ≥ 65 years of age, 
and just 2% were ≥ 75 years of age. Twelve percent (12%) of patients were diabetic, 34% were 
hyperlipidemic and the most frequent cardiovascular condition was stable angina pectoris in 3.5% of 
the participants. 
 
The primary objective of this study was to compare the proportion of patients whose SeDBP was 
controlled (SeDBP < 90 mmHg) at Week 5 of treatment. Forty-seven percent (47.2%) of patients on 
the combination achieved trough SeDBP < 90 mmHg compared to 33.2% of patients on irbesartan 
(p = 0.0005). The mean baseline blood pressure was approximately 172/113 mmHg in each treatment 
group and decreases of SeSBP/SeDBP at five weeks were 30.8/24.0 mmHg and 21.1/19.3 mmHg for 
irbesartan/hydrochlorothiazide and irbesartan, respectively (p < 0.0001). 
 
The types and incidences of adverse events reported for patients treated with the combination were 
similar to the adverse event profile for patients on monotherapy. During the 8-week treatment period, 
there were no reported cases of syncope in either treatment group. There were 0.6% and 0% of patients 
with hypotension and 2.8% and 3.1% of patients with dizziness as adverse reactions reported in the 
combination and monotherapy groups, respectively. 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) 
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in 
combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs 
Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an 
angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of 
cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of 
end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and 
diabetic nephropathy. 
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and 
mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as 
compared to monotherapy was observed. Given their similar pharmacodynamic properties, these 
results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. 
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in 
patients with diabetic nephropathy. 
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) 
was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor 
or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney 
disease, cardiovascular disease, or both. The study was terminated early because of an increased risk 
of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the 
aliskiren group that in the placebo group and adverse events and serious adverse events of interest 
(hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren 
group than in the placebo group. 
 
 



 30 

Non-melanoma skin cancer:  

Based on available data from epidemiological studies, cumulative dosedependent 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 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). 
 
5.2 Pharmacokinetic properties 
 
Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the 
pharmacokinetics of either medicinal product. 
 
Absorption 
 
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for 
their activity. Following oral administration of Irbesartan Hydrochlorothiazide Zentiva, the absolute 
oral bioavailability is 60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food 
does not affect the bioavailability of Irbesartan Hydrochlorothiazide Zentiva. Peak plasma 
concentration occurs at 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for 
hydrochlorothiazide. 
 
Distribution 
 
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. 
 
Linearity / non-linearity 
 
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 inolder people. The mean 
plasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hours. 
 
Biotransformation 
 
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.  
 
Elimination 
 



 31 

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. 
 
5.3 Preclinical safety data 
 
Irbesartan/hydrochlorothiazide 
 
The potential toxicity of the irbesartan/hydrochlorothiazide combination after oral administration was 
evaluated in rats and macaques in studies lasting up to 6 months. There were no toxicological findings 
observed of relevance to human therapeutic use. 
The following changes, observed in rats and macaques receiving the irbesartan/hydrochlorothiazide 
combination at 10/10 and 90/90 mg/kg/day, were also seen with one of the two medicinal products 
alone and/or were secondary to decreases in blood pressure (no significant toxicologic interactions 
were observed): 
• kidney changes, characterized by slight increases in serum urea and creatinine, and 

hyperplasia/hypertrophy of the juxtaglomerular apparatus, which are a direct consequence of the 
interaction of irbesartan with the renin-angiotensin system; 

• slight decreases in erythrocyte parameters (erythrocytes, haemoglobin, haematocrit); 
• stomach discoloration, ulcers and focal necrosis of gastric mucosa were observed in few rats in 

a 6 months toxicity study at irbesartan 90 mg/kg/day, hydrochlorothiazide 90 mg/kg/day, and 
irbesartan/hydrochlorothiazide 10/10 mg/kg/day. These lesions were not observed in macaques; 

• decreases in serum potassium due to hydrochlorothiazide and partly prevented when 
hydrochlorothiazide was given in combination with irbesartan. 

 
Most of the above mentioned effects appear to be due to the pharmacological activity of irbesartan 
(blockade of angiotensin-II-induced inhibition of renin release, with stimulation of the renin-producing 
cells) and occur also with angiotensin converting enzyme inhibitors. These findings appear to have no 
relevance to the use of therapeutic doses of irbesartan/hydrochlorothiazide in humans. 
 
No teratogenic effects were seen in rats given irbesartan and hydrochlorothiazide in combination at 
doses that produced maternal toxicity. The effects of the irbesartan/hydrochlorothiazide combination 
on fertility have not been evaluated in animal studies, as there is no evidence of adverse effect on 
fertility in animals or humans with either irbesartan or hydrochlorothiazide when administered alone. 
However, another angiotensin-II antagonist affected fertility parameters in animal studies when given 
alone. These findings were also observed with lower doses of this other angiotensin-II antagonist when 
given in combination with hydrochlorothiazide. 
 
There was no evidence of mutagenicity or clastogenicity with the irbesartan/hydrochlorothiazide 
combination. The carcinogenic potential of irbesartan and hydrochlorothiazide in combination has not 
been evaluated in animal studies. 
 



 32 

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 
foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. 
Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. 
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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Microcrystalline cellulose 
Croscarmellose sodium 
Lactose monohydrate 
Magnesium stearate 
Colloidal hydrated silica 
Pregelatinised maize starch 
Red and yellow ferric oxides (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 



 33 

6.4 Special precautions for storage 
 
Do not store above 30°C. 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
Cartons of 14 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 28 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 98 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 x 1 tablets in PVC/PVDC/Aluminium perforated unit dose blisters. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/377/006-010 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 January 2007 
Date of latest renewal: 19 January 2012 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/ 



 34 

1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 150 mg of irbesartan and 12.5 mg of hydrochlorothiazide. 
 
Excipient with known effect: 
Each film-coated tablet contains 38.5 mg of lactose (as lactose monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
Peach, biconvex, oval-shaped, with a heart debossed on one side and the number 2875 engraved on the 
other side. 
 
 
4. CLINICAL PARTICULARS 
 
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). 
 
4.2 Posology and method of administration 
 
Posology 
 
Irbesartan Hydrochlorothiazide Zentiva can be taken once daily, with or without food.  
Dose titration with the individual components (i.e. irbesartan and hydrochlorothiazide) may be 
recommended. 
 
When clinically appropriate direct change from monotherapy to the fixed combinations may be 
considered: 
• Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg may be administered in patients whose 

blood pressure is not adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone; 
• Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg may be administered in patients 

insufficiently controlled by irbesartan 300 mg or by Irbesartan Hydrochlorothiazide 
Zentiva 150 mg/12.5 mg. 

• Irbesartan Hydrochlorothiazide Zentiva 300 mg/25 mg may be administered in patients 
insufficiently controlled by Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg. 

 
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended. 
When necessary, Irbesartan Hydrochlorothiazide Zentiva may be administered with another 
antihypertensive medicinal product (see sections 4.3, 4.4, 4.5 and 5.1). 
 
Special populations 
 
Renal impairment 

 



 35 

Due to the hydrochlorothiazide component, Irbesartan Hydrochlorothiazide Zentiva is not 
recommended for patients with severe renal dysfunction (creatinine clearance <30 ml/min). Loop 
diuretics are preferred to thiazides in this population. No dosage adjustment is necessary in patients 
with renal impairment whose renal creatinine clearance is ≥30 ml/min (see sections 4.3 and 4.4). 
 
Hepatic impairment 

 
Irbesartan Hydrochlorothiazide Zentiva is not indicated in patients with severe hepatic impairment. 
Thiazides should be used with caution in patients with impaired hepatic function. No dosage 
adjustment of Irbesartan Hydrochlorothiazide Zentiva is necessary in patients with mild to moderate 
hepatic impairment (see section 4.3). 
 
Older people 

 

No dosage adjustment of Irbesartan Hydrochlorothiazide Zentiva is necessary in older people. 
 
Paediatric population 

 

Irbesartan Hydrochlorothiazide Zentiva 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. 
 
4.3 Contraindications 
 
▪ Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or to 

other sulfonamide-derived substances (hydrochlorothiazide is a sulfonamide-derived substance) 
▪ Second and third trimesters of pregnancy (see sections 4.4 and 4.6) 
▪ Severe renal impairment (creatinine clearance <30 ml/min) 
▪ Refractory hypokalaemia, hypercalcaemia 
▪ Severe hepatic impairment, biliary cirrhosis and cholestasis 
▪ The concomitant use of Irbesartan Hydrochlorothiazide Zentiva with aliskiren-containing products 

is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate 
(GFR) <60 ml/min/1.73 m²) (see sections 4.5 and 5.1). 

 
 
4.4 Special warnings and precautions for use 
 
Hypotension - Volume-depleted patients: Irbesartan Hydrochlorothiazide Zentiva has been rarely 
associated with symptomatic hypotension in hypertensive patients without other risk factors for 
hypotension. Symptomatic hypotension may be expected to occur in patients who are volume and/or 
sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such 
conditions should be corrected before initiating therapy with Irbesartan Hydrochlorothiazide Zentiva. 
 
Renal artery stenosis - Renovascular hypertension: there is an increased risk of severe hypotension and 
renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single 
functioning kidney are treated with angiotensin converting enzyme inhibitors or angiotensin-II 
receptor antagonists. While this is not documented with Irbesartan Hydrochlorothiazide Zentiva, a 
similar effect should be anticipated. 
 
Renal impairment and kidney transplantation: when Irbesartan Hydrochlorothiazide Zentiva is used in 
patients with impaired renal function, a periodic monitoring of potassium, creatinine and uric acid 
serum levels is recommended. There is no experience regarding the administration of Irbesartan 
Hydrochlorothiazide Zentiva in patients with a recent kidney transplantation. Irbesartan 
Hydrochlorothiazide Zentiva should not be used in patients with severe renal impairment (creatinine 



 36 

clearance <30 ml/min) (see section 4.3). Thiazide diuretic-associated azotemia may occur in patients 
with impaired renal function. No dosage adjustment is necessary in patients with renal impairment 
whose creatinine clearance is ≥ 30 ml/min. However, in patients with mild to moderate renal 
impairment (creatinine clearance ≥ 30 ml/min but <60 ml/min) this fixed dose combination should be 
administered with caution. 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the 
concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of 
hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual 
blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or 
aliskiren is therefore not recommended (see sections 4.5 and 5.1).  If dual blockade therapy is 
considered absolutely necessary, this should only occur under specialist supervision and subject to 
frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and 
angiotensin II receptor blockers should not be used concomitantly in patients with diabetic 
nephropathy. 
 
 
Hepatic impairment: thiazides should be used with caution in patients with impaired hepatic function 
or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate 
hepatic coma. There is no clinical experience with Irbesartan Hydrochlorothiazide Zentiva in patients 
with hepatic impairment. 
 
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, 
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive 
hypertrophic cardiomyopathy. 
 
Primary aldosteronism: patients with primary aldosteronism generally will not respond to 
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. 
Therefore, the use of Irbesartan Hydrochlorothiazide Zentiva is not recommended. 
 
Metabolic and endocrine effects: thiazide therapy may impair glucose tolerance. In diabetic patients 
dosage adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes mellitus 
may become manifest during thiazide therapy. 
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; 
however at the 12.5 mg dose contained in Irbesartan Hydrochlorothiazide Zentiva, minimal or no 
effects were reported. 
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide 
therapy. 
 
Electrolyte imbalance: as for any patient receiving diuretic therapy, periodic determination of serum 
electrolytes should be performed at appropriate intervals. 
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia, 
hyponatraemia, and hypochloremic alkalosis). Warning signs of fluid or electrolyte imbalance are 
dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, 
muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea 
or vomiting. 
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with 
irbesartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patients 
with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving 
inadequate oral intake of electrolytes and in patients receiving concomitant therapy with 
corticosteroids or ACTH. Conversely, due to the irbesartan component of Irbesartan 
Hydrochlorothiazide Zentiva hyperkalaemia might occur, especially in the presence of renal 
impairment and/or heart failure, and diabetes mellitus. Adequate monitoring of serum potassium in 
patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-
containing salts substitutes should be co-administered cautiously with Irbesartan Hydrochlorothiazide 
Zentiva (see section 4.5). 



 37 

There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatraemia. Chloride 
deficit is generally mild and usually does not require treatment. 
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of 
serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia 
may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out 
tests for parathyroid function. 
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in 
hypomagnaesemia. 
 
Lithium: the combination of lithium and Irbesartan Hydrochlorothiazide Zentiva is not recommended 
(see section 4.5). 
 
Anti-doping test: hydrochlorothiazide contained in this medicinal product could produce a positive 
analytic result in an anti-doping test. 
 
General: in patients whose vascular tone and renal function depend predominantly on the activity of 
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or 
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting 
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated 
with acute hypotension, azotemia, oliguria, or rarely acute renal failure (see Section 4.5). As with any 
antihypertensive agent, excessive blood pressure decrease in patients with ischemic cardiopathy or 
ischemic cardiovascular disease could result in a myocardial infarction or stroke. 
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of 
allergy or bronchial asthma, but are more likely in patients with such a history. 
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide 
diuretics. 
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If 
photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-
administration 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). 
 
 
Acute Myopia and Secondary Acute Angle-Closure Glaucoma: sulfonamide drugs or sulfonamide 
derivative drugs can cause an idiosyncratic reaction, resulting in transient myopia and acute angle-
closure glaucoma. While hydrochlorothiazide is a sulfonamide, only isolated cases of acute angle-
closure glaucoma have been reported so far with hydrochlorothiazide. Symptoms include acute onset 
of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. 
Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to 
discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be 
considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-
closure glaucoma may include a history of sulfonamide or penicillin allergy (see section 4.8). 
 
Lactose: patients with rare hereditary problems of galactose intolerance, total lactase deficiency or 
glucose-galactose malabsorption should not take this medicine. 
 
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. 



 38 

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



 39 

consideration should be given to monitoring renal function after initiation of concomitant therapy, and 
periodically thereafter. 
 
Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan 
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser 
extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were 
observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by 
CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan 
have not been evaluated. The pharmacokinetic of digoxin was not altered by co-administration of 
irbesartan. 
 
Additional information on hydrochlorothiazide interactions: when administered concurrently, the 
following medicinal products may interact with thiazide diuretics: 
 
Alcohol: potentiation of orthostatic hypotension may occur; 
 
Antidiabetic medicinal products (oral agents and insulins): dosage adjustment of the antidiabetic 
medicinal product may be required (see section 4.4); 
 
Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is impaired in the presence of 
anionic exchange resins. Irbesartan Hydrochlorothiazide Zentiva should be taken at least one hour 
before or four hours after these medications; 
 
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be increased; 
 
Digitalis glycosides: thiazide induced hypokalaemia or hypomagnaesemia favour the onset of 
digitalis-induced cardiac arrhythmias (see section 4.4); 
 
Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory drug 
may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients; 
 
Pressor amines (e.g. noradrenaline): the effect of pressor amines may be decreased, but not 
sufficiently to preclude their use; 
 
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): the effect of nondepolarizing skeletal 
muscle relaxants may be potentiated by hydrochlorothiazide; 
 
Antigout medicinal products: dosage adjustments of antigout medicinal products may be necessary as 
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or 
sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence 
of hypersensitivity reactions to allopurinol; 
 
Calcium salts: thiazide diuretics may increase serum calcium levels due to decreased excretion. If 
calcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be 
prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly; 
 
Carbamazepine: concomitant use of carbamazepine and hydrochlorothiazide has been associated with 
the risk of symptomatic hyponatraemia. Electrolytes should be monitored during concomitant use. If 
possible, another class of diuretics should be used; 
 

Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by 
thiazides. Anticholinergic agents (e.g. atropine, beperiden) may increase the bioavailability of 
thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides 
may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal 
excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their 
myelosuppressive effects. 
 



 40 

4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
Angiotensin II Receptor Antagonists (AIIRAs) 

 
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The 
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 
and 4.4). 
 
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors 
during the first trimester of pregnancy has not been conclusive; however a small increase in risk 
cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II 
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued 
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative 
antihypertensive treatments which have an established safety profile for use in pregnancy. When 
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, 
alternative therapy should be started. 
 
Exposure to AIIRA therapy during the second and third trimesters is known to induce human 
foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal 
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see 
sections 4.3 and 4.4). 
 
Hydrochlorothiazide 

 
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first 
trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the 
pharmacological mechanism of action of hydrochlorothiazide its use during the second and third 
trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like 
icterus, disturbance of electrolyte balance and thrombocytopenia. 
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or 
preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a 
beneficial effect on the course of the disease. 
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare 
situations where no other treatment could be used. 
 
Since Irbesartan Hydrochlorothiazide Zentiva contains hydrochlorothiazide, it is not recommended 
during the first trimester of pregnancy. A switch to a suitable alternative treatment should be carried 
out in advance of a planned pregnancy. 
 
Breast-feeding 
 
Angiotensin II Receptor Antagonists (AIIRAs) 

 
Because no information is available regarding the use of Irbesartan Hydrochlorothiazide Zentiva 
during breast-feeding, Irbesartan Hydrochlorothiazide Zentiva is not recommended and alternative 
treatments with better established safety profiles during breast-feeding are preferable, especially while 
nursing a newborn or preterm infant. 
 
It is unknown whether irbesartan or its metabolites are excreted in human milk.  
Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its 
metabolites in milk (for details see 5.3). 
 



 41 

Hydrochlorothiazide 

 
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing 
intense diuresis can inhibit the milk production. The use of Irbesartan Hydrochlorothiazide Zentiva 
during breast feeding is not recommended. If Irbesartan Hydrochlorothiazide Zentiva 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). 
 
4.7 Effects on ability to drive and use machines 
 
Based on its pharmacodynamic properties, Irbesartan Hydrochlorothiazide Zentiva is unlikely to affect 
the ability to drive and use machines. When driving vehicles or operating machines, it should be taken 
into account that occasionally dizziness or weariness may occur during treatment of hypertension. 
 
4.8 Undesirable effects 
 
Irbesartan/hydrochlorothiazide combination: 
Among 898 hypertensive patients who received various doses of irbesartan/hydrochlorothiazide 
(range: 37.5 mg/6.25 mg to 300 mg/25 mg) in placebo-controlled trials, 29.5% of the patients 
experienced adverse reactions. The most commonly reported ADRs were dizziness (5.6%), fatigue 
(4.9%), nausea/vomiting (1.8%), and abnormal urination (1.4%). In addition, increases in blood urea 
nitrogen (BUN) (2.3%), creatine kinase (1.7%) and creatinine (1.1%) were also commonly observed in 
the trials. 
 
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled 
trials. 
 
The frequency of adverse reactions listed below is defined using the following convention: 
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare 
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects 
are presented in order of decreasing seriousness. 
 

Table 1: Adverse Reactions in Placebo-Controlled Trials and Spontaneous Reports 
Investigations: Common: increases in blood urea nitrogen (BUN), 

creatinine and creatine kinase 
Uncommon: decreases in serum potassium and sodium 

Cardiac disorders: Uncommon: syncope, hypotension, tachycardia, oedema 
Nervous system disorders: Common: dizziness 

Uncommon: orthostatic dizziness 
Not known: headache 

Ear and labyrinth disorders: Not known: tinnitus 
Respiratory, thoracic and 

mediastinal disorders: 

Not known: cough 

Gastrointestinal disorders: Common: nausea/vomiting 
Uncommon: diarrhoea 
Not known: dyspepsia, dysgeusia 

Renal and urinary disorders: Common: abnormal urination 
Not known: impaired renal function including isolated cases 

of renal failure in patients at risk (see 
section 4.4) 

Musculoskeletal and connective 

tissue disorders: 
Uncommon: swelling extremity 
Not known: arthralgia, myalgia 



 42 

Metabolism and nutrition 

disorders: 

Not known: hyperkalaemia 

Vascular disorders: Uncommon: flushing 
General disorders and 

administration site conditions: 
Common: fatigue 

Immune system disorders: Not known: cases of hypersensitivity reactions such as 
angioedema, rash, urticaria 

Hepatobiliary disorders: Uncommon: 
Not known: 

jaundice 
hepatitis, abnormal liver function 

Reproductive system and breast 

disorders: 
Uncommon: sexual dysfunction, libido changes 

 
Additional information on individual components: in addition to the adverse reactions listed above for 
the combination product, other adverse reactions previously reported with one of the individual 
components may be potential adverse reactions with Irbesartan Hydrochlorothiazide Zentiva. Tables 2 
and 3 below detail the adverse reactions reported with the individual components of Irbesartan 
Hydrochlorothiazide Zentiva. 
 
Table 2: Adverse reactions reported with the use of irbesartan alone 
Blood and lymphatic system 

disorders: 

Not known: thrombocytopenia  

General disorders and 

administration site conditions: 

Uncommon: chest pain 

Immune system disorders: Not known: Anaphylactic reaction including anaphylactic 
shock 

 
Table 3: Adverse reactions reported with the use of hydrochlorothiazide alone 
Investigations: Not known: electrolyte imbalance (including hypokalaemia 

and hyponatraemia, see section 4.4), 
hyperuricaemia, glycosuria, hyperglycaemia, 
increases in cholesterol and triglycerides 

Cardiac disorders: Not known: cardiac arrhythmias 
Blood and lymphatic system 

disorders: 
Not known: aplastic anaemia, bone marrow depression, 

neutropenia/agranulocytosis, haemolytic 
anaemia, leucopenia, thrombocytopenia 

Nervous system disorders: Not known: vertigo, paraesthesia, light-headedness, 
restlessness 

Eye disorders: Not known: transient blurred vision, xanthopsia, acute 
myopia and secondary acute angle-closure 
glaucoma 

Respiratory, thoracic and 

mediastinal disorders: 

Not known: respiratory distress (including pneumonitis and 
pulmonary oedema) 

Gastrointestinal disorders: Not known: pancreatitis, anorexia, diarrhoea, constipation, 
gastric irritation, sialadenitis, loss of appetite 

Renal and urinary disorders: Not known: interstitial nephritis, renal dysfunction 
Skin and subcutaneous tissue 

disorders: 

Not known: anaphylactic reactions, toxic epidermal 
necrolysis, necrotizing angitis (vasculitis, 
cutaneous vasculitis), cutaneous lupus 
erythematosus-like reactions, reactivation of 
cutaneous lupus erythematosus, photosensitivity 
reactions, rash, urticaria 

Musculoskeletal and connective 

tissue disorders: 

Not known: weakness, muscle spasm 

Vascular disorders: Not known: postural hypotension 
General disorders and 

administration site conditions: 

Not known: fever 



 43 

Hepatobiliary disorders: Not known: jaundice (intrahepatic cholestatic jaundice) 
Psychiatric disorders: Not known: depression, sleep disturbances 
Neoplasms benign, malignant 

and unspecified (incl cysts and 

polyps) 

Not known: non-melanoma skin cancer (basal cell 
carcinoma and squamous cell carcinoma) 

 
Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose 
dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1). 
 
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may 
increase when titrating the hydrochlorothiazide. 
 
Reporting of suspected adverse reactions  
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 in Appendix V.  
 
4.9 Overdose 
 
No specific information is available on the treatment of overdose with Irbesartan Hydrochlorothiazide 
Zentiva. 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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: angiotensin-II antagonists, combinations 
ATC code: C09DA04. 
 
Mechanism of action 
 
Irbesartan Hydrochlorothiazide Zentiva 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 



 44 

or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors 
results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma 
aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at 
the recommended doses in patients without risk of electrolyte imbalance (see sections 4.4 and 4.5). 
Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also 
degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its 
activity. 
 
Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive effect of thiazide 
diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, 
directly increasing excretion of sodium and chloride in approximately equivalent amounts. The 
diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, 
increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, 
and decreases in serum potassium. Presumably through blockade of the renin-angiotensin-aldosterone 
system, co-administration of irbesartan tends to reverse the potassium loss associated with these 
diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at 
about 4 hours, while the action persists for approximately 6-12 hours. 
 
The combination of hydrochlorothiazide and irbesartan produces dose-related additive reductions in 
blood pressure across their therapeutic dose ranges. The addition of 12.5 mg hydrochlorothiazide to 
300 mg irbesartan once daily in patients not adequately controlled on 300 mg irbesartan alone resulted 
in further placebo-corrected diastolic blood pressure reductions at trough (24 hours post-dosing) of 
6.1 mm Hg. The combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide resulted in an 
overall placebo-subtracted systolic/diastolic reductions of up to 13.6/11.5 mm Hg. 
 
Limited clinical data (7 out of 22 patients) suggest that patients not controlled with the 
300 mg/12.5 mg combination may respond when uptitrated to 300 mg/25 mg. In these patients, an 
incremental blood pressure lowering effect was observed for both systolic blood pressure (SBP) and 
diastolic blood pressure (DBP) (13.3 and 8.3 mm Hg, respectively). 
 
Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide gave systolic/diastolic 
mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of 12.9/6.9 mm Hg 
in patients with mild-to-moderate hypertension. Peak effects occurred at 3-6 hours. When assessed by 
ambulatory blood pressure monitoring, the combination 150 mg irbesartan and 12.5 mg 
hydrochlorothiazide once daily produced consistent reduction in blood pressure over the 24 hours 
period with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mm Hg. When 
measured by ambulatory blood pressure monitoring, the trough to peak effects of Irbesartan 
Hydrochlorothiazide Zentiva 150 mg/12.5 mg were 100%. The trough to peak effects measured by 
cuff during office visits were 68% and 76% for Irbesartan Hydrochlorothiazide 
Zentiva 150 mg/12.5 mg and Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg, respectively. 
These 24-hour effects were observed without excessive blood pressure lowering at peak and are 
consistent with safe and effective blood-pressure lowering over the once-daily dosing interval. 
 
In patients not adequately controlled on 25 mg hydrochlorothiazide alone, the addition of irbesartan 
gave an added placebo-subtracted systolic/diastolic mean reduction of 11.1/7.2 mm Hg. 
 
The blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide is apparent 
after the first dose and substantially present within 1-2 weeks, with the maximal effect occurring by 
6-8 weeks. In long-term follow-up studies, the effect of irbesartan/hydrochlorothiazide was maintained 
for over one year. Although not specifically studied with the Irbesartan Hydrochlorothiazide Zentiva, 
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. 
 



 45 

There is no difference in response to Irbesartan Hydrochlorothiazide Zentiva, 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. 
 
Clinical efficacy and safety 
 
Efficacy and safety of Irbesartan Hydrochlorothiazide Zentiva as initial therapy for severe 
hypertension (defined as SeDBP ≥ 110 mmHg) was evaluated in a multicentre, 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 force-titrated (before assessing the response to the lower dose) after one week to 
irbesartan/hydrochlorothiazide 300 mg/25 mg or irbesartan 300 mg, respectively. 
 
The study recruited 58% males. The mean age of patients was 52.5 years, 13% were ≥ 65 years of age, 
and just 2% were ≥ 75 years of age. Twelve percent (12%) of patients were diabetic, 34% were 
hyperlipidemic and the most frequent cardiovascular condition was stable angina pectoris in 3.5% of 
the participants. 
 
The primary objective of this study was to compare the proportion of patients whose SeDBP was 
controlled (SeDBP < 90 mmHg) at Week 5 of treatment. Forty-seven percent (47.2%) of patients on 
the combination achieved trough SeDBP < 90 mmHg compared to 33.2% of patients on irbesartan 
(p = 0.0005). The mean baseline blood pressure was approximately 172/113 mmHg in each treatment 
group and decreases of SeSBP/SeDBP at five weeks were 30.8/24.0 mmHg and 21.1/19.3 mmHg for 
irbesartan/hydrochlorothiazide and irbesartan, respectively (p < 0.0001). 
 
The types and incidences of adverse events reported for patients treated with the combination were 
similar to the adverse event profile for patients on monotherapy. During the 8-week treatment period, 
there were no reported cases of syncope in either treatment group. There were 0.6% and 0% of patients 
with hypotension and 2.8% and 3.1% of patients with dizziness as adverse reactions reported in the 
combination and monotherapy groups, respectively. 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) 
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in 
combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs 
Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an 
angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of 
cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of 
end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and 
diabetic nephropathy. 
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and 
mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as 
compared to monotherapy was observed. Given their similar pharmacodynamic properties, these 
results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. 
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in 
patients with diabetic nephropathy. 
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) 
was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor 
or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney 
disease, cardiovascular disease, or both. The study was terminated early because of an increased risk 
of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the 
aliskiren group that in the placebo group and adverse events and serious adverse events of interest 
(hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren 
group than in the placebo group. 
 
 



 46 

Non-melanoma skin cancer:  

Based on available data from epidemiological studies, cumulative dosedependent 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 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). 
 
5.2 Pharmacokinetic properties 
 
Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the 
pharmacokinetics of either medicinal product. 
 
Absorption 
 
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for 
their activity. Following oral administration of Irbesartan Hydrochlorothiazide Zentiva, the absolute 
oral bioavailability is 60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food 
does not affect the bioavailability of Irbesartan Hydrochlorothiazide Zentiva. Peak plasma 
concentration occurs at 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for 
hydrochlorothiazide. 
 
Distribution 
 
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. 
 
Linearity / non-linearity 
 
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 oldersubjects (≥ 65 years) than those of young subjects (18-40 years). However the terminal 
half-life was not significantly altered. No dosage adjustment is necessary inolder people. The mean 
plasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hours. 
 
Biotransformation 
 
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.  
 
Elimination 
 



 47 

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. 
 
5.3 Preclinical safety data 
 
Irbesartan/hydrochlorothiazide 
 
The potential toxicity of the irbesartan/hydrochlorothiazide combination after oral administration was 
evaluated in rats and macaques in studies lasting up to 6 months. There were no toxicological findings 
observed of relevance to human therapeutic use. 
The following changes, observed in rats and macaques receiving the irbesartan/hydrochlorothiazide 
combination at 10/10 and 90/90 mg/kg/day, were also seen with one of the two medicinal products 
alone and/or were secondary to decreases in blood pressure (no significant toxicologic interactions 
were observed): 
• kidney changes, characterized by slight increases in serum urea and creatinine, and 

hyperplasia/hypertrophy of the juxtaglomerular apparatus, which are a direct consequence of the 
interaction of irbesartan with the renin-angiotensin system; 

• slight decreases in erythrocyte parameters (erythrocytes, haemoglobin, haematocrit); 
• stomach discoloration, ulcers and focal necrosis of gastric mucosa were observed in few rats in 

a 6 months toxicity study at irbesartan 90 mg/kg/day, hydrochlorothiazide 90 mg/kg/day, and 
irbesartan/hydrochlorothiazide 10/10 mg/kg/day. These lesions were not observed in macaques; 

• decreases in serum potassium due to hydrochlorothiazide and partly prevented when 
hydrochlorothiazide was given in combination with irbesartan. 

Most of the above mentioned effects appear to be due to the pharmacological activity of irbesartan 
(blockade of angiotensin-II-induced inhibition of renin release, with stimulation of the renin-producing 
cells) and occur also with angiotensin converting enzyme inhibitors. These findings appear to have no 
relevance to the use of therapeutic doses of irbesartan/hydrochlorothiazide in humans. 
 
No teratogenic effects were seen in rats given irbesartan and hydrochlorothiazide in combination at 
doses that produced maternal toxicity. The effects of the irbesartan/hydrochlorothiazide combination 
on fertility have not been evaluated in animal studies, as there is no evidence of adverse effect on 
fertility in animals or humans with either irbesartan or hydrochlorothiazide when administered alone. 
However, another angiotensin-II antagonist affected fertility parameters in animal studies when given 
alone. These findings were also observed with lower doses of this other angiotensin-II antagonist when 
given in combination with hydrochlorothiazide. 
 
There was no evidence of mutagenicity or clastogenicity with the irbesartan/hydrochlorothiazide 
combination. The carcinogenic potential of irbesartan and hydrochlorothiazide in combination has not 
been evaluated in animal studies. 
 
Irbesartan 



 48 

 
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 
foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. 
Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. 
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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
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 
 
6.2 Incompatibilities 
 
Not applicable. 



 49 

 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Do not store above 30°C. 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
Cartons of 14 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 28 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 30 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 84 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 90 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 98 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 x 1 film-coated tablets in PVC/PVDC/Aluminium perforated unit dose blisters. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/377/011-016 
EU/1/06/377/029-030 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 January 2007 
Date of latest renewal: 19 January 2012 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/ 



 50 

1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 300 mg of irbesartan and 12.5 mg of hydrochlorothiazide. 
 
Excipient with known effect: 
Each film-coated tablet contains 89.5 mg of lactose (as lactose monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
Peach, biconvex, oval-shaped, with a heart debossed on one side and the number 2876 engraved on the 
other side. 
 
 
4. CLINICAL PARTICULARS 
 
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). 
 
4.2 Posology and method of administration 
 
Posology 
 
Irbesartan Hydrochlorothiazide Zentiva can be taken once daily, with or without food.  
Dose titration with the individual components (i.e. irbesartan and hydrochlorothiazide) may be 
recommended. 
 
When clinically appropriate direct change from monotherapy to the fixed combinations may be 
considered: 
• Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg may be administered in patients whose 

blood pressure is not adequately controlled with hydrochlorothiazide or irbesartan 150 mg 
alone; 

• Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg may be administered in patients 
insufficiently controlled by irbesartan 300 mg or by Irbesartan Hydrochlorothiazide 
Zentiva 150 mg/12.5 mg. 

• Irbesartan Hydrochlorothiazide Zentiva 300 mg/25 mg may be administered in patients 
insufficiently controlled by Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg. 

 
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended. 
When necessary, Irbesartan Hydrochlorothiazide Zentiva may be administered with another 
antihypertensive medicinal product (see sections 4.3, 4.4, 4.5 and 5.1). 
 
Special populations 
 
Renal impairment 

 



 51 

Due to the hydrochlorothiazide component, Irbesartan Hydrochlorothiazide Zentiva is not 
recommended for patients with severe renal dysfunction (creatinine clearance <30 ml/min). Loop 
diuretics are preferred to thiazides in this population. No dosage adjustment is necessary in patients 
with renal impairment whose renal creatinine clearance is ≥30 ml/min (see sections 4.3 and 4.4). 
 
Hepatic impairment 

 

Irbesartan Hydrochlorothiazide Zentiva is not indicated in patients with severe hepatic impairment. 
Thiazides should be used with caution in patients with impaired hepatic function. No dosage 
adjustment of Irbesartan Hydrochlorothiazide Zentiva is necessary in patients with mild to moderate 
hepatic impairment (see section 4.3). 
 
Older people 

 

No dosage adjustment of Irbesartan Hydrochlorothiazide Zentiva is necessary inolder people. 
 
Paediatric population 

 

Irbesartan Hydrochlorothiazide Zentiva 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. 
 
4.3 Contraindications 
 
▪ Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or to 

other sulfonamide-derived substances (hydrochlorothiazide is a sulfonamide-derived substance) 
▪ Second and third trimesters of pregnancy (see sections 4.4 and 4.6) 
▪ Severe renal impairment (creatinine clearance < 30 ml/min) 
▪ Refractory hypokalaemia, hypercalcaemia 
▪ Severe hepatic impairment, biliary cirrhosis and cholestasis 
▪ The concomitant use of Irbesartan Hydrochlorothiazide Zentiva with aliskiren-containing products 

is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate 
(GFR) <60 ml/min/1.73 m²) (see sections 4.5 and 5.1). 

 
4.4 Special warnings and precautions for use 
 
Hypotension - Volume-depleted patients: Irbesartan Hydrochlorothiazide Zentiva has been rarely 
associated with symptomatic hypotension in hypertensive patients without other risk factors for 
hypotension. Symptomatic hypotension may be expected to occur in patients who are volume and/or 
sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such 
conditions should be corrected before initiating therapy with Irbesartan Hydrochlorothiazide Zentiva. 
 
Renal artery stenosis - Renovascular hypertension: there is an increased risk of severe hypotension and 
renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single 
functioning kidney are treated with angiotensin converting enzyme inhibitors or angiotensin-II 
receptor antagonists. While this is not documented with Irbesartan Hydrochlorothiazide Zentiva, a 
similar effect should be anticipated. 
 
Renal impairment and kidney transplantation: when Irbesartan Hydrochlorothiazide Zentiva is used in 
patients with impaired renal function, a periodic monitoring of potassium, creatinine and uric acid 
serum levels is recommended. There is no experience regarding the administration of Irbesartan 
Hydrochlorothiazide Zentiva in patients with a recent kidney transplantation. Irbesartan 
Hydrochlorothiazide Zentiva 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 



 52 

with impaired renal function. No dosage adjustment is necessary in patients with renal impairment 
whose creatinine clearance is ≥30 ml/min. However, in patients with mild to moderate renal 
impairment (creatinine clearance ≥30 ml/min but <60 ml/min) this fixed dose combination should be 
administered with caution. 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the 
concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of 
hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual 
blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or 
aliskiren is therefore not recommended (see sections 4.5 and 5.1).  If dual blockade therapy is 
considered absolutely necessary, this should only occur under specialist supervision and subject to 
frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and 
angiotensin II receptor blockers should not be used concomitantly in patients with diabetic 
nephropathy. 
 
Hepatic impairment: thiazides should be used with caution in patients with impaired hepatic function 
or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate 
hepatic coma. There is no clinical experience with Irbesartan Hydrochlorothiazide Zentiva in patients 
with hepatic impairment. 
 
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, 
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive 
hypertrophic cardiomyopathy. 
 
Primary aldosteronism: patients with primary aldosteronism generally will not respond to 
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. 
Therefore, the use of Irbesartan Hydrochlorothiazide Zentiva is not recommended. 
 
Metabolic and endocrine effects: thiazide therapy may impair glucose tolerance. In diabetic patients 
dosage adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes mellitus 
may become manifest during thiazide therapy. 
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; 
however at the 12.5 mg dose contained in Irbesartan Hydrochlorothiazide Zentiva, minimal or no 
effects were reported. 
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide 
therapy. 
 
Electrolyte imbalance: as for any patient receiving diuretic therapy, periodic determination of serum 
electrolytes should be performed at appropriate intervals. 
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia, 
hyponatraemia, and hypochloremic alkalosis). Warning signs of fluid or electrolyte imbalance are 
dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, 
muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea 
or vomiting. 
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with 
irbesartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patients 
with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving 
inadequate oral intake of electrolytes and in patients receiving concomitant therapy with 
corticosteroids or ACTH. Conversely, due to the irbesartan component of Irbesartan 
Hydrochlorothiazide Zentiva hyperkalaemia might occur, especially in the presence of renal 
impairment and/or heart failure, and diabetes mellitus. Adequate monitoring of serum potassium in 
patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-
containing salts substitutes should be co-administered cautiously with Irbesartan Hydrochlorothiazide 
Zentiva (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. 



 53 

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of 
serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia 
may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out 
tests for parathyroid function. 
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in 
hypomagnaesemia. 
 
Lithium: the combination of lithium and Irbesartan Hydrochlorothiazide Zentiva is not recommended 
(see section 4.5). 
 
Anti-doping test: hydrochlorothiazide contained in this medicinal product could produce a positive 
analytic result in an anti-doping test. 
 
General: in patients whose vascular tone and renal function depend predominantly on the activity of 
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or 
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting 
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated 
with acute hypotension, azotemia, oliguria, or rarely acute renal failure (see Section 4.5). As with any 
antihypertensive agent, excessive blood pressure decrease in patients with ischemic cardiopathy or 
ischemic cardiovascular disease could result in a myocardial infarction or stroke. 
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of 
allergy or bronchial asthma, but are more likely in patients with such a history. 
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide 
diuretics. 
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If 
photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-
administration 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). 
 
Acute Myopia and Secondary Acute Angle-Closure Glaucoma: sulfonamide drugs or sulfonamide 
derivative drugs can cause an idiosyncratic reaction, resulting in transient myopia and acute angle-
closure glaucoma. While hydrochlorothiazide is a sulfonamide, only isolated cases of acute angle-
closure glaucoma have been reported so far with hydrochlorothiazide. Symptoms include acute onset 
of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. 
Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to 
discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be 
considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-
closure glaucoma may include a history of sulfonamide or penicillin allergy (see section 4.8). 
 
Lactose: patients with rare hereditary problems of galactose intolerance, total lactase deficiency or 
glucose-galactose malabsorption should not take this medicine. 
 
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 



 54 

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



 55 

Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan 
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser 
extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were 
observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by 
CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan 
have not been evaluated. The pharmacokinetic of digoxin was not altered by co-administration of 
irbesartan. 
 
Additional information on hydrochlorothiazide interactions: when administered concurrently, the 
following medicinal products may interact with thiazide diuretics: 
 
Alcohol: potentiation of orthostatic hypotension may occur; 
 
Antidiabetic medicinal products (oral agents and insulins): dosage adjustment of the antidiabetic 
medicinal product may be required (see section 4.4); 
 
Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is impaired in the presence of 
anionic exchange resins. Irbesartan Hydrochlorothiazide Zentiva should be taken at least one hour 
before or four hours after these medications; 
 
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be increased; 
 
Digitalis glycosides: thiazide induced hypokalaemia or hypomagnaesemia favour the onset of 
digitalis-induced cardiac arrhythmias (see section 4.4); 
 
Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory drug 
may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients; 
 
Pressor amines (e.g. noradrenaline): the effect of pressor amines may be decreased, but not 
sufficiently to preclude their use; 
 
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): the effect of nondepolarizing skeletal 
muscle relaxants may be potentiated by hydrochlorothiazide; 
 
Antigout medicinal products: dosage adjustments of antigout medicinal products may be necessary as 
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or 
sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence 
of hypersensitivity reactions to allopurinol; 
 
Calcium salts: thiazide diuretics may increase serum calcium levels due to decreased excretion. If 
calcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be 
prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly; 
 
Carbamazepine: concomitant use of carbamazepine and hydrochlorothiazide has been associated with 
the risk of symptomatic hyponatraemia. Electrolytes should be monitored during concomitant use. If 
possible, another class of diuretics should be used; 
 

Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by 
thiazides. Anticholinergic agents (e.g. atropine, beperiden) may increase the bioavailability of 
thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides 
may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal 
excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their 
myelosuppressive effects. 
 



 56 

4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
Angiotensin II Receptor Antagonists (AIIRAs) 

 
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The 
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 
and 4.4). 
 
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors 
during the first trimester of pregnancy has not been conclusive; however a small increase in risk 
cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II 
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued 
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative 
antihypertensive treatments which have an established safety profile for use in pregnancy. When 
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, 
alternative therapy should be started. 
 
Exposure to AIIRA therapy during the second and third trimesters is known to induce human 
foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal 
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see 
sections 4.3 and 4.4). 
 
Hydrochlorothiazide 

 
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first 
trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the 
pharmacological mechanism of action of hydrochlorothiazide its use during the second and third 
trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like 
icterus, disturbance of electrolyte balance and thrombocytopenia. 
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or 
preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a 
beneficial effect on the course of the disease. 
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare 
situations where no other treatment could be used. 
 
Since Irbesartan Hydrochlorothiazide Zentiva contains hydrochlorothiazide, it is not recommended 
during the first trimester of pregnancy. A switch to a suitable alternative treatment should be carried 
out in advance of a planned pregnancy. 
 
Breast-feeding 
 
Angiotensin II Receptor Antagonists (AIIRAs) 

 
Because no information is available regarding the use of Irbesartan Hydrochlorothiazide Zentiva 
during breast-feeding, Irbesartan Hydrochlorothiazide Zentiva is not recommended and alternative 
treatments with better established safety profiles during breast-feeding are preferable, especially while 
nursing a newborn or preterm infant. 
 
It is unknown whether irbesartan or its metabolites are excreted in human milk.  
Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its 
metabolites in milk (for details see 5.3). 
 



 57 

Hydrochlorothiazide 

 
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing 
intense diuresis can inhibit the milk production. The use of Irbesartan Hydrochlorothiazide Zentiva 
during breast feeding is not recommended. If Irbesartan Hydrochlorothiazide Zentiva 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). 
 
4.7 Effects on ability to drive and use machines 
 
Based on its pharmacodynamic properties, Irbesartan Hydrochlorothiazide Zentiva is unlikely to affect 
the ability to drive and use machines. When driving vehicles or operating machines, it should be taken 
into account that occasionally dizziness or weariness may occur during treatment of hypertension. 
 
4.8 Undesirable effects 
 
Irbesartan/hydrochlorothiazide combination: 
Among 898 hypertensive patients who received various doses of irbesartan/hydrochlorothiazide 
(range: 37.5 mg/6.25 mg to 300 mg/25 mg) in placebo-controlled trials, 29.5% of the patients 
experienced adverse reactions. The most commonly reported ADRs were dizziness (5.6%), fatigue 
(4.9%), nausea/vomiting (1.8%), and abnormal urination (1.4%). In addition, increases in blood urea 
nitrogen (BUN) (2.3%), creatine kinase (1.7%) and creatinine (1.1%) were also commonly observed in 
the trials. 
 
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled 
trials. 
 
The frequency of adverse reactions listed below is defined using the following convention: 
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare 
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects 
are presented in order of decreasing seriousness. 
 

Table 1: Adverse Reactions in Placebo-Controlled Trials and Spontaneous Reports 
Investigations: Common: increases in blood urea nitrogen (BUN), 

creatinine and creatine kinase 
Uncommon: decreases in serum potassium and sodium 

Cardiac disorders: Uncommon: syncope, hypotension, tachycardia, oedema 
Nervous system disorders: Common: dizziness 

Uncommon: orthostatic dizziness 
Not known: headache 

Ear and labyrinth disorders: Not known: tinnitus 
Respiratory, thoracic and 

mediastinal disorders: 

Not known: cough 

Gastrointestinal disorders: Common: nausea/vomiting 
Uncommon: diarrhoea 
Not known: dyspepsia, dysgeusia 

Renal and urinary disorders: Common: abnormal urination 
Not known: impaired renal function including isolated cases 

of renal failure in patients at risk (see 
section 4.4) 

Musculoskeletal and connective 

tissue disorders: 
Uncommon: swelling extremity 
Not known: arthralgia, myalgia 



 58 

Metabolism and nutrition 

disorders: 

Not known: hyperkalaemia 

Vascular disorders: Uncommon: flushing 
General disorders and 

administration site conditions: 
Common: fatigue 

Immune system disorders: Not known: cases of hypersensitivity reactions such as 
angioedema, rash, urticaria 

Hepatobiliary disorders: Uncommon: 
Not known: 

jaundice 
hepatitis, abnormal liver function 

Reproductive system and breast 

disorders: 
Uncommon: sexual dysfunction, libido changes 

 
Additional information on individual components: in addition to the adverse reactions listed above for 
the combination product, other adverse reactions previously reported with one of the individual 
components may be potential adverse reactions with Irbesartan Hydrochlorothiazide Zentiva. Tables 2 
and 3 below detail the adverse reactions reported with the individual components of Irbesartan 
Hydrochlorothiazide Zentiva. 
 
Table 2: Adverse reactions reported with the use of irbesartan alone 
Blood and lymphatic system 

disorders: 

Not known: thrombocytopenia  

General disorders and 

administration site conditions: 

Uncommon: chest pain 

Immune system disorders: Not known: Anaphylactic reaction including anaphylactic 
shock 

 
Table 3: Adverse reactions reported with the use of hydrochlorothiazide alone 
Investigations: Not known: electrolyte imbalance (including hypokalaemia 

and hyponatraemia, see section 4.4), 
hyperuricaemia, glycosuria, hyperglycaemia, 
increases in cholesterol and triglycerides 

Cardiac disorders: Not known: cardiac arrhythmias 
Blood and lymphatic system 

disorders: 
Not known: aplastic anaemia, bone marrow depression, 

neutropenia/agranulocytosis, haemolytic 
anaemia, leucopenia, thrombocytopenia 

Nervous system disorders: Not known: vertigo, paraesthesia, light-headedness, 
restlessness 

Eye disorders: Not known: transient blurred vision, xanthopsia, acute 
myopia and secondary acute angle-closure 
glaucoma 

Respiratory, thoracic and 

mediastinal disorders: 

Not known: respiratory distress (including pneumonitis and 
pulmonary oedema) 

Gastrointestinal disorders: Not known: pancreatitis, anorexia, diarrhoea, constipation, 
gastric irritation, sialadenitis, loss of appetite 

Renal and urinary disorders: Not known: interstitial nephritis, renal dysfunction 
Skin and subcutaneous tissue 

disorders: 

Not known: anaphylactic reactions, toxic epidermal 
necrolysis, necrotizing angitis (vasculitis, 
cutaneous vasculitis), cutaneous lupus 
erythematosus-like reactions, reactivation of 
cutaneous lupus erythematosus, photosensitivity 
reactions, rash, urticaria 

Musculoskeletal and connective 

tissue disorders: 

Not known: weakness, muscle spasm 

Vascular disorders: Not known: postural hypotension 
General disorders and 

administration site conditions: 

Not known: fever 



 59 

Hepatobiliary disorders: Not known: jaundice (intrahepatic cholestatic jaundice) 
Psychiatric disorders: Not known: depression, sleep disturbances 
Neoplasms benign, malignant 

and unspecified (incl cysts and 

polyps) 

Not known: non-melanoma skin cancer (basal cell 
carcinoma and squamous cell carcinoma) 

 
Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose 
dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1). 
 
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may 
increase when titrating the hydrochlorothiazide. 
 
Reporting of suspected adverse reactions  
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 in Appendix V.  
 
4.9 Overdose 
 
No specific information is available on the treatment of overdose with Irbesartan Hydrochlorothiazide 
Zentiva. 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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: angiotensin-II antagonists, combinations 
ATC code: C09DA04. 
 
Mechanisme of action 
 
Irbesartan Hydrochlorothiazide Zentiva 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 



 60 

or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors 
results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma 
aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at 
the recommended doses in patients without risk of electrolyte imbalance (see sections 4.4 and 4.5). 
Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also 
degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its 
activity. 
 
Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive effect of thiazide 
diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, 
directly increasing excretion of sodium and chloride in approximately equivalent amounts. The 
diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, 
increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, 
and decreases in serum potassium. Presumably through blockade of the renin-angiotensin-aldosterone 
system, co-administration of irbesartan tends to reverse the potassium loss associated with these 
diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at 
about 4 hours, while the action persists for approximately 6-12 hours. 
 
The combination of hydrochlorothiazide and irbesartan produces dose-related additive reductions in 
blood pressure across their therapeutic dose ranges. The addition of 12.5 mg hydrochlorothiazide to 
300 mg irbesartan once daily in patients not adequately controlled on 300 mg irbesartan alone resulted 
in further placebo-corrected diastolic blood pressure reductions at trough (24 hours post-dosing) of 
6.1 mm Hg. The combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide resulted in an 
overall placebo-subtracted systolic/diastolic reductions of up to 13.6/11.5 mm Hg. 
 
Limited clinical data (7 out of 22 patients) suggest that patients not controlled with the 
300 mg/12.5 mg combination may respond when uptitrated to 300 mg/25 mg. In these patients, an 
incremental blood pressure lowering effect was observed for both systolic blood pressure (SBP) and 
diastolic blood pressure (DBP) (13.3 and 8.3 mm Hg, respectively). 
 
Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide gave systolic/diastolic 
mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of 12.9/6.9 mm Hg 
in patients with mild-to-moderate hypertension. Peak effects occurred at 3-6 hours. When assessed by 
ambulatory blood pressure monitoring, the combination 150 mg irbesartan and 12.5 mg 
hydrochlorothiazide once daily produced consistent reduction in blood pressure over the 24 hours 
period with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mm Hg. When 
measured by ambulatory blood pressure monitoring, the trough to peak effects of Irbesartan 
Hydrochlorothiazide Zentiva 150 mg/12.5 mg were 100%. The trough to peak effects measured by 
cuff during office visits were 68% and 76% for Irbesartan Hydrochlorothiazide 
Zentiva 150 mg/12.5 mg and Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg, respectively. 
These 24-hour effects were observed without excessive blood pressure lowering at peak and are 
consistent with safe and effective blood-pressure lowering over the once-daily dosing interval. 
 
In patients not adequately controlled on 25 mg hydrochlorothiazide alone, the addition of irbesartan 
gave an added placebo-subtracted systolic/diastolic mean reduction of 11.1/7.2 mm Hg. 
 
The blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide is apparent 
after the first dose and substantially present within 1-2 weeks, with the maximal effect occurring by 
6-8 weeks. In long-term follow-up studies, the effect of irbesartan/hydrochlorothiazide was maintained 
for over one year. Although not specifically studied with the Irbesartan Hydrochlorothiazide Zentiva, 
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. 
 



 61 

There is no difference in response to Irbesartan Hydrochlorothiazide Zentiva, 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. 
 
Clinical efficacy and safety 
 
Efficacy and safety of Irbesartan Hydrochlorothiazide Zentiva as initial therapy for severe 
hypertension (defined as SeDBP ≥ 110 mmHg) was evaluated in a multicentre, 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 force-titrated (before assessing the response to the lower dose) after one week to 
irbesartan/hydrochlorothiazide 300 mg/25 mg or irbesartan 300 mg, respectively. 
 
The study recruited 58% males. The mean age of patients was 52.5 years, 13% were ≥ 65 years of age, 
and just 2% were ≥ 75 years of age. Twelve percent (12%) of patients were diabetic, 34% were 
hyperlipidemic and the most frequent cardiovascular condition was stable angina pectoris in 3.5% of 
the participants. 
 
The primary objective of this study was to compare the proportion of patients whose SeDBP was 
controlled (SeDBP < 90 mmHg) at Week 5 of treatment. Forty-seven percent (47.2%) of patients on 
the combination achieved trough SeDBP < 90 mmHg compared to 33.2% of patients on irbesartan 
(p = 0.0005). The mean baseline blood pressure was approximately 172/113 mmHg in each treatment 
group and decreases of SeSBP/SeDBP at five weeks were 30.8/24.0 mmHg and 21.1/19.3 mmHg for 
irbesartan/hydrochlorothiazide and irbesartan, respectively (p < 0.0001). 
 
The types and incidences of adverse events reported for patients treated with the combination were 
similar to the adverse event profile for patients on monotherapy. During the 8-week treatment period, 
there were no reported cases of syncope in either treatment group. There were 0.6% and 0% of patients 
with hypotension and 2.8% and 3.1% of patients with dizziness as adverse reactions reported in the 
combination and monotherapy groups, respectively. 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) 
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in 
combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs 
Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an 
angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of 
cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of 
end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and 
diabetic nephropathy. 
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and 
mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as 
compared to monotherapy was observed. Given their similar pharmacodynamic properties, these 
results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. 
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in 
patients with diabetic nephropathy. 
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) 
was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor 
or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney 
disease, cardiovascular disease, or both. The study was terminated early because of an increased risk 
of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the 
aliskiren group that in the placebo group and adverse events and serious adverse events of interest 
(hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren 
group than in the placebo group. 
 
Non-melanoma skin cancer:  



 62 

Based on available data from epidemiological studies, cumulative dosedependent 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 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). 
 
5.2 Pharmacokinetic properties 
 
Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the 
pharmacokinetics of either medicinal product. 
 
Absorption 
 
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for 
their activity. Following oral administration of Irbesartan Hydrochlorothiazide Zentiva, the absolute 
oral bioavailability is 60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food 
does not affect the bioavailability of Irbesartan Hydrochlorothiazide Zentiva. Peak plasma 
concentration occurs at 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for 
hydrochlorothiazide. 
 
Distribution 
 
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. 
 
Linearity / non-linearity 
 
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 inolder people. The mean 
plasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hours. 
 
Biotransformation 
 
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.  
 
Elimination 
 



 63 

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. 
 
5.3 Preclinical safety data 
 
Irbesartan/hydrochlorothiazide 
 
The potential toxicity of the irbesartan/hydrochlorothiazide combination after oral administration was 
evaluated in rats and macaques in studies lasting up to 6 months. There were no toxicological findings 
observed of relevance to human therapeutic use. 
The following changes, observed in rats and macaques receiving the irbesartan/hydrochlorothiazide 
combination at 10/10 and 90/90 mg/kg/day, were also seen with one of the two medicinal products 
alone and/or were secondary to decreases in blood pressure (no significant toxicologic interactions 
were observed): 
• kidney changes, characterized by slight increases in serum urea and creatinine, and 

hyperplasia/hypertrophy of the juxtaglomerular apparatus, which are a direct consequence of the 
interaction of irbesartan with the renin-angiotensin system; 

• slight decreases in erythrocyte parameters (erythrocytes, haemoglobin, haematocrit); 
• stomach discoloration, ulcers and focal necrosis of gastric mucosa were observed in few rats in a 

6 months toxicity study at irbesartan 90 mg/kg/day, hydrochlorothiazide 90 mg/kg/day, and 
irbesartan/hydrochlorothiazide 10/10 mg/kg/day. These lesions were not observed in macaques; 

• decreases in serum potassium due to hydrochlorothiazide and partly prevented when 
hydrochlorothiazide was given in combination with irbesartan. 

 
Most of the above mentioned effects appear to be due to the pharmacological activity of irbesartan 
(blockade of angiotensin-II-induced inhibition of renin release, with stimulation of the renin-producing 
cells) and occur also with angiotensin converting enzyme inhibitors. These findings appear to have no 
relevance to the use of therapeutic doses of irbesartan/hydrochlorothiazide in humans. 
 
No teratogenic effects were seen in rats given irbesartan and hydrochlorothiazide in combination at 
doses that produced maternal toxicity. The effects of the irbesartan/hydrochlorothiazide combination 
on fertility have not been evaluated in animal studies, as there is no evidence of adverse effect on 
fertility in animals or humans with either irbesartan or hydrochlorothiazide when administered alone. 
However, another angiotensin-II antagonist affected fertility parameters in animal studies when given 
alone. These findings were also observed with lower doses of this other angiotensin-II antagonist when 
given in combination with hydrochlorothiazide. 
 
There was no evidence of mutagenicity or clastogenicity with the irbesartan/hydrochlorothiazide 
combination. The carcinogenic potential of irbesartan and hydrochlorothiazide in combination has not 
been evaluated in animal studies. 
 



 64 

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 
foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. 
Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. 
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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
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 
 



 65 

6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Do not store above 30°C. 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
Cartons of 14 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 28 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 30 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 84 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 90 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 98 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 x 1 film-coated tablets in PVC/PVDC/Aluminium perforated unit dose blisters. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/377/017-022 
EU/1/06/377/031-032 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 January 2007 
Date of latest renewal: 19 January 2012 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/ 



 66 

1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/25 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 300 mg of irbesartan and 25 mg of hydrochlorothiazide. 
 
Excipient with known effect: 
Each film-coated tablet contains 53.3 mg of lactose (as lactose monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
Pink, biconvex, oval-shaped, with a heart debossed on one side and the number 2788 engraved on the 
other side. 
 
 
4. CLINICAL PARTICULARS 
 
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). 
 
4.2 Posology and method of administration 
 
Posology 
 
Irbesartan Hydrochlorothiazide Zentiva can be taken once daily, with or without food.  
Dose titration with the individual components (i.e. irbesartan and hydrochlorothiazide) may be 
recommended. 
 
When clinically appropriate direct change from monotherapy to the fixed combinations may be 
considered: 
• Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg may be administered in patients whose 

blood pressure is not adequately controlled with hydrochlorothiazide or irbesartan 150 mg 
alone; 

• Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg may be administered in patients 
insufficiently controlled by irbesartan 300 mg or by Irbesartan Hydrochlorothiazide 
Zentiva 150 mg/12.5 mg. 

• Irbesartan Hydrochlorothiazide Zentiva 300 mg/25 mg may be administered in patients 
insufficiently controlled by Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg. 

 
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended. 
When necessary, Irbesartan Hydrochlorothiazide Zentiva may be administered with another 
antihypertensive medicinal product (see sections 4.3, 4.4,  4.5 and 5.1). 
 
Special populations 
 
Renal impairment 

 



 67 

Due to the hydrochlorothiazide component, Irbesartan Hydrochlorothiazide Zentiva is not 
recommended for patients with severe renal dysfunction (creatinine clearance <30 ml/min). Loop 
diuretics are preferred to thiazides in this population. No dosage adjustment is necessary in patients 
with renal impairment whose renal creatinine clearance is ≥30 ml/min (see sections 4.3 and 4.4). 
 
Hepatic impairment 

 

Irbesartan Hydrochlorothiazide Zentiva is not indicated in patients with severe hepatic impairment. 
Thiazides should be used with caution in patients with impaired hepatic function. No dosage 
adjustment of Irbesartan Hydrochlorothiazide Zentiva is necessary in patients with mild to moderate 
hepatic impairment (see section 4.3). 
 
Older people 

 

No dosage adjustment of Irbesartan Hydrochlorothiazide Zentiva is necessary in older people. 
 
Paediatric population 

 
Irbesartan Hydrochlorothiazide Zentiva 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. 
 
4.3 Contraindications 
 
▪ Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or to 

other sulfonamide-derived substances (hydrochlorothiazide is a sulfonamide-derived substance) 
▪ Second and third trimesters of pregnancy (see sections 4.4 and 4.6) 
▪ Severe renal impairment (creatinine clearance < 30 ml/min) 
▪ Refractory hypokalaemia, hypercalcaemia 
▪ Severe hepatic impairment, biliary cirrhosis and cholestasis 
▪ The concomitant use of Irbesartan Hydrochlorothiazide Zentiva with aliskiren-containing products 

is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate 
(GFR) <60 ml/min/1.73 m²) (see sections 4.5 and 5.1). 

 
 
4.4 Special warnings and precautions for use 
 
Hypotension - Volume-depleted patients: Irbesartan Hydrochlorothiazide Zentiva has been rarely 
associated with symptomatic hypotension in hypertensive patients without other risk factors for 
hypotension. Symptomatic hypotension may be expected to occur in patients who are volume and/or 
sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such 
conditions should be corrected before initiating therapy with Irbesartan Hydrochlorothiazide Zentiva. 
 
Renal artery stenosis - Renovascular hypertension: there is an increased risk of severe hypotension and 
renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single 
functioning kidney are treated with angiotensin converting enzyme inhibitors or angiotensin-II 
receptor antagonists. While this is not documented with Irbesartan Hydrochlorothiazide Zentiva, a 
similar effect should be anticipated. 
 
Renal impairment and kidney transplantation: when Irbesartan Hydrochlorothiazide Zentiva is used in 
patients with impaired renal function, a periodic monitoring of potassium, creatinine and uric acid 
serum levels is recommended. There is no experience regarding the administration of Irbesartan 
Hydrochlorothiazide Zentiva in patients with a recent kidney transplantation. Irbesartan 
Hydrochlorothiazide Zentiva should not be used in patients with severe renal impairment (creatinine 



 68 

clearance <30 ml/min) (see section 4.3). Thiazide diuretic-associated azotemia may occur in patients 
with impaired renal function. No dosage adjustment is necessary in patients with renal impairment 
whose creatinine clearance is ≥30 ml/min. However, in patients with mild to moderate renal 
impairment (creatinine clearance ≥30 ml/min but <60 ml/min) this fixed dose combination should be 
administered with caution. 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the 
concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of 
hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual 
blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or 
aliskiren is therefore not recommended (see sections 4.5 and 5.1).  If dual blockade therapy is 
considered absolutely necessary, this should only occur under specialist supervision and subject to 
frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and 
angiotensin II receptor blockers should not be used concomitantly in patients with diabetic 
nephropathy. 
 
Hepatic impairment: thiazides should be used with caution in patients with impaired hepatic function 
or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate 
hepatic coma. There is no clinical experience with Irbesartan Hydrochlorothiazide Zentiva in patients 
with hepatic impairment. 
 
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, 
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive 
hypertrophic cardiomyopathy. 
 
Primary aldosteronism: patients with primary aldosteronism generally will not respond to 
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. 
Therefore, the use of Irbesartan Hydrochlorothiazide Zentiva is not recommended. 
 
Metabolic and endocrine effects: thiazide therapy may impair glucose tolerance. In diabetic patients 
dosage adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes mellitus 
may become manifest during thiazide therapy. 
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; 
however at the 12.5 mg dose contained in Irbesartan Hydrochlorothiazide Zentiva, minimal or no 
effects were reported. 
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide 
therapy. 
 
Electrolyte imbalance: as for any patient receiving diuretic therapy, periodic determination of serum 
electrolytes should be performed at appropriate intervals. 
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia, 
hyponatraemia, and hypochloremic alkalosis). Warning signs of fluid or electrolyte imbalance are 
dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, 
muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea 
or vomiting. 
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with 
irbesartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patients 
with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving 
inadequate oral intake of electrolytes and in patients receiving concomitant therapy with 
corticosteroids or ACTH. Conversely, due to the irbesartan component of Irbesartan 
Hydrochlorothiazide Zentiva hyperkalaemia might occur, especially in the presence of renal 
impairment and/or heart failure, and diabetes mellitus. Adequate monitoring of serum potassium in 
patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-
containing salts substitutes should be co-administered cautiously with Irbesartan Hydrochlorothiazide 
Zentiva (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. 



 69 

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of 
serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia 
may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out 
tests for parathyroid function. 
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in 
hypomagnaesemia. 
 
Lithium: the combination of lithium and Irbesartan Hydrochlorothiazide Zentiva is not recommended 
(see section 4.5). 
 
Anti-doping test: hydrochlorothiazide contained in this medicinal product could produce a positive 
analytic result in an anti-doping test. 
 
General: in patients whose vascular tone and renal function depend predominantly on the activity of 
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or 
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting 
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated 
with acute hypotension, azotemia, oliguria, or rarely acute renal failure (see Section 4.5). As with any 
antihypertensive agent, excessive blood pressure decrease in patients with ischemic cardiopathy or 
ischemic cardiovascular disease could result in a myocardial infarction or stroke. 
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of 
allergy or bronchial asthma, but are more likely in patients with such a history. 
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide 
diuretics. 
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If 
photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-
administration 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). 
 
 
Acute Myopia and Secondary Acute Angle-Closure Glaucoma: sulfonamide drugs or sulfonamide 
derivative drugs can cause an idiosyncratic reaction, resulting in transient myopia and acute angle-
closure glaucoma. While hydrochlorothiazide is a sulfonamide, only isolated cases of acute angle-
closure glaucoma have been reported so far with hydrochlorothiazide. Symptoms include acute onset 
of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. 
Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to 
discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be 
considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-
closure glaucoma may include a history of sulfonamide or penicillin allergy (see section 4.8). 
 
Lactose: patients with rare hereditary problems of galactose intolerance, total lactase deficiency or 
glucose-galactose malabsorption should not take this medicine. 
 
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 



 70 

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



 71 

Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan 
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser 
extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were 
observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by 
CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan 
have not been evaluated. The pharmacokinetic of digoxin was not altered by co-administration of 
irbesartan. 
 
Additional information on hydrochlorothiazide interactions: when administered concurrently, the 
following medicinal products may interact with thiazide diuretics: 
 
Alcohol: potentiation of orthostatic hypotension may occur; 
 
Antidiabetic medicinal products (oral agents and insulins): dosage adjustment of the antidiabetic 
medicinal product may be required (see section 4.4); 
 
Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is impaired in the presence of 
anionic exchange resins. Irbesartan Hydrochlorothiazide Zentiva should be taken at least one hour 
before or four hours after these medications; 
 
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be increased; 
 
Digitalis glycosides: thiazide induced hypokalaemia or hypomagnaesemia favour the onset of 
digitalis-induced cardiac arrhythmias (see section 4.4); 
 
Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory drug 
may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients; 
 
Pressor amines (e.g. noradrenaline): the effect of pressor amines may be decreased, but not 
sufficiently to preclude their use; 
 
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): the effect of nondepolarizing skeletal 
muscle relaxants may be potentiated by hydrochlorothiazide; 
 
Antigout medicinal products: dosage adjustments of antigout medicinal products may be necessary as 
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or 
sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence 
of hypersensitivity reactions to allopurinol; 
 
Calcium salts: thiazide diuretics may increase serum calcium levels due to decreased excretion. If 
calcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be 
prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly; 
 
Carbamazepine: concomitant use of carbamazepine and hydrochlorothiazide has been associated with 
the risk of symptomatic hyponatraemia. Electrolytes should be monitored during concomitant use. If 
possible, another class of diuretics should be used; 
 

Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by 
thiazides. Anticholinergic agents (e.g. atropine, beperiden) may increase the bioavailability of 
thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides 
may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal 
excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their 
myelosuppressive effects. 
 



 72 

4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
Angiotensin II Receptor Antagonists (AIIRAs) 

 
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The 
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 
and 4.4). 
 
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors 
during the first trimester of pregnancy has not been conclusive; however a small increase in risk 
cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II 
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued 
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative 
antihypertensive treatments which have an established safety profile for use in pregnancy. When 
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, 
alternative therapy should be started. 
 
Exposure to AIIRA therapy during the second and third trimesters is known to induce human 
foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal 
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see 
sections 4.3 and 4.4). 
 
Hydrochlorothiazide 

 
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first 
trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the 
pharmacological mechanism of action of hydrochlorothiazide its use during the second and third 
trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like 
icterus, disturbance of electrolyte balance and thrombocytopenia. 
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or 
preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a 
beneficial effect on the course of the disease. 
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare 
situations where no other treatment could be used. 
 
Since Irbesartan Hydrochlorothiazide Zentiva contains hydrochlorothiazide, it is not recommended 
during the first trimester of pregnancy. A switch to a suitable alternative treatment should be carried 
out in advance of a planned pregnancy. 
 
Breast-feeding 
 
Angiotensin II Receptor Antagonists (AIIRAs) 

 
Because no information is available regarding the use of Irbesartan Hydrochlorothiazide Zentiva 
during breast-feeding, Irbesartan Hydrochlorothiazide Zentiva is not recommended and alternative 
treatments with better established safety profiles during breast-feeding are preferable, especially while 
nursing a newborn or preterm infant. 
 
It is unknown whether irbesartan or its metabolites are excreted in human milk.  
Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its 
metabolites in milk (for details see 5.3). 
 



 73 

Hydrochlorothiazide 

 
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing 
intense diuresis can inhibit the milk production. The use of Irbesartan Hydrochlorothiazide Zentiva 
during breast feeding is not recommended. If Irbesartan Hydrochlorothiazide Zentiva 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). 
 
4.7 Effects on ability to drive and use machines 
 
Based on its pharmacodynamic properties, Irbesartan Hydrochlorothiazide Zentiva is unlikely to affect 
the ability to drive and use machines. When driving vehicles or operating machines, it should be taken 
into account that occasionally dizziness or weariness may occur during treatment of hypertension. 
 
4.8 Undesirable effects 
 
Irbesartan/hydrochlorothiazide combination: 
Among 898 hypertensive patients who received various doses of irbesartan/hydrochlorothiazide 
(range: 37.5 mg/6.25 mg to 300 mg/25 mg) in placebo-controlled trials, 29.5% of the patients 
experienced adverse reactions. The most commonly reported ADRs were dizziness (5.6%), fatigue 
(4.9%), nausea/vomiting (1.8%), and abnormal urination (1.4%). In addition, increases in blood urea 
nitrogen (BUN) (2.3%), creatine kinase (1.7%) and creatinine (1.1%) were also commonly observed in 
the trials. 
 
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled 
trials. 
 
The frequency of adverse reactions listed below is defined using the following convention: 
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare 
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects 
are presented in order of decreasing seriousness. 
 

Table 1: Adverse Reactions in Placebo-Controlled Trials and Spontaneous Reports 
Investigations: Common: increases in blood urea nitrogen (BUN), 

creatinine and creatine kinase 
Uncommon: decreases in serum potassium and sodium 

Cardiac disorders: Uncommon: syncope, hypotension, tachycardia, oedema 
Nervous system disorders: Common: dizziness 

Uncommon: orthostatic dizziness 
Not known: headache 

Ear and labyrinth disorders: Not known: tinnitus 
Respiratory, thoracic and 

mediastinal disorders: 

Not known: cough 

Gastrointestinal disorders: Common: nausea/vomiting 
Uncommon: diarrhoea 
Not known: dyspepsia, dysgeusia 

Renal and urinary disorders: Common: abnormal urination 
Not known: impaired renal function including isolated cases 

of renal failure in patients at risk (see 
section 4.4) 

Musculoskeletal and connective 

tissue disorders: 
Uncommon: swelling extremity 
Not known: arthralgia, myalgia 



 74 

Metabolism and nutrition 

disorders: 

Not known: hyperkalaemia 

Vascular disorders: Uncommon: flushing 
General disorders and 

administration site conditions: 
Common: fatigue 

Immune system disorders: Not known: cases of hypersensitivity reactions such as 
angioedema, rash, urticaria 

Hepatobiliary disorders: Uncommon: 
Not known: 

jaundice 
hepatitis, abnormal liver function 

Reproductive system and breast 

disorders: 
Uncommon: sexual dysfunction, libido changes 

 
Additional information on individual components: in addition to the adverse reactions listed above for 
the combination product, other adverse reactions previously reported with one of the individual 
components may be potential adverse reactions with Irbesartan Hydrochlorothiazide Zentiva. Tables 2 
and 3 below detail the adverse reactions reported with the individual components of Irbesartan 
Hydrochlorothiazide Zentiva. 
 
Table 2: Adverse reactions reported with the use of irbesartan alone 
Blood and lymphatic system 

disorders: 

Not known: thrombocytopenia  

General disorders and 

administration site conditions: 

Uncommon: chest pain 

Immune system disorders: Not known: Anaphylactic reaction including anaphylactic 
shock 

 
Table 3: Adverse reactions reported with the use of hydrochlorothiazide alone 
Investigations: Not known: electrolyte imbalance (including hypokalaemia 

and hyponatraemia, see section 4.4), 
hyperuricaemia, glycosuria, hyperglycaemia, 
increases in cholesterol and triglycerides 

Cardiac disorders: Not known: cardiac arrhythmias 
Blood and lymphatic system 

disorders: 
Not known: aplastic anaemia, bone marrow depression, 

neutropenia/agranulocytosis, haemolytic 
anaemia, leucopenia, thrombocytopenia 

Nervous system disorders: Not known: vertigo, paraesthesia, light-headedness, 
restlessness 

Eye disorders: Not known: transient blurred vision, xanthopsia, acute 
myopia and secondary acute angle-closure 
glaucoma 

Respiratory, thoracic and 

mediastinal disorders: 

Not known: respiratory distress (including pneumonitis and 
pulmonary oedema) 

Gastrointestinal disorders: Not known: pancreatitis, anorexia, diarrhoea, constipation, 
gastric irritation, sialadenitis, loss of appetite 

Renal and urinary disorders: Not known: interstitial nephritis, renal dysfunction 
Skin and subcutaneous tissue 

disorders: 

Not known: anaphylactic reactions, toxic epidermal 
necrolysis, necrotizing angitis (vasculitis, 
cutaneous vasculitis), cutaneous lupus 
erythematosus-like reactions, reactivation of 
cutaneous lupus erythematosus, photosensitivity 
reactions, rash, urticaria 

Musculoskeletal and connective 

tissue disorders: 

Not known: weakness, muscle spasm 

Vascular disorders: Not known: postural hypotension 
General disorders and 

administration site conditions: 

Not known: fever 



 75 

Hepatobiliary disorders: Not known: jaundice (intrahepatic cholestatic jaundice) 
Psychiatric disorders: Not known: depression, sleep disturbances 
Neoplasms benign, malignant 

and unspecified (incl cysts and 

polyps) 

Not known: non-melanoma skin cancer (basal cell 
carcinoma and squamous cell carcinoma) 

 
Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose 
dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1). 
 
 
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may 
increase when titrating the hydrochlorothiazide. 
 
Reporting of suspected adverse reactions  
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 in Appendix V.  
 
4.9 Overdose 
 
No specific information is available on the treatment of overdose with Irbesartan Hydrochlorothiazide 
Zentiva. 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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: angiotensin-II antagonists, combinations 
ATC code: C09DA04. 
 
Mechanism of action 
 
Irbesartan Hydrochlorothiazide Zentiva 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. 
 



 76 

Irbesartan is a potent, orally active, selective angiotensin-II receptor (AT1 subtype) antagonist. It is 
expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source 
or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors 
results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma 
aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at 
the recommended doses in patients without risk of electrolyte imbalance (see sections 4.4 and 4.5). 
Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also 
degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its 
activity. 
 
Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive effect of thiazide 
diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, 
directly increasing excretion of sodium and chloride in approximately equivalent amounts. The 
diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, 
increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, 
and decreases in serum potassium. Presumably through blockade of the renin-angiotensin-aldosterone 
system, co-administration of irbesartan tends to reverse the potassium loss associated with these 
diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at 
about 4 hours, while the action persists for approximately 6-12 hours. 
 
The combination of hydrochlorothiazide and irbesartan produces dose-related additive reductions in 
blood pressure across their therapeutic dose ranges. The addition of 12.5 mg hydrochlorothiazide to 
300 mg irbesartan once daily in patients not adequately controlled on 300 mg irbesartan alone resulted 
in further placebo-corrected diastolic blood pressure reductions at trough (24 hours post-dosing) of 
6.1 mm Hg. The combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide resulted in an 
overall placebo-subtracted systolic/diastolic reductions of up to 13.6/11.5 mm Hg. 
 
Limited clinical data (7 out of 22 patients) suggest that patients not controlled with the 
300 mg/12.5 mg combination may respond when uptitrated to 300 mg/25 mg. In these patients, an 
incremental blood pressure lowering effect was observed for both systolic blood pressure (SBP) and 
diastolic blood pressure (DBP) (13.3 and 8.3 mm Hg, respectively). 
 
Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide gave systolic/diastolic 
mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of 12.9/6.9 mm Hg 
in patients with mild-to-moderate hypertension. Peak effects occurred at 3-6 hours. When assessed by 
ambulatory blood pressure monitoring, the combination 150 mg irbesartan and 12.5 mg 
hydrochlorothiazide once daily produced consistent reduction in blood pressure over the 24 hours 
period with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mm Hg. When 
measured by ambulatory blood pressure monitoring, the trough to peak effects of Irbesartan 
Hydrochlorothiazide Zentiva 150 mg/12.5 mg were 100%. The trough to peak effects measured by 
cuff during office visits were 68% and 76% for Irbesartan Hydrochlorothiazide 
Zentiva 150 mg/12.5 mg and Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg, respectively. 
These 24-hour effects were observed without excessive blood pressure lowering at peak and are 
consistent with safe and effective blood-pressure lowering over the once-daily dosing interval. 
 
In patients not adequately controlled on 25 mg hydrochlorothiazide alone, the addition of irbesartan 
gave an added placebo-subtracted systolic/diastolic mean reduction of 11.1/7.2 mm Hg. 
 
The blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide is apparent 
after the first dose and substantially present within 1-2 weeks, with the maximal effect occurring by 
6-8 weeks. In long-term follow-up studies, the effect of irbesartan/hydrochlorothiazide was maintained 
for over one year. Although not specifically studied with the Irbesartan Hydrochlorothiazide Zentiva, 
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. 



 77 

 
There is no difference in response to Irbesartan Hydrochlorothiazide Zentiva, 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. 
 
Clinical efficacy and safety 
 
Efficacy and safety of Irbesartan Hydrochlorothiazide Zentiva as initial therapy for severe 
hypertension (defined as SeDBP ≥ 110 mmHg) was evaluated in a multicentre, 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 force-titrated (before assessing the response to the lower dose) after one week to 
irbesartan/hydrochlorothiazide 300 mg/25 mg or irbesartan 300 mg, respectively. 
 
The study recruited 58% males. The mean age of patients was 52.5 years, 13% were ≥ 65 years of age, 
and just 2% were ≥ 75 years of age. Twelve percent (12%) of patients were diabetic, 34% were 
hyperlipidemic and the most frequent cardiovascular condition was stable angina pectoris in 3.5% of 
the participants. 
 
The primary objective of this study was to compare the proportion of patients whose SeDBP was 
controlled (SeDBP < 90 mmHg) at Week 5 of treatment. Forty-seven percent (47.2%) of patients on 
the combination achieved trough SeDBP < 90 mmHg compared to 33.2% of patients on irbesartan 
(p = 0.0005). The mean baseline blood pressure was approximately 172/113 mmHg in each treatment 
group and decreases of SeSBP/SeDBP at five weeks were 30.8/24.0 mmHg and 21.1/19.3 mmHg for 
irbesartan/hydrochlorothiazide and irbesartan, respectively (p < 0.0001). 
 
The types and incidences of adverse events reported for patients treated with the combination were 
similar to the adverse event profile for patients on monotherapy. During the 8-week treatment period, 
there were no reported cases of syncope in either treatment group. There were 0.6% and 0% of patients 
with hypotension and 2.8% and 3.1% of patients with dizziness as adverse reactions reported in the 
combination and monotherapy groups, respectively. 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) 
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in 
combination with Ramipril Global Endpoint Trial) 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 aliskiren 
group than in the placebo group. 
 



 78 

Non-melanoma skin cancer:  

Based on available data from epidemiological studies, cumulative dosedependent 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 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). 
 
5.2 Pharmacokinetic properties 
 
Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the 
pharmacokinetics of either medicinal product. 
 
Absorption 
 
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for 
their activity. Following oral administration of Irbesartan Hydrochlorothiazide Zentiva, the absolute 
oral bioavailability is 60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food 
does not affect the bioavailability of Irbesartan Hydrochlorothiazide Zentiva. Peak plasma 
concentration occurs at 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for 
hydrochlorothiazide. 
 
Distribution 
 
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. 
 
Linearity / non-linearity 
 
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 inolder people. The mean 
plasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hours. 
 
Biotransformation 
 
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.  
 
Elimination 
 



 79 

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. 
 
5.3 Preclinical safety data 
 
Irbesartan/hydrochlorothiazide 
 
The potential toxicity of the irbesartan/hydrochlorothiazide combination after oral administration was 
evaluated in rats and macaques in studies lasting up to 6 months. There were no toxicological findings 
observed of relevance to human therapeutic use. 
The following changes, observed in rats and macaques receiving the irbesartan/hydrochlorothiazide 
combination at 10/10 and 90/90 mg/kg/day, were also seen with one of the two medicinal products 
alone and/or were secondary to decreases in blood pressure (no significant toxicologic interactions 
were observed): 
• kidney changes, characterized by slight increases in serum urea and creatinine, and 

hyperplasia/hypertrophy of the juxtaglomerular apparatus, which are a direct consequence of the 
interaction of irbesartan with the renin-angiotensin system; 

• slight decreases in erythrocyte parameters (erythrocytes, haemoglobin, haematocrit); 
• stomach discoloration, ulcers and focal necrosis of gastric mucosa were observed in few rats in 

a 6 months toxicity study at irbesartan 90 mg/kg/day, hydrochlorothiazide 90 mg/kg/day, and 
irbesartan/hydrochlorothiazide 10/10 mg/kg/day. These lesions were not observed in macaques; 

• decreases in serum potassium due to hydrochlorothiazide and partly prevented when 
hydrochlorothiazide was given in combination with irbesartan. 

 
Most of the above mentioned effects appear to be due to the pharmacological activity of irbesartan 
(blockade of angiotensin-II-induced inhibition of renin release, with stimulation of the renin-producing 
cells) and occur also with angiotensin converting enzyme inhibitors. These findings appear to have no 
relevance to the use of therapeutic doses of irbesartan/hydrochlorothiazide in humans. 
 
No teratogenic effects were seen in rats given irbesartan and hydrochlorothiazide in combination at 
doses that produced maternal toxicity. The effects of the irbesartan/hydrochlorothiazide combination 
on fertility have not been evaluated in animal studies, as there is no evidence of adverse effect on 
fertility in animals or humans with either irbesartan or hydrochlorothiazide when administered alone. 
However, another angiotensin-II antagonist affected fertility parameters in animal studies when given 
alone. These findings were also observed with lower doses of this other angiotensin-II antagonist when 
given in combination with hydrochlorothiazide. 
 
There was no evidence of mutagenicity or clastogenicity with the irbesartan/hydrochlorothiazide 
combination. The carcinogenic potential of irbesartan and hydrochlorothiazide in combination has not 
been evaluated in animal studies. 
 



 80 

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 
foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. 
Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. 
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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Lactose monohydrate 
Microcrystalline cellulose 
Croscarmellose sodium 
Pregelatinised starch 
Silicon dioxide 
Magnesium stearate 
Red and yellow ferric oxides 
 
Film-coating: 
Lactose monohydrate 
Hypromellose 
Titanium dioxide 
Macrogol 3350 
Red and black ferric oxides 
Carnauba wax 
 



 81 

6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Do not store above 30°C. 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
Cartons of 14 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 28 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 30 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 84 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 90 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 98 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 x 1 film-coated tablets in PVC/PVDC/Aluminium perforated unit dose blisters. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/377/023-028 
EU/1/06/377/033-034 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 January 2007 
Date of latest renewal: 19 January 2012 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/ 
 



 82 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 



 83 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
Sanofi Winthrop Industrie 
1 rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex 
France 
 
Chinoin Private Co. Ltd. 
Lévai u.5. 
2112 Veresegyhaz 
Hungary 
 
Sanofi Winthrop Industrie 
30-36, avenue Gustave Eiffel BP7166 
F-37071, 37100 Tours 
France 
 
SANOFI-AVENTIS, S.A. 
Ctra. C-35 (La Batlloria-Hostalric), km. 63.09 
17404 Riells i Viabrea (Girona) – Spain 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 

 
The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for 
under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
▪ Risk Management Plan (RMP) 
 
Not applicable. 
 



 84 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



 85 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 86 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg tablets 
irbesartan/hydrochlorothiazide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCES 
 
Each tablet contains: irbesartan 150 mg and hydrochlorothiazide 12.5 mg 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: also contains lactose monohydrate. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
56 tablets 
56 x 1 tablets 
98 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
Store in the original package in order to protect from moisture. 
 
 



 87 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
12. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/377/001 - 14 tablets 
EU/1/06/377/002 - 28 tablets 
EU/1/06/377/003 - 56 tablets 
EU/1/06/377/004 - 56 x 1 tablets 
EU/1/06/377/005 - 98 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN: 



 88 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg tablets 
irbesartan/hydrochlorothiazide 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
14 - 28 - 56 - 98 tablets: 
Mon 
Tue 
Wed 
Thu 
Fri 
Sat 
Sun 
 
56 x 1 tablets 



 89 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg tablets 
irbesartan/hydrochlorothiazide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCES 
 
Each tablet contains: irbesartan 300 mg and hydrochlorothiazide 12.5 mg 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: also contains lactose monohydrate. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
56 tablets 
56 x 1 tablets 
98 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
Store in the original package in order to protect from moisture. 
 
 



 90 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
12. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/377/006 - 14 tablets 
EU/1/06/377/007 - 28 tablets 
EU/1/06/377/008 - 56 tablets 
EU/1/06/377/009 - 56 x 1 tablets 
EU/1/06/377/010 - 98 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN: 



 91 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg tablets 
irbesartan/hydrochlorothiazide 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
14 - 28 - 56 - 98 tablets: 
Mon 
Tue 
Wed 
Thu 
Fri 
Sat 
Sun 
 
56 x 1 tablets 



 92 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg film-coated tablets 
irbesartan/hydrochlorothiazide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCES 
 
Each tablet contains: irbesartan 150 mg and hydrochlorothiazide 12.5 mg 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: also contains lactose monohydrate. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
30 tablets 
56 tablets 
56 x 1 tablets 
84 tablets 
90 tablets 
98 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 



 93 

Store in the original package in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
12. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/377/011 - 14 tablets 
EU/1/06/377/012 - 28 tablets 
EU/1/06/377/029 - 30 tablets 
EU/1/06/377/013 - 56 tablets 
EU/1/06/377/014 - 56 x 1 tablets 
EU/1/06/377/015 - 84 tablets 
EU/1/06/377/030 - 90 tablets 
EU/1/06/377/016 - 98 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN: 



 94 

 
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg tablets 
irbesartan/hydrochlorothiazide 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
14 - 28 - 56 - 84 - 98 tablets: 
Mon 
Tue 
Wed 
Thu 
Fri 
Sat 
Sun 
 
30 - 56 x 1 - 90 tablets 



 95 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg film-coated tablets 
irbesartan/hydrochlorothiazide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCES 
 
Each tablet contains: irbesartan 300 mg and hydrochlorothiazide 12.5 mg 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: also contains lactose monohydrate. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
30 tablets 
56 tablets 
56 x 1 tablets 
84 tablets 
90 tablets 
98 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 



 96 

Store in the original package in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
12. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/377/017 - 14 tablets 
EU/1/06/377/018 - 28 tablets 
EU/1/06/377/031 - 30 tablets 
EU/1/06/377/019 - 56 tablets 
EU/1/06/377/020 - 56 x 1 tablets 
EU/1/06/377/021 - 84 tablets 
EU/1/06/377/032 - 90 tablets 
EU/1/06/377/022 - 98 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN: 



 97 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg tablets 
irbesartan/hydrochlorothiazide 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
14 - 28 - 56 - 84 - 98 tablets: 
Mon 
Tue 
Wed 
Thu 
Fri 
Sat 
Sun 
 
30 - 56 x 1 - 90 tablets 



 98 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/25 mg film-coated tablets 
irbesartan/hydrochlorothiazide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCES 
 
Each tablet contains: irbesartan 300 mg and hydrochlorothiazide 25 mg 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: also contains lactose monohydrate. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
30 tablets 
56 tablets 
56 x 1 tablets 
84 tablets 
90 tablets 
98 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 



 99 

Store in the original package in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
12. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/377/023 - 14 tablets 
EU/1/06/377/024 - 28 tablets 
EU/1/06/377/033 - 30 tablets 
EU/1/06/377/025 - 56 tablets 
EU/1/06/377/026 - 56 x 1 tablets 
EU/1/06/377/027 - 84 tablets 
EU/1/06/377/034 - 90 tablets 
EU/1/06/377/028 - 98 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/25 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN: 



 100 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/25 mg tablets 
irbesartan/hydrochlorothiazide 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
14 - 28 - 56 - 84 - 98 tablets: 
Mon 
Tue 
Wed 
Thu 
Fri 
Sat 
Sun 
 
30 - 56 x 1 - 90 tablets 
 



 101 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 102 

Package leaflet: Information for the patient 
Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg tablets 

irbesartan/hydrochlorothiazide 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 

•  Keep this leaflet. You may need to read it again. 
•  If you have any further questions, ask your doctor or pharmacist. 
•  This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
•  If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Irbesartan Hydrochlorothiazide Zentiva is and what it is used for 
2. What you need to know before you take Irbesartan Hydrochlorothiazide Zentiva 
3. How to take Irbesartan Hydrochlorothiazide Zentiva 
4. Possible side effects 
5. How to store Irbesartan Hydrochlorothiazide Zentiva 
6. Contents of the pack and other information 
 
 
1. What Irbesartan Hydrochlorothiazide Zentiva is and what it is used for 
 
Irbesartan Hydrochlorothiazide Zentiva is a combination of two active substances, irbesartan and 
hydrochlorothiazide. 
Irbesartan belongs to a group of medicines known as angiotensin-II receptor antagonists. 
Angiotensin-II is a substance produced in the body that binds to receptors in blood vessels causing 
them to tighten. This results in an increase in blood pressure. Irbesartan prevents the binding of 
angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. 
Hydrochlorothiazide is one of a group of medicines (called thiazide diuretics) that causes increased 
urine output and so causes a lowering of blood pressure. 
The two active ingredients in Irbesartan Hydrochlorothiazide Zentiva work together to lower blood 
pressure further than if either was given alone. 
 
Irbesartan Hydrochlorothiazide Zentiva is used to treat high blood pressure, when treatment with 
irbesartan or hydrochlorothiazide alone did not provide adequate control of your blood pressure. 
 
 
2. What you need to know before you take Irbesartan Hydrochlorothiazide Zentiva 
 
Do not take Irbesartan Hydrochlorothiazide Zentiva 
▪ if you are allergic to irbesartan or any of the other ingredients of this medicine (listed in section 6) 
▪ if you are allergic  to hydrochlorothiazide or any other sulfonamide-derived medicines 
▪ if you are more than 3 months pregnant. (It is also better to avoid Irbesartan Hydrochlorothiazide 

Zentiva in early pregnancy – see pregnancy section) 
▪ if you have severe liver or kidney problems 
▪ if you have difficulty in producing urine 
▪ if your doctor determines that you have persistently high calcium or low potassium levels in 

your blood 
▪ if you have diabetes or impaired kidney function and you are treated with a blood pressure 

lowering medicine containing aliskiren. 
 
 
 



 103 

Warnings and precautions 
Talk to your doctor before taking Irbesartan Hydrochlorothiazide Zentiva and if any of the following 
apply to you: 
▪ if you get excessive vomiting or diarrhoea 
▪ if you suffer from kidney problems or have a kidney transplant 
▪ if you suffer from heart problems 
▪ if you suffer from liver problems 
▪ if you suffer from diabetes 
▪ if you suffer from lupus erythematosus (also known as lupus or SLE) 
▪ if you suffer from primary aldosteronism (a condition related to high production of the 

hormone aldosterone, which causes sodium retention and, in turn, an increase in blood 
pressure). 

▪ if you are taking any of the following medicines used to treat high blood pressure: 
o an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have 

diabetes-related kidney problems. 
o aliskiren. 

▪ if you have had skin cancer or if you develop an unexpected skin lesion during the treatment. 
Treatment with hydrochlorothiazide, particularly long term use with high doses, may increase the 
risk of some types of skin and lip cancer (non-melanoma skin cancer). Protect your skin from sun 
exposure and UV rays while taking Karvezide. 
 

Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. 
potassium) in your blood at regular intervals. 
 
See also information under the heading “Do not take Irbesartan Hydrochlorothiazide Zentiva”. 
 
You must tell your doctor if you think you are (or might become) pregnant. Irbesartan 
Hydrochlorothiazide Zentiva is not recommended in early pregnancy, and must not be taken if you are 
more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see 
pregnancy section). 
 
You should also tell your doctor: 
▪ if you are on a low-salt diet 
▪ if you have signs such as abnormal thirst, dry mouth, general weakness, drowsiness, muscle 

pain or cramps, nausea, vomiting, or an abnormally fast heart beat which may indicate an 
excessive effect of hydrochlorothiazide (contained in Irbesartan Hydrochlorothiazide Zentiva) 

▪ if you experience an increased sensitivity of the skin to the sun with symptoms of sunburn (such 
as redness, itching, swelling, blistering) occurring more quickly than normal 

▪ if you are going to have an operation (surgery) or be given anaesthetics 
▪ if you have changes in your vision or pain in one or both of your eyes while taking Irbesartan 

Hydrochlorothiazide Zentiva. This could be a sign that you are developing glaucoma, increased 
pressure in your eye(s). You should discontinue Irbesartan Hydrochlorothiazide Zentiva treatment 
and seek medical attention. 

 
The hydrochlorothiazide contained in this medicine could produce a positive result in an anti-doping 
test. 
 
Children and adolescents 
Irbesartan Hydrochlorothiazide Zentiva should not be given to children and adolescents 
(under 18 years). 
 
Other medicines and Irbesartan Hydrochlorothiazide Zentiva 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 



 104 

Diuretic agents such as the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide Zentiva 
may have an effect on other medicines. Preparations containing lithium should not be taken with 
Irbesartan Hydrochlorothiazide Zentiva without close supervision by your doctor. 
 
Your doctor may need to change your dose and/or to take other precautions: 
 If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take 
Irbesartan Hydrochlorothiazide Zentiva” and “Warnings and precautions”). 
  
You may need to have blood checks if you take: 
▪ potassium supplements 
▪ salt substitutes containing potassium 
▪ potassium sparing medicines or other diuretics (water tablets) 
▪ some laxatives 
▪ medicines for the treatment of gout 
▪ therapeutic vitamin D supplements 
▪ medicines to control heart rhythm 
▪ medicines for diabetes (oral agents or insulins) 
▪ carbamazepine (a medicine for the treatment of epilepsy). 
 
It is also important to tell your doctor if you are taking other medicines to reduce your blood pressure, 
steroids, medicines to treat cancer, pain killers, arthritis medicines, or colestyramine and colestipol 
resins for lowering blood cholesterol. 
 
Irbesartan Hydrochlorothiazide Zentiva with food and drink 
Irbesartan Hydrochlorothiazide Zentiva can be taken with or without food. 
 
Due to the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide Zentiva, if you drink 
alcohol while on treatment with this medicine, you may have an increased feeling of dizziness on 
standing up, specially when getting up from a sitting position. 
 
Pregnancy, breast-feeding and fertility 
Pregnancy 
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally 
advise you to stop taking Irbesartan Hydrochlorothiazide Zentiva before you become pregnant or as 
soon as you know you are pregnant and will advise you to take another medicine instead of Irbesartan 
Hydrochlorothiazide Zentiva. Irbesartan Hydrochlorothiazide Zentiva is not recommended in early 
pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to 
your baby if used after the third month of pregnancy. 
 
Breast-feeding 
Tell your doctor if you are breast-feeding or about to start breast-feeding. Irbesartan 
Hydrochlorothiazide Zentiva is not recommended for mothers who are breast-feeding, and your doctor 
may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, 
or was born prematurely. 
 
Driving and using machines 
Irbesartan Hydrochlorothiazide Zentiva is unlikely to affect your ability to drive or use machines. 
However, occasionally dizziness or weariness may occur during treatment of high blood pressure. If 
you experience these, talk to your doctor before attempting to drive or use machines. 
 
Irbesartan Hydrochlorothiazide Zentiva contains lactose. If you have been told by your doctor that 
you have an intolerance to some sugars (e.g. lactose), contact your doctor before taking this medicinal 
product. 
 
 



 105 

3. How to take Irbesartan Hydrochlorothiazide Zentiva 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Dosage 
The recommended dose of Irbesartan Hydrochlorothiazide Zentiva is one or two tablets a day. 
Irbesartan Hydrochlorothiazide Zentiva will usually be prescribed by your doctor when your previous 
treatment did not reduce your blood pressure enough. Your doctor will instruct you how to switch 
from the previous treatment to Irbesartan Hydrochlorothiazide Zentiva. 
 
Method of administration 
Irbesartan Hydrochlorothiazide Zentiva is for oral use. Swallow the tablets with a sufficient amount of 
fluid (e.g. one glass of water). You can take Irbesartan Hydrochlorothiazide Zentiva with or without 
food. Try to take your daily dose at about the same time each day. It is important that you continue to 
take Irbesartan Hydrochlorothiazide Zentiva until your doctor tells you otherwise. 
 
The maximal blood pressure lowering effect should be reached 6-8 weeks after beginning treatment. 
 
If you take more Irbesartan Hydrochlorothiazide Zentiva than you should 
If you accidentally take too many tablets, contact your doctor immediately. 
 
Children should not take Irbesartan Hydrochlorothiazide Zentiva 
Irbesartan Hydrochlorothiazide Zentiva should not be given to children under 18 years of age. If a 
child swallows some tablets, contact your doctor immediately. 
 
If you forget to take Irbesartan Hydrochlorothiazide Zentiva 
If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to 
make up for a forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
Some of these effects may be serious and may require medical attention. 
 
Rare cases of allergic skin reactions (rash, urticaria), as well as localised swelling of the face, lips 
and/or tongue have been reported in patients taking irbesartan. 
If you get any of the above symptoms or get short of breath, stop taking Irbesartan 
Hydrochlorothiazide Zentiva and contact your doctor immediately. 
 
The frequency of the side effects listed below is defined using the following convention: 
Common: may affect up to 1 in 10 people 
Uncommon: may affect up to 1 in 100 people 
 
Side effects reported in clinical studies for patients treated with Irbesartan Hydrochlorothiazide 
Zentiva were: 
 
Common side effects (may affect up to 1 in 10 people): 
▪ nausea/vomiting 
▪ abnormal urination 
▪ fatigue 
▪ dizziness (including when getting up from a lying or sitting position) 



 106 

▪ blood tests may show raised levels of an enzyme that measures the muscle and heart function 
(creatine kinase) or raised levels of substances that measure kidney function (blood urea nitrogen, 
creatinine). 

If any of these side effects causes you problems, talk to your doctor. 
 
Uncommon side effects (may affect up to 1 in 100 people): 
▪ diarrhoea  
▪ low blood pressure  
▪ fainting  
▪ heart rate increased  
▪ flushing  
▪ swelling  
▪ sexual dysfunction (problems with sexual performance) 
▪ blood tests may show lowered levels of potassium and sodium in your blood. 
If any of these side effects causes you problems, talk to your doctor. 
 
Side effects reported since the launch of Irbesartan Hydrochlorothiazide Zentiva 
Some undesirable effects have been reported since marketing of Irbesartan Hydrochlorothiazide 
Zentiva. Undesirable effects where the frequency is not known are: headache, ringing in the ears, 
cough, taste disturbance, indigestion, pain in joints and muscles, liver function abnormal and impaired 
kidney function, increased level of potassium in your blood and allergic reactions such as rash, hives, 
swelling of the face, lips, mouth, tongue or throat. Uncommon cases of jaundice (yellowing of the skin 
and/or whites of the eyes) have also been reported. 
 
As for any combination of two active substances, side effects associated with each individual 
component cannot be excluded.  
 
Side effects associated with irbesartan alone 
In addition to the side effects listed above, chest pain,  severe allergic reactions (anaphylactic shock) 
and decrease in te number of platelets (a blood cell essential for the clotting of the blood) have also 
been reported. 
 
Side effects associated with hydrochlorothiazide alone 
Loss of appetite; stomach irritation; stomach cramps; constipation; jaundice (yellowing of the skin 
and/or whites of the eyes); inflammation of the pancreas characterised by severe upper stomach pain, 
often with nausea and vomiting; sleep disorders; depression; blurred vision; lack of white blood cells, 
which can result in frequent infections, fever; decrease in the number of platelets (a blood cell 
essential for the clotting of the blood), decreased number of red blood cells (anaemia) characterised by 
tiredness, headaches, being short of breath when exercising, dizziness and looking pale; kidney 
disease; lung problems including pneumonia or build-up of fluid in the lungs; increased sensitivity of 
the skin to the sun; inflammation of blood vessels; a skin disease characterized by the peeling of the 
skin all over the body; cutaneous lupus erythematosus, which is identified by a rash that may appear 
on the face, neck, and scalp; allergic reactions; weakness and muscle spasm; altered heart rate; reduced 
blood pressure after a change in body position; swelling of the salivary glands; high sugar levels in the 
blood; sugar in the urine; increases in some kinds of blood fat; high uric acid levels in the blood, 
which may cause gout. 
Not known (frequency cannot be estimated from the available data): skin and lip cancer (non-
melanoma skin cancer) 
 
It is known that side effects associated with hydrochlorothiazide may increase with higher doses of 
hydrochlorothiazide. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 



 107 

 
 
5. How to store Irbesartan Hydrochlorothiazide Zentiva 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and on the blister after 
EXP. The expiry date refers to the last day of that month. 
 
Do not store above 30°C. 
 
Store in the original package in order to protect from moisture. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Irbesartan Hydrochlorothiazide Zentiva contains 
▪  The active substances are irbesartan and hydrochlorothiazide. Each tablet of Irbesartan 

Hydrochlorothiazide Zentiva 150 mg/12.5 mg contains 150 mg irbesartan and 12.5 mg 
hydrochlorothiazide. 

▪  The other ingredients are microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, 
magnesium stearate, colloidal hydrated silica, pregelatinised maize starch, red and yellow ferric 
oxides (E172). Please see section 2 “Irbesartan Hydrochlorothiazide Zentiva contains lactose”. 

 
What Irbesartan Hydrochlorothiazide Zentiva looks like and contents of the pack 
Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg tablets are peach, biconvex, oval-shaped, 
with a heart debossed on one side and the number 2775 engraved on the other side. 
 
Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg tablets are supplied in blister packs of 14, 28, 
56 or 98 tablets. Unit dose blister packs of 56 x 1 tablet for delivery in hospitals are also available. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
Manufacturer 
SANOFI WINTHROP INDUSTRIE 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex - France 
 
CHINOIN PRIVATE CO. LTD. 
Lévai u.5. 
2112 Veresegyház - Hungary 
 
SANOFI WINTHROP INDUSTRIE 
30-36 Avenue Gustave Eiffel 
37100 Tours - France 
 
 



 108 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Zentiva, k.s. 
Tél/Tel: +32 280 86 420 
PV-Belgium@zentiva.com 
 

Lietuva 
Zentiva, k.s. 
Tel: +370 52152025 
PV-Lithuania@zentiva.com 

България 
Zentiva, k.s. 
Тел: + 359 2 805 72 08 
PV-Bulgaria@zentiva.com 
 

Luxembourg/Luxemburg 
Zentiva, k.s. 
Tél/Tel: +352 208 82330 
PV-Luxembourg@zentiva.com 

Česká republika 
Zentiva, k.s. 
Tel: +420 267 241 111 
PV-Czech-Republic@zentiva.com 

Magyarország 
Zentiva, k.s. 
Tel.: +36 165 55 722 
PV-Hungary@zentiva.com 

Danmark 
Zentiva, k.s. 
Tlf: +45 787 68 400 
PV-Denmark@zentiva.com 
 

Malta 
Zentiva, k.s. 
Tel: +356 277 82 052 
PV-Malta@zentiva.com 

Deutschland 
Zentiva Pharma GmbH  
Tel: +49 (0) 800 53 53 010 
PV-Germany@zentiva.com 
 

Nederland 
Zentiva, k.s. 
Tel: +31 202 253 638 
PV-Netherlands@zentiva.com 

Eesti 
Zentiva, k.s. 
Tel: +372 52 70308 
PV-Estonia@zentiva.com 
 

Norge 
Zentiva, k.s. 
Tlf: +47 219 66 203 
PV-Norway@zentiva.com 

Ελλάδα 
Zentiva, k.s. 
Τηλ: +30 211 198 7510 
PV-Greece@zentiva.com 
 

Österreich 
Zentiva, k.s. 
Tel: +43 720 778 877 
PV-Austria@zentiva.com 

España 
Zentiva, k.s. 
Tel: +34 931 815 250 
PV-Spain@zentiva.com 
 

Polska 
Zentiva Polska Sp. z o.o. 
Tel: + 48 22 375 92 00 
PV-Poland@zentiva.com 

France 
Zentiva France 
Tél: +33 (0) 800 089 219  
PV-France@zentiva.com 
 

Portugal 
Zentiva Portugal, Lda 
Tel: +351210601360 
PV-Portugal@zentiva.com 

Hrvatska 
Zentiva, k.s. 
Tel: +385 155 17 772 
PV-Croatia@zentiva.com 
 
Ireland 
Zentiva, k.s. 
Tel: +353 766 803 944 
PV-Ireland@zentiva.com 

România 
S.C. ZENTIVA S.A. 
Tel: +40 021 317 31 36 
PV-Romania@zentiva.com 
 
Slovenija 
Zentiva, k.s. 
Tel: +386 360 00 408 
PV-Slovenia@zentiva.com 



 109 

 
Ísland 
Zentiva, k.s. 
Sími: +354 539 0650 
PV-Iceland@zentiva.com 
 

Slovenská republika 
Zentiva, a.s. 
Tel: +421 2 3918 3010 
PV-Slovakia@zentiva.com 

Italia 
Zentiva Italia S.r.l. 
 +39-02-38598801 
PV-Italy@zentiva.com 

Suomi/Finland 
Zentiva, k.s. 
Puh/Tel: +358 942 598 648 
PV-Finland@zentiva.com 
 

Κύπρος 
Zentiva, k.s. 
Τηλ: +357 240 30 144 
PV-Cyprus@zentiva.com 
 

Sverige 
Zentiva, k.s. 
Tel: +46 840 838 822 
PV-Sweden@zentiva.com 

Latvija 
Zentiva, k.s. 
Tel: +371 67893939 
PV-Latvia@zentiva.com 

United Kingdom 
Zentiva Pharma UK Limited 
Tel: +44 (0) 845 372 7101 
PV-United-Kingdom@zentiva.com 

  
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/ 
 



 110 

Package leaflet: Information for the patient 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg tablets 

irbesartan/hydrochlorothiazide 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
▪ Keep this leaflet. You may need to read it again. 
▪ If you have any further questions, ask your doctor or pharmacist. 
▪ This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
▪ If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Irbesartan Hydrochlorothiazide Zentiva is and what it is used for 
2. What you need to know before you take Irbesartan Hydrochlorothiazide Zentiva 
3. How to take Irbesartan Hydrochlorothiazide Zentiva 
4. Possible side effects 
5. How to store Irbesartan Hydrochlorothiazide Zentiva 
6. Contents of the pack and other information 
 
 
1. What Irbesartan Hydrochlorothiazide Zentiva is and what it is used for 
 
Irbesartan Hydrochlorothiazide Zentiva is a combination of two active substances, irbesartan and 
hydrochlorothiazide. 
Irbesartan belongs to a group of medicines known as angiotensin-II receptor antagonists. 
Angiotensin-II is a substance produced in the body that binds to receptors in blood vessels causing 
them to tighten. This results in an increase in blood pressure. Irbesartan prevents the binding of 
angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. 
Hydrochlorothiazide is one of a group of medicines (called thiazide diuretics) that causes increased 
urine output and so causes a lowering of blood pressure. 
The two active ingredients in Irbesartan Hydrochlorothiazide Zentiva work together to lower blood 
pressure further than if either was given alone. 
 
Irbesartan Hydrochlorothiazide Zentiva is used to treat high blood pressure, when treatment with 
irbesartan or hydrochlorothiazide alone did not provide adequate control of your blood pressure. 
 
 
2. What you need to know before you take Irbesartan Hydrochlorothiazide Zentiva 
 
Do not take Irbesartan Hydrochlorothiazide Zentiva 
▪ if you are allergic to irbesartan or any of the other ingredients of this medicine (listed in section 6) 
▪ if you are allergic  to hydrochlorothiazide or any other sulfonamide-derived medicines 
▪ if you are more than 3 months pregnant. (It is also better to avoid Irbesartan Hydrochlorothiazide 

Zentiva in early pregnancy – see pregnancy section) 
▪ if you have severe liver or kidney problems 
▪ if you have difficulty in producing urine 
▪ if your doctor determines that you have persistently high calcium or low potassium levels in 

your blood 
▪ if you have diabetes or impaired kidney function and you are treated with a blood pressure 

lowering medicine containing aliskiren.  
 
 
Warnings and precautions 
Talk to your doctor before taking Irbesartan Hydrochlorothiazide Zentiva and if any of the following 
apply to you: 



 111 

▪ if you get excessive vomiting or diarrhoea 
▪ if you suffer from kidney problems or have a kidney transplant 
▪ if you suffer from heart problems 
▪ if you suffer from liver problems 
▪ if you suffer from diabetes 
▪ if you suffer from lupus erythematosus (also known as lupus or SLE) 
▪ if you suffer from primary aldosteronism (a condition related to high production of the 

hormone aldosterone, which causes sodium retention and, in turn, an increase in blood 
pressure). 

▪ if you are taking  any of the following medicines used to treat high blood pressure: 
o an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have 

diabetes-related kidney problems. 
o aliskiren. 

▪ if you have had skin cancer or if you develop an unexpected skin lesion during the treatment. 
Treatment with hydrochlorothiazide, particularly long term use with high doses, may increase the 
risk of some types of skin and lip cancer (non-melanoma skin cancer). Protect your skin from sun 
exposure and UV rays while taking Karvezide. 
 

Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. 
potassium) in your blood at regular intervals. 
 
See also information under the heading “Do not take Irbesartan Hydrochlorothiazide Zentiva”. 
 
You must tell your doctor if you think you are (or might become) pregnant. Irbesartan 
Hydrochlorothiazide Zentiva is not recommended in early pregnancy, and must not be taken if you are 
more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see 
pregnancy section). 
 
You should also tell your doctor: 

 if you are on a low-salt diet 
▪ if you have signs such as abnormal thirst, dry mouth, general weakness, drowsiness, muscle 

pain or cramps, nausea, vomiting, or an abnormally fast heart beat which may indicate an 
excessive effect of hydrochlorothiazide (contained in Irbesartan Hydrochlorothiazide Zentiva) 

▪ if you experience an increased sensitivity of the skin to the sun with symptoms of sunburn (such 
as redness, itching, swelling, blistering) occurring more quickly than normal 

 if you are going to have an operation (surgery) or be given anaesthetics 
▪ if you have changes in your vision or pain in one or both of your eyes while taking Irbesartan 

Hydrochlorothiazide Zentiva. This could be a sign that you are developing glaucoma, increased 
pressure in your eye(s). You should discontinue Irbesartan Hydrochlorothiazide Zentiva treatment 
and seek medical attention. 

 
The hydrochlorothiazide contained in this medicine could produce a positive result in an anti-doping 
test. 
 
Children and adolescents 
Irbesartan Hydrochlorothiazide Zentiva should not be given to children and adolescents 
(under 18 years). 
 
Other medicines and Irbesartan Hydrochlorothiazide Zentiva 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Diuretic agents such as the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide Zentiva 
may have an effect on other medicines. Preparations containing lithium should not be taken with 
Irbesartan Hydrochlorothiazide Zentiva without close supervision by your doctor. 
 
Your doctor may need to change your dose and/or to take other precautions: 



 112 

 If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take 
Irbesartan Hydrochlorothiazide Zentiva” and “Warnings and precautions”). 
  
You may need to have blood checks if you take: 
▪ potassium supplements 
▪ salt substitutes containing potassium 
▪ potassium sparing medicines or other diuretics (water tablets) 
▪ some laxatives 
▪ medicines for the treatment of gout 
▪ therapeutic vitamin D supplements 
▪ medicines to control heart rhythm 
▪ medicines for diabetes (oral agents or insulins) 
▪ carbamazepine (a medicine for the treatment of epilepsy). 
 
It is also important to tell your doctor if you are taking other medicines to reduce your blood pressure, 
steroids, medicines to treat cancer, pain killers, arthritis medicines, or colestyramine and colestipol 
resins for lowering blood cholesterol. 
 
Irbesartan Hydrochlorothiazide Zentiva with food and drink 
Irbesartan Hydrochlorothiazide Zentiva can be taken with or without food. 
 
Due to the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide Zentiva, if you drink 
alcohol while on treatment with this medicine, you may have an increased feeling of dizziness on 
standing up, specially when getting up from a sitting position. 
 
Pregnancy, breast-feeding and fertility 
Pregnancy 
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally 
advise you to stop taking Irbesartan Hydrochlorothiazide Zentiva before you become pregnant or as 
soon as you know you are pregnant and will advise you to take another medicine instead of Irbesartan 
Hydrochlorothiazide Zentiva. Irbesartan Hydrochlorothiazide Zentiva is not recommended in early 
pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to 
your baby if used after the third month of pregnancy. 
 
Breast-feeding 
Tell your doctor if you are breast-feeding or about to start breast-feeding. Irbesartan 
Hydrochlorothiazide Zentiva is not recommended for mothers who are breast-feeding, and your doctor 
may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, 
or was born prematurely. 
 
Driving and using machines 
Irbesartan Hydrochlorothiazide Zentiva is unlikely to affect your ability to drive or use machines. 
However, occasionally dizziness or weariness may occur during treatment of high blood pressure. If 
you experience these, talk to your doctor before attempting to drive or use machines. 
 
Irbesartan Hydrochlorothiazide Zentiva contains lactose. If you have been told by your doctor that 
you have an intolerance to some sugars (e.g. lactose), contact your doctor before taking this medicinal 
product. 
 
 
3. How to take Irbesartan Hydrochlorothiazide Zentiva 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 



 113 

Dosage 
The recommended dose of Irbesartan Hydrochlorothiazide Zentiva is one tablet a day. Irbesartan 
Hydrochlorothiazide Zentiva will usually be prescribed by your doctor when your previous treatment 
did not reduce your blood pressure enough. Your doctor will instruct you how to switch from the 
previous treatment to Irbesartan Hydrochlorothiazide Zentiva. 
 
Method of administration 
Irbesartan Hydrochlorothiazide Zentiva is for oral use. Swallow the tablets with a sufficient amount of 
fluid (e.g. one glass of water). You can take Irbesartan Hydrochlorothiazide Zentiva with or without 
food. Try to take your daily dose at about the same time each day. It is important that you continue to 
take Irbesartan Hydrochlorothiazide Zentiva until your doctor tells you otherwise. 
 
The maximal blood pressure lowering effect should be reached 6-8 weeks after beginning treatment. 
 
If you take more Irbesartan Hydrochlorothiazide Zentiva than you should 
If you accidentally take too many tablets, contact your doctor immediately. 
 
Children should not take Irbesartan Hydrochlorothiazide Zentiva 
Irbesartan Hydrochlorothiazide Zentiva should not be given to children under 18 years of age. If a 
child swallows some tablets, contact your doctor immediately. 
 
If you forget to take Irbesartan Hydrochlorothiazide Zentiva 
If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to 
make up for a forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
Some of these effects may be serious and may require medical attention. 
 
Rare cases of allergic skin reactions (rash, urticaria), as well as localised swelling of the face, lips 
and/or tongue have been reported in patients taking irbesartan. 
If you get any of the above symptoms or get short of breath, stop taking Irbesartan 
Hydrochlorothiazide Zentiva and contact your doctor immediately. 
 
The frequency of the side effects listed below is defined using the following convention: 
Common: may affect up to 1 in 10 people 
Uncommon: may affect up to 1 in 100 people 
 
Side effects reported in clinical studies for patients treated with Irbesartan Hydrochlorothiazide 
Zentiva were: 
 
Common side effects (may affect more than 1 in 10 people): 
▪ nausea/vomiting 
▪ abnormal urination 
▪ fatigue 
▪ dizziness (including when getting up from a lying or sitting position) 
▪ blood tests may show raised levels of an enzyme that measures the muscle and heart function 

(creatine kinase) or raised levels of substances that measure kidney function (blood urea nitrogen, 
creatinine). 

If any of these side effects causes you problems, talk to your doctor. 
 
Uncommon side effects (may affect up to 1 in 100 people): 
▪ diarrhoea  



 114 

▪ low blood pressure  
▪ fainting  
▪ heart rate increased  
▪ flushing  
▪ swelling  
▪ sexual dysfunction (problems with sexual performance) 
▪ blood tests may show lowered levels of potassium and sodium in your blood. 
If any of these side effects causes you problems, talk to your doctor. 
 
Side effects reported since the launch of Irbesartan Hydrochlorothiazide Zentiva 
Some undesirable effects have been reported since marketing of Irbesartan Hydrochlorothiazide 
Zentiva. Undesirable effects where the frequency is not known are: headache, ringing in the ears, 
cough, taste disturbance, indigestion, pain in joints and muscles, liver function abnormal and impaired 
kidney function, increased level of potassium in your blood and allergic reactions such as rash, hives, 
swelling of the face, lips, mouth, tongue or throat. Uncommon cases of jaundice (yellowing of the skin 
and/or whites of the eyes) have also been reported. 
 
As for any combination of two active substances, side effects associated with each individual 
component cannot be excluded.  
 
Side effects associated with irbesartan alone 
In addition to the side effects listed above, chest pain, severe allergic reactions (anaphylactic shock) 
and decrease in te number of platelets (a blood cell essential for the clotting of the blood) have also 
been reported. 
 
Side effects associated with hydrochlorothiazide alone 
Loss of appetite; stomach irritation; stomach cramps; constipation; jaundice (yellowing of the skin 
and/or whites of the eyes); inflammation of the pancreas characterised by severe upper stomach pain, 
often with nausea and vomiting; sleep disorders; depression; blurred vision; lack of white blood cells, 
which can result in frequent infections, fever; decrease in the number of platelets (a blood cell 
essential for the clotting of the blood), decreased number of red blood cells (anaemia) characterised by 
tiredness, headaches, being short of breath when exercising, dizziness and looking pale; kidney 
disease; lung problems including pneumonia or build-up of fluid in the lungs; increased sensitivity of 
the skin to the sun; inflammation of blood vessels; a skin disease characterized by the peeling of the 
skin all over the body; cutaneous lupus erythematosus, which is identified by a rash that may appear 
on the face, neck, and scalp; allergic reactions; weakness and muscle spasm; altered heart rate; reduced 
blood pressure after a change in body position; swelling of the salivary glands; high sugar levels in the 
blood; sugar in the urine; increases in some kinds of blood fat; high uric acid levels in the blood, 
which may cause gout. 
Not known (frequency cannot be estimated from the available data): skin and lip cancer (non-
melanoma skin cancer). 
 
It is known that side effects associated with hydrochlorothiazide may increase with higher doses of 
hydrochlorothiazide. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Irbesartan Hydrochlorothiazide Zentiva 
 
Keep this medicine out of the sight and reach of children. 
 



 115 

Do not use this medicine after the expiry date which is stated on the carton and on the blister after 
EXP. The expiry date refers to the last day of that month. 
 
Do not store above 30°C. 
 
Store in the original package in order to protect from moisture. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Irbesartan Hydrochlorothiazide Zentiva contains 
▪ The active substances are irbesartan and hydrochlorothiazide. Each tablet of Irbesartan 

Hydrochlorothiazide Zentiva 300 mg/12.5 mg contains 300 mg irbesartan and 12.5 mg 
hydrochlorothiazide. 

▪ The other ingredients are microcrystalline cellulose, croscarmellose sodium, lactose 
monohydrate, magnesium stearate, colloidal hydrated silica, pregelatinised maize starch, red 
and yellow ferric oxides (E172). Please see section 2 “Irbesartan Hydrochlorothiazide Zentiva 
contains lactose”. 

 
What Irbesartan Hydrochlorothiazide Zentiva looks like and contents of the pack 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg tablets are peach, biconvex, oval-shaped, 
with a heart debossed on one side and the number 2776 engraved on the other side. 
 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg tablets are supplied in blister packs of 14, 28, 
56 or 98 tablets. Unit dose blister packs of 56 x 1 tablet for delivery in hospitals are also available. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
Manufacturer 
SANOFI WINTHROP INDUSTRIE 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex - France 
 
CHINOIN PRIVATE CO. LTD. 
Lévai u.5. 
2112 Veresegyház - Hungary 
 
SANOFI WINTHROP INDUSTRIE 
30-36 Avenue Gustave Eiffel 
37100 Tours - France 
 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Zentiva, k.s. 

Lietuva 
Zentiva, k.s. 



 116 

Tél/Tel: +32 280 86 420 
PV-Belgium@zentiva.com 
 

Tel: +370 52152025 
PV-Lithuania@zentiva.com 

България 
Zentiva, k.s. 
Тел: + 359 2 805 72 08 
PV-Bulgaria@zentiva.com 
 

Luxembourg/Luxemburg 
Zentiva, k.s. 
Tél/Tel: +352 208 82330 
PV-Luxembourg@zentiva.com 

Česká republika 
Zentiva, k.s. 
Tel: +420 267 241 111 
PV-Czech-Republic@zentiva.com 

Magyarország 
Zentiva, k.s. 
Tel.: +36 165 55 722 
PV-Hungary@zentiva.com 

Danmark 
Zentiva, k.s. 
Tlf: +45 787 68 400 
PV-Denmark@zentiva.com 
 

Malta 
Zentiva, k.s. 
Tel: +356 277 82 052 
PV-Malta@zentiva.com 

Deutschland 
Zentiva Pharma GmbH  
Tel: +49 (0) 800 53 53 010 
PV-Germany@zentiva.com 
 

Nederland 
Zentiva, k.s. 
Tel: +31 202 253 638 
PV-Netherlands@zentiva.com 

Eesti 
Zentiva, k.s. 
Tel: +372 52 70308 
PV-Estonia@zentiva.com 
 

Norge 
Zentiva, k.s. 
Tlf: +47 219 66 203 
PV-Norway@zentiva.com 

Ελλάδα 
Zentiva, k.s. 
Τηλ: +30 211 198 7510 
PV-Greece@zentiva.com 
 

Österreich 
Zentiva, k.s. 
Tel: +43 720 778 877 
PV-Austria@zentiva.com 

España 
Zentiva, k.s. 
Tel: +34 931 815 250 
PV-Spain@zentiva.com 
 

Polska 
Zentiva Polska Sp. z o.o. 
Tel: + 48 22 375 92 00 
PV-Poland@zentiva.com 

France 
Zentiva France 
Tél: +33 (0) 800 089 219  
PV-France@zentiva.com 
 

Portugal 
Zentiva Portugal, Lda 
Tel: +351210601360 
PV-Portugal@zentiva.com 

Hrvatska 
Zentiva, k.s. 
Tel: +385 155 17 772 
PV-Croatia@zentiva.com 
 
Ireland 
Zentiva, k.s. 
Tel: +353 766 803 944 
PV-Ireland@zentiva.com 
 

România 
S.C. ZENTIVA S.A. 
Tel: +40 021 317 31 36 
PV-Romania@zentiva.com 
 
Slovenija 
Zentiva, k.s. 
Tel: +386 360 00 408 
PV-Slovenia@zentiva.com 

Ísland 
Zentiva, k.s. 
Sími: +354 539 0650 
PV-Iceland@zentiva.com 

Slovenská republika 
Zentiva, a.s. 
Tel: +421 2 3918 3010 
PV-Slovakia@zentiva.com 



 117 

 
Italia 
Zentiva Italia S.r.l. 
 +39-02-38598801 
PV-Italy@zentiva.com 

Suomi/Finland 
Zentiva, k.s. 
Puh/Tel: +358 942 598 648 
PV-Finland@zentiva.com 
 

Κύπρος 
Zentiva, k.s. 
Τηλ: +357 240 30 144 
PV-Cyprus@zentiva.com 
 

Sverige 
Zentiva, k.s. 
Tel: +46 840 838 822 
PV-Sweden@zentiva.com 

Latvija 
Zentiva, k.s. 
Tel: +371 67893939 
PV-Latvia@zentiva.com 

United Kingdom 
Zentiva Pharma UK Limited 
Tel: +44 (0) 845 372 7101 
PV-United-Kingdom@zentiva.com 

  
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/ 
 



 118 

Package leaflet: Information for the patient 
Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg film-coated tablets 

irbesartan/hydrochlorothiazide 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
▪ Keep this leaflet. You may need to read it again. 
▪ If you have any further questions, ask your doctor or pharmacist. 
▪ This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
▪ If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Irbesartan Hydrochlorothiazide Zentiva is and what it is used for 
2. What you need to know before you take Irbesartan Hydrochlorothiazide Zentiva 
3. How to take Irbesartan Hydrochlorothiazide Zentiva 
4. Possible side effects 
5. How to store Irbesartan Hydrochlorothiazide Zentiva 
6. Contents of the pack and other information 
 
 
1. What Irbesartan Hydrochlorothiazide Zentiva is and what it is used for 
 
Irbesartan Hydrochlorothiazide Zentiva is a combination of two active substances, irbesartan and 
hydrochlorothiazide. 
Irbesartan belongs to a group of medicines known as angiotensin-II receptor antagonists. 
Angiotensin-II is a substance produced in the body that binds to receptors in blood vessels causing 
them to tighten. This results in an increase in blood pressure. Irbesartan prevents the binding of 
angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. 
Hydrochlorothiazide is one of a group of medicines (called thiazide diuretics) that causes increased 
urine output and so causes a lowering of blood pressure. 
The two active ingredients in Irbesartan Hydrochlorothiazide Zentiva work together to lower blood 
pressure further than if either was given alone. 
 
Irbesartan Hydrochlorothiazide Zentiva is used to treat high blood pressure, when treatment with 
irbesartan or hydrochlorothiazide alone did not provide adequate control of your blood pressure. 
 
 
2. What you need to know before you take Irbesartan Hydrochlorothiazide Zentiva 
 
Do not take Irbesartan Hydrochlorothiazide Zentiva 
▪ if you are allergic to irbesartan or any of the other ingredients of this medicine (listed in section 6) 
▪ if you are allergic  to hydrochlorothiazide or any other sulfonamide-derived medicines 
▪ if you are more than 3 months pregnant. (It is also better to avoid Irbesartan 

Hydrochlorothiazide Zentiva in early pregnancy – see pregnancy section) 
▪ if you have severe liver or kidney problems 
▪ if you have difficulty in producing urine 
▪ if your doctor determines that you have persistently high calcium or low potassium levels in 

your blood 
▪ if you have diabetes or impaired kidney function and you are treated with a blood pressure 

lowering medicine containing aliskiren. 
 
 
 



 119 

Warnings and precautions 
Talk to your doctor before taking Irbesartan Hydrochlorothiazide Zentiva and if any of the following 
apply to you: 
▪ if you get excessive vomiting or diarrhoea 
▪ if you suffer from kidney problems or have a kidney transplant 
▪ if you suffer from heart problems 
▪ if you suffer from liver problems 
▪ if you suffer from diabetes 
▪ if you suffer from lupus erythematosus (also known as lupus or SLE) 
▪ if you suffer from primary aldosteronism (a condition related to high production of the hormone 

aldosterone, which causes sodium retention and, in turn, an increase in blood pressure). 
▪ if you are taking  any of the following medicines used to treat high blood pressure: 

o an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have 
diabetes-related kidney problems. 

o aliskiren. 
▪ if you have had skin cancer or if you develop an unexpected skin lesion during the treatment. 

Treatment with hydrochlorothiazide, particularly long term use with high doses, may increase the 
risk of some types of skin and lip cancer (non-melanoma skin cancer). Protect your skin from sun 
exposure and UV rays while taking Karvezide. 

 
Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. 
potassium) in your blood at regular intervals. 
 
See also information under the heading “Do not take Irbesartan Hydrochlorothiazide Zentiva”. 
 
You must tell your doctor if you think you are (or might become) pregnant. Irbesartan 
Hydrochlorothiazide Zentiva is not recommended in early pregnancy, and must not be taken if you are 
more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see 
pregnancy section). 
 
You should also tell your doctor: 
▪ if you are on a low-salt diet 
▪ if you have signs such as abnormal thirst, dry mouth, general weakness, drowsiness, muscle 

pain or cramps, nausea, vomiting, or an abnormally fast heart beat which may indicate an 
excessive effect of hydrochlorothiazide (contained in Irbesartan Hydrochlorothiazide Zentiva) 

▪ if you experience an increased sensitivity of the skin to the sun with symptoms of sunburn 
(such as redness, itching, swelling, blistering) occurring more quickly than normal 

▪ if you are going to have an operation (surgery) or be given anaesthetics  
▪ if you have changes in your vision or pain in one or both of your eyes while taking Irbesartan 

Hydrochlorothiazide Zentiva. This could be a sign that you are developing glaucoma, increased 
pressure in your eye(s). You should discontinue Irbesartan Hydrochlorothiazide Zentiva 
treatment and seek medical attention. 

 
The hydrochlorothiazide contained in this medicine could produce a positive result in an anti-doping 
test. 
 
Children and adolescents 
Irbesartan Hydrochlorothiazide Zentiva should not be given to children and adolescents 
(under 18 years). 
 
Other medicines and Irbesartan Hydrochlorothiazide Zentiva 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Diuretic agents such as the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide Zentiva 
may have an effect on other medicines. Preparations containing lithium should not be taken with 
Irbesartan Hydrochlorothiazide Zentiva without close supervision by your doctor. 



 120 

 
Your doctor may need to change your dose and/or to take other precautions: 
 If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take 
Irbesartan Hydrochlorothiazide Zentiva” and “Warnings and precautions”). 
 
You may need to have blood checks if you take: 
▪ potassium supplements 
▪ salt substitutes containing potassium 
▪ potassium sparing medicines or other diuretics (water tablets) 
▪ some laxatives 
▪ medicines for the treatment of gout 
▪ therapeutic vitamin D supplements 
▪ medicines to control heart rhythm 
▪ medicines for diabetes (oral agents or insulins)  
▪ carbamazepine (a medicine for the treatment of epilepsy). 
 
It is also important to tell your doctor if you are taking other medicines to reduce your blood pressure, 
steroids, medicines to treat cancer, pain killers, arthritis medicines, or colestyramine and colestipol 
resins for lowering blood cholesterol. 
 
Irbesartan Hydrochlorothiazide Zentiva with food and drink 
Irbesartan Hydrochlorothiazide Zentiva can be taken with or without food. 
 
Due to the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide Zentiva, if you drink 
alcohol while on treatment with this medicine, you may have an increased feeling of dizziness on 
standing up, specially when getting up from a sitting position. 
 
Pregnancy, breast-feeding and fertility 
Pregnancy 
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally 
advise you to stop taking Irbesartan Hydrochlorothiazide Zentiva before you become pregnant or as 
soon as you know you are pregnant and will advise you to take another medicine instead of Irbesartan 
Hydrochlorothiazide Zentiva. Irbesartan Hydrochlorothiazide Zentiva is not recommended in early 
pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to 
your baby if used after the third month of pregnancy. 
 
Breast-feeding 
Tell your doctor if you are breast-feeding or about to start breast-feeding. Irbesartan 
Hydrochlorothiazide Zentiva is not recommended for mothers who are breast-feeding, and your doctor 
may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, 
or was born prematurely. 
 
Driving and using machines 
Irbesartan Hydrochlorothiazide Zentiva is unlikely to affect your ability to drive or use machines. 
However, occasionally dizziness or weariness may occur during treatment of high blood pressure. If 
you experience these, talk to your doctor before attempting to drive or use machines. 
 
Irbesartan Hydrochlorothiazide Zentiva contains lactose. If you have been told by your doctor that 
you have an intolerance to some sugars (e.g. lactose), contact your doctor before taking this medicinal 
product. 
 
 
3. How to take Irbesartan Hydrochlorothiazide Zentiva 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 



 121 

Dosage 
The recommended dose of Irbesartan Hydrochlorothiazide Zentiva is one or two tablets a day. 
Irbesartan Hydrochlorothiazide Zentiva will usually be prescribed by your doctor when your previous 
treatment did not reduce your blood pressure enough. Your doctor will instruct you how to switch 
from the previous treatment to Irbesartan Hydrochlorothiazide Zentiva. 
 
Method of administration 
Irbesartan Hydrochlorothiazide Zentiva is for oral use. Swallow the tablets with a sufficient amount of 
fluid (e.g. one glass of water). You can take Irbesartan Hydrochlorothiazide Zentiva with or without 
food. Try to take your daily dose at about the same time each day. It is important that you continue to 
take Irbesartan Hydrochlorothiazide Zentiva until your doctor tells you otherwise. 
 
The maximal blood pressure lowering effect should be reached 6-8 weeks after beginning treatment. 
 
If you take more Irbesartan Hydrochlorothiazide Zentiva than you should 
If you accidentally take too many tablets, contact your doctor immediately. 
 
Children should not take Irbesartan Hydrochlorothiazide Zentiva 
Irbesartan Hydrochlorothiazide Zentiva should not be given to children under 18 years of age. If a 
child swallows some tablets, contact your doctor immediately. 
 
If you forget to take Irbesartan Hydrochlorothiazide Zentiva 
If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to 
make up for a forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
Some of these effects may be serious and may require medical attention. 
 
Rare cases of allergic skin reactions (rash, urticaria), as well as localised swelling of the face, lips 
and/or tongue have been reported in patients taking irbesartan. 
If you get any of the above symptoms or get short of breath, stop taking Irbesartan 
Hydrochlorothiazide Zentiva and contact your doctor immediately. 
 
The frequency of the side effects listed below is defined using the following convention: 
Common: may affect up to 1 in 10 people 
Uncommon: may affect up to 1 in 100 people 
 
Side effects reported in clinical studies for patients treated with Irbesartan Hydrochlorothiazide 
Zentiva were: 
 
Common side effects ( may affect up to 1 in 10 people): 
▪ nausea/vomiting 
▪ abnormal urination 
▪ fatigue 
▪ dizziness (including when getting up from a lying or sitting position) 
▪ blood tests may show raised levels of an enzyme that measures the muscle and heart function 

(creatine kinase) or raised levels of substances that measure kidney function (blood urea nitrogen, 
creatinine). 

If any of these side effects causes you problems, talk to your doctor. 
 
Uncommon side effects (may affect up to 1 in 100 people): 
▪ diarrhoea 



 122 

▪ low blood pressure 
▪ fainting 
▪ heart rate increased 
▪ flushing 
▪ swelling 
▪ sexual dysfunction (problems with sexual performance) 
▪ blood tests may show lowered levels of potassium and sodium in your blood. 
If any of these side effects causes you problems, talk to your doctor. 
 
Side effects reported since the launch of Irbesartan Hydrochlorothiazide Zentiva 
Some undesirable effects have been reported since marketing of Irbesartan Hydrochlorothiazide 
Zentiva. Undesirable effects where the frequency is not known are: headache, ringing in the ears, 
cough, taste disturbance, indigestion, pain in joints and muscles, liver function abnormal and impaired 
kidney function, increased level of potassium in your blood and allergic reactions such as rash, hives, 
swelling of the face, lips, mouth, tongue or throat. Uncommon cases of jaundice (yellowing of the skin 
and/or whites of the eyes) have also been reported. 
 
As for any combination of two active substances, side effects associated with each individual 
component cannot be excluded. 
 
Side effects associated with irbesartan alone 
In addition to the side effects listed above, chest pain, severe allergic reactions (anaphylactic shock) 
and decrease in te number of platelets (a blood cell essential for the clotting of the blood) have also 
been reported. 
 
Side effects associated with hydrochlorothiazide alone 
Loss of appetite; stomach irritation; stomach cramps; constipation; jaundice (yellowing of the skin 
and/or whites of the eyes); inflammation of the pancreas characterised by severe upper stomach pain, 
often with nausea and vomiting; sleep disorders; depression; blurred vision; lack of white blood cells, 
which can result in frequent infections, fever; decrease in the number of platelets (a blood cell 
essential for the clotting of the blood), decreased number of red blood cells (anaemia) characterised by 
tiredness, headaches, being short of breath when exercising, dizziness and looking pale; kidney 
disease; lung problems including pneumonia or build-up of fluid in the lungs; increased sensitivity of 
the skin to the sun; inflammation of blood vessels; a skin disease characterized by the peeling of the 
skin all over the body; cutaneous lupus erythematosus, which is identified by a rash that may appear 
on the face, neck, and scalp; allergic reactions; weakness and muscle spasm; altered heart rate; reduced 
blood pressure after a change in body position; swelling of the salivary glands; high sugar levels in the 
blood; sugar in the urine; increases in some kinds of blood fat; high uric acid levels in the blood, 
which may cause gout. 
Not known (frequency cannot be estimated from the available data): skin and lip cancer (non-
melanoma skin cancer) 
 
It is known that side effects associated with hydrochlorothiazide may increase with higher doses of 
hydrochlorothiazide. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Irbesartan Hydrochlorothiazide Zentiva 
 
Keep this medicine out of the sight and reach of children. 
 



 123 

Do not use this medicine after the expiry date which is stated on the carton and on the blister after 
EXP. The expiry date refers to the last day of that month. 
 
Do not store above 30°C. 
 
Store in the original package in order to protect from moisture. 
 
Do not throw awy any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Irbesartan Hydrochlorothiazide Zentiva contains 

▪  The active substances are irbesartan and hydrochlorothiazide. Each film-coated tablet of 
Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg contains 150 mg irbesartan and 
12.5 mg hydrochlorothiazide. 

▪  The other ingredients are lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, hypromellose, silicon dioxide, magnesium stearate, titanium dioxide, macrogol 3000, 
red and yellow ferric oxides, carnauba wax. Please see section 2 “Irbesartan 
Hydrochlorothiazide Zentiva contains lactose”. 

 
What Irbesartan Hydrochlorothiazide Zentiva looks like and contents of the pack 
Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg film-coated tablets are peach, biconvex, oval-
shaped, with a heart debossed on one side and the number 2875 engraved on the other side. 
 
Irbesartan Hydrochlorothiazide Zentiva 150 mg/12.5 mg film-coated tablets are supplied in blister 
packs of 14, 28, 30, 56, 84, 90 or 98 film-coated tablets. Unit dose blister packs of 56 x 1 film-coated 
tablet for delivery in hospitals are also available. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
Manufacturer 
SANOFI WINTHROP INDUSTRIE 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex - France 
 
CHINOIN PRIVATE CO. LTD. 
Lévai u.5. 
2112 Veresegyház - Hungary 
 
SANOFI WINTHROP INDUSTRIE 
30-36 Avenue Gustave Eiffel 
37100 Tours - France 
 
SANOFI-AVENTIS, S.A. 
Ctra. C-35 (La Batlloria-Hostalric), km. 63.09 
17404 Riells i Viabrea (Girona) – Spain 
 



 124 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Zentiva, k.s. 
Tél/Tel: +32 280 86 420 
PV-Belgium@zentiva.com 
 

Lietuva 
Zentiva, k.s. 
Tel: +370 52152025 
PV-Lithuania@zentiva.com 

България 
Zentiva, k.s. 
Тел: + 359 2 805 72 08 
PV-Bulgaria@zentiva.com 
 

Luxembourg/Luxemburg 
Zentiva, k.s. 
Tél/Tel: +352 208 82330 
PV-Luxembourg@zentiva.com 

Česká republika 
Zentiva, k.s. 
Tel: +420 267 241 111 
PV-Czech-Republic@zentiva.com 

Magyarország 
Zentiva, k.s. 
Tel.: +36 165 55 722 
PV-Hungary@zentiva.com 

Danmark 
Zentiva, k.s. 
Tlf: +45 787 68 400 
PV-Denmark@zentiva.com 
 

Malta 
Zentiva, k.s. 
Tel: +356 277 82 052 
PV-Malta@zentiva.com 

Deutschland 
Zentiva Pharma GmbH  
Tel: +49 (0) 800 53 53 010 
PV-Germany@zentiva.com 
 

Nederland 
Zentiva, k.s. 
Tel: +31 202 253 638 
PV-Netherlands@zentiva.com 

Eesti 
Zentiva, k.s. 
Tel: +372 52 70308 
PV-Estonia@zentiva.com 
 

Norge 
Zentiva, k.s. 
Tlf: +47 219 66 203 
PV-Norway@zentiva.com 

Ελλάδα 
Zentiva, k.s. 
Τηλ: +30 211 198 7510 
PV-Greece@zentiva.com 
 

Österreich 
Zentiva, k.s. 
Tel: +43 720 778 877 
PV-Austria@zentiva.com 

España 
Zentiva, k.s. 
Tel: +34 931 815 250 
PV-Spain@zentiva.com 
 

Polska 
Zentiva Polska Sp. z o.o. 
Tel: + 48 22 375 92 00 
PV-Poland@zentiva.com 

France 
Zentiva France 
Tél: +33 (0) 800 089 219  
PV-France@zentiva.com 
 

Portugal 
Zentiva Portugal, Lda 
Tel: +351210601360 
PV-Portugal@zentiva.com 

Hrvatska 
Zentiva, k.s. 
Tel: +385 155 17 772 
PV-Croatia@zentiva.com 
 
Ireland 
Zentiva, k.s. 
Tel: +353 766 803 944 
PV-Ireland@zentiva.com 

România 
S.C. ZENTIVA S.A. 
Tel: +40 021 317 31 36 
PV-Romania@zentiva.com 
 
Slovenija 
Zentiva, k.s. 
Tel: +386 360 00 408 
PV-Slovenia@zentiva.com 



 125 

 
Ísland 
Zentiva, k.s. 
Sími: +354 539 0650 
PV-Iceland@zentiva.com 
 

Slovenská republika 
Zentiva, a.s. 
Tel: +421 2 3918 3010 
PV-Slovakia@zentiva.com 

Italia 
Zentiva Italia S.r.l. 
 +39-02-38598801 
PV-Italy@zentiva.com 

Suomi/Finland 
Zentiva, k.s. 
Puh/Tel: +358 942 598 648 
PV-Finland@zentiva.com 
 

Κύπρος 
Zentiva, k.s. 
Τηλ: +357 240 30 144 
PV-Cyprus@zentiva.com 
 

Sverige 
Zentiva, k.s. 
Tel: +46 840 838 822 
PV-Sweden@zentiva.com 

Latvija 
Zentiva, k.s. 
Tel: +371 67893939 
PV-Latvia@zentiva.com 

United Kingdom 
Zentiva Pharma UK Limited 
Tel: +44 (0) 845 372 7101 
PV-United-Kingdom@zentiva.com 

  
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/ 



 126 

Package leaflet: Information for the patient 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg film-coated tablets 

irbesartan/hydrochlorothiazide 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
▪ Keep this leaflet. You may need to read it again. 
▪ If you have any further questions, ask your doctor or pharmacist. 
▪ This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
▪ If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 

What is in this leaflet 
1. What Irbesartan Hydrochlorothiazide Zentiva is and what it is used for 
2. What you need to know before you take Irbesartan Hydrochlorothiazide Zentiva 
3. How to take Irbesartan Hydrochlorothiazide Zentiva 
4. Possible side effects 
5. How to store Irbesartan Hydrochlorothiazide Zentiva 
6. Contents of the pack and other information 
 
 
1. What Irbesartan Hydrochlorothiazide Zentiva is and what it is used for 
 
Irbesartan Hydrochlorothiazide Zentiva is a combination of two active substances, irbesartan and 
hydrochlorothiazide. 
Irbesartan belongs to a group of medicines known as angiotensin-II receptor antagonists. 
Angiotensin-II is a substance produced in the body that binds to receptors in blood vessels causing 
them to tighten. This results in an increase in blood pressure. Irbesartan prevents the binding of 
angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. 
Hydrochlorothiazide is one of a group of medicines (called thiazide diuretics) that causes increased 
urine output and so causes a lowering of blood pressure. 
The two active ingredients in Irbesartan Hydrochlorothiazide Zentiva work together to lower blood 
pressure further than if either was given alone. 
 
Irbesartan Hydrochlorothiazide Zentiva is used to treat high blood pressure, when treatment with 
irbesartan or hydrochlorothiazide alone did not provide adequate control of your blood pressure. 
 
 
2. What you need to know before you take Irbesartan Hydrochlorothiazide Zentiva 
 
Do not take Irbesartan Hydrochlorothiazide Zentiva 
▪ if you are allergic to irbesartan or any of the other ingredients of this medicine (listed in 

section 6) 
▪ if you are allergic  to hydrochlorothiazide or any other sulfonamide-derived medicines 
▪ if you are more than 3 months pregnant. (It is also better to avoid Irbesartan 

Hydrochlorothiazide Zentiva in early pregnancy – see pregnancy section) 
▪ if you have severe liver or kidney problems 
▪ if you have difficulty in producing urine 
▪ if your doctor determines that you have persistently high calcium or low potassium levels in 

your blood 
▪ if you have diabetes or impaired kidney function and you are treated with a blood pressure 

lowering medicine containing aliskiren.  
 
 
 



 127 

Warnings and precautions 
Talk to your doctor before taking Irbesartan Hydrochlorothiazide Zentiva and if any of the following 
apply to you: 
▪ if you get excessive vomiting or diarrhoea 
▪ if you suffer from kidney problems or have a kidney transplant 
▪ if you suffer from heart problems 
▪ if you suffer from liver problems 
▪ if you suffer from diabetes 
▪ if you suffer from lupus erythematosus (also known as lupus or SLE) 
▪ if you suffer from primary aldosteronism (a condition related to high production of the 

hormone aldosterone, which causes sodium retention and, in turn, an increase in blood 
pressure). 

▪ if you are taking  any of the following medicines used to treat high blood pressure: 
o an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have 

diabetes-related kidney problems. 
o aliskiren. 

▪ if you have had skin cancer or if you develop an unexpected skin lesion during the treatment. 
Treatment with hydrochlorothiazide, particularly long term use with high doses, may increase the 
risk of some types of skin and lip cancer (non-melanoma skin cancer). Protect your skin from sun 
exposure and UV rays while taking Karvezide. 

 
Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. 
potassium) in your blood at regular intervals. 
 
See also information under the heading “Do not take Irbesartan Hydrochlorothiazide Zentiva”. 
 
You must tell your doctor if you think you are (or might become) pregnant. Irbesartan 
Hydrochlorothiazide Zentiva is not recommended in early pregnancy, and must not be taken if you are 
more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see 
pregnancy section). 
 
You should also tell your doctor: 
▪ if you are on a low-salt diet 
▪ if you have signs such as abnormal thirst, dry mouth, general weakness, drowsiness, muscle 

pain or cramps, nausea, vomiting, or an abnormally fast heart beat which may indicate an 
excessive effect of hydrochlorothiazide (contained in Irbesartan Hydrochlorothiazide Zentiva) 

▪ if you experience an increased sensitivity of the skin to the sun with symptoms of sunburn 
(such as redness, itching, swelling, blistering) occurring more quickly than normal 

▪ if you are going to have an operation (surgery) or be given anaesthetics  
▪ if you have changes in your vision or pain in one or both of your eyes while taking Irbesartan 

Hydrochlorothiazide Zentiva. This could be a sign that you are developing glaucoma, increased 
pressure in your eye(s). You should discontinue Irbesartan Hydrochlorothiazide Zentiva 
treatment and seek medical attention. 

 
The hydrochlorothiazide contained in this medicine could produce a positive result in an anti-doping 
test. 
 
Children and adolescents 
Irbesartan Hydrochlorothiazide Zentiva should not be given to children and adolescents 
(under 18 years). 
 
Other medicines and Irbesartan Hydrochlorothiazide Zentiva 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 



 128 

Diuretic agents such as the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide Zentiva 
may have an effect on other medicines. Preparations containing lithium should not be taken with 
Irbesartan Hydrochlorothiazide Zentiva without close supervision by your doctor. 
 
Your doctor may need to change your dose and/or to take other precautions: 
 If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take 
Irbesartan Hydrochlorothiazide Zentiva” and “Warnings and precautions”). 
 
 
You may need to have blood checks if you take: 
▪ potassium supplements 
▪ salt substitutes containing potassium 
▪ potassium sparing medicines or other diuretics (water tablets) 
▪ some laxatives 
▪ medicines for the treatment of gout 
▪ therapeutic vitamin D supplements 
▪ medicines to control heart rhythm 
▪ medicines for diabetes (oral agents or insulins)  
▪ carbamazepine (a medicine for the treatment of epilepsy). 
 
It is also important to tell your doctor if you are taking other medicines to reduce your blood pressure, 
steroids, medicines to treat cancer, pain killers, arthritis medicines, or colestyramine and colestipol 
resins for lowering blood cholesterol. 
 
Irbesartan Hydrochlorothiazide Zentiva with food and drink 
Irbesartan Hydrochlorothiazide Zentiva can be taken with or without food. 
 
Due to the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide Zentiva, if you drink 
alcohol while on treatment with this medicine, you may have an increased feeling of dizziness on 
standing up, specially when getting up from a sitting position. 
 
Pregnancy, breast-feeding and fertility 
Pregnancy 
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally 
advise you to stop taking Irbesartan Hydrochlorothiazide Zentiva before you become pregnant or as 
soon as you know you are pregnant and will advise you to take another medicine instead of Irbesartan 
Hydrochlorothiazide Zentiva. Irbesartan Hydrochlorothiazide Zentiva is not recommended in early 
pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to 
your baby if used after the third month of pregnancy. 
 
Breast-feeding 
Tell your doctor if you are breast-feeding or about to start breast-feeding. Irbesartan 
Hydrochlorothiazide Zentiva is not recommended for mothers who are breast-feeding, and your doctor 
may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, 
or was born prematurely. 
 
Driving and using machines 
Irbesartan Hydrochlorothiazide Zentiva is unlikely to affect your ability to drive or use machines. 
However, occasionally dizziness or weariness may occur during treatment of high blood pressure. If 
you experience these, talk to your doctor before attempting to drive or use machines. 
 
Irbesartan Hydrochlorothiazide Zentiva contains lactose. If you have been told by your doctor that 
you have an intolerance to some sugars (e.g. lactose), contact your doctor before taking this medicinal 
product. 
 
 



 129 

3. How to take Irbesartan Hydrochlorothiazide Zentiva 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Dosage 
The recommended dose of Irbesartan Hydrochlorothiazide Zentiva is one tablet a day. Irbesartan 
Hydrochlorothiazide Zentiva will usually be prescribed by your doctor when your previous treatment 
did not reduce your blood pressure enough. Your doctor will instruct you how to switch from the 
previous treatment to Irbesartan Hydrochlorothiazide Zentiva. 
 
Method of administration 
Irbesartan Hydrochlorothiazide Zentiva is for oral use. Swallow the tablets with a sufficient amount of 
fluid (e.g. one glass of water). You can take Irbesartan Hydrochlorothiazide Zentiva with or without 
food. Try to take your daily dose at about the same time each day. It is important that you continue to 
take Irbesartan Hydrochlorothiazide Zentiva until your doctor tells you otherwise. 
 
The maximal blood pressure lowering effect should be reached 6-8 weeks after beginning treatment. 
 
If you take more Irbesartan Hydrochlorothiazide Zentiva than you should 
If you accidentally take too many tablets, contact your doctor immediately. 
 
Children should not take Irbesartan Hydrochlorothiazide Zentiva 
Irbesartan Hydrochlorothiazide Zentiva should not be given to children under 18 years of age. If a 
child swallows some tablets, contact your doctor immediately. 
 
If you forget to take Irbesartan Hydrochlorothiazide Zentiva 
If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to 
make up for a forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
Some of these effects may be serious and may require medical attention. 
 
Rare cases of allergic skin reactions (rash, urticaria), as well as localised swelling of the face, lips 
and/or tongue have been reported in patients taking irbesartan. 
If you get any of the above symptoms or get short of breath, stop taking Irbesartan 
Hydrochlorothiazide Zentiva and contact your doctor immediately. 
 
The frequency of the side effects listed below is defined using the following convention: 
Common: may affect up to 1 in 10 people 
Uncommon: may affect up to 1 in 100 people 
 
Side effects reported in clinical studies for patients treated with Irbesartan Hydrochlorothiazide 
Zentiva were: 
 
Common side effects (may affect up to 1 in 10 people): 
▪ nausea/vomiting 
▪ abnormal urination 
▪ fatigue 
▪ dizziness (including when getting up from a lying or sitting position) 



 130 

▪ blood tests may show raised levels of an enzyme that measures the muscle and heart function 
(creatine kinase) or raised levels of substances that measure kidney function (blood urea nitrogen, 
creatinine). 

If any of these side effects causes you problems, talk to your doctor. 
 
Uncommon side effects ( may affect up to 1 in 100 people): 
▪ diarrhoea 
▪ low blood pressure 
▪ fainting 
▪ heart rate increased 
▪ flushing 
▪ swelling 
▪ sexual dysfunction (problems with sexual performance) 
▪ blood tests may show lowered levels of potassium and sodium in your blood. 
If any of these side effects causes you problems, talk to your doctor. 
 
Side effects reported since the launch of Irbesartan Hydrochlorothiazide Zentiva 
Some undesirable effects have been reported since marketing of Irbesartan Hydrochlorothiazide 
Zentiva. Undesirable effects where the frequency is not known are: headache, ringing in the ears, 
cough, taste disturbance, indigestion, pain in joints and muscles, liver function abnormal and impaired 
kidney function, increased level of potassium in your blood and allergic reactions such as rash, hives, 
swelling of the face, lips, mouth, tongue or throat. Uncommon cases of jaundice (yellowing of the skin 
and/or whites of the eyes) have also been reported. 
 
As for any combination of two active substances, side effects associated with each individual 
component cannot be excluded. 
 
Side effects associated with irbesartan alone 
In addition to the side effects listed above, chest pain, severe allergic reactions (anaphylactic shock) 
and decrease in te number of platelets (a blood cell essential for the clotting of the blood) have also 
been reported. 
 
Side effects associated with hydrochlorothiazide alone 
Loss of appetite; stomach irritation; stomach cramps; constipation; jaundice (yellowing of the skin 
and/or whites of the eyes); inflammation of the pancreas characterised by severe upper stomach pain, 
often with nausea and vomiting; sleep disorders; depression; blurred vision; lack of white blood cells, 
which can result in frequent infections, fever; decrease in the number of platelets (a blood cell 
essential for the clotting of the blood), decreased number of red blood cells (anaemia) characterised by 
tiredness, headaches, being short of breath when exercising, dizziness and looking pale; kidney 
disease; lung problems including pneumonia or build-up of fluid in the lungs; increased sensitivity of 
the skin to the sun; inflammation of blood vessels; a skin disease characterized by the peeling of the 
skin all over the body; cutaneous lupus erythematosus, which is identified by a rash that may appear 
on the face, neck, and scalp; allergic reactions; weakness and muscle spasm; altered heart rate; reduced 
blood pressure after a change in body position; swelling of the salivary glands; high sugar levels in the 
blood; sugar in the urine; increases in some kinds of blood fat; high uric acid levels in the blood, 
which may cause gout. 
Not known (frequency cannot be estimated from the available data): skin and lip cancer (non-
melanoma skin cancer). 
 
It is known that side effects associated with hydrochlorothiazide may increase with higher doses of 
hydrochlorothiazide. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 



 131 

 
 
5. How to store Irbesartan Hydrochlorothiazide Zentiva 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and on the blister after 
EXP. The expiry date refers to the last day of that month. 
 
Do not store above 30°C. 
 
Store in the original package in order to protect from moisture. 
 
Do not throw awy any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Irbesartan Hydrochlorothiazide Zentiva contains 
▪ The active substances are irbesartan and hydrochlorothiazide. Each film-coated tablet of 

Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg contains 300 mg irbesartan and 
12.5 mg hydrochlorothiazide. 

▪ The other ingredients are lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, hypromellose, silicon dioxide, magnesium stearate, titanium dioxide, macrogol 3000, 
red and yellow ferric oxides, carnauba wax. Please see section 2 “Irbesartan 
Hydrochlorothiazide Zentiva contains lactose”. 

 
What Irbesartan Hydrochlorothiazide Zentiva looks like and contents of the pack 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg film-coated tablets are peach, biconvex, oval-
shaped, with a heart debossed on one side and the number 2876 engraved on the other side. 
 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/12.5 mg film-coated tablets are supplied in blister 
packs of 14, 28, 30, 56, 84, 90 or 98 film-coated tablets. Unit dose blister packs of 56 x 1 film-coated 
tablet for delivery in hospitals are also available. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
Manufacturer 
SANOFI WINTHROP INDUSTRIE 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex - France 
 
CHINOIN PRIVATE CO. LTD. 
Lévai u.5. 
2112 Veresegyház - Hungary 
 
SANOFI WINTHROP INDUSTRIE 
30-36 Avenue Gustave Eiffel 
37100 Tours - France 



 132 

 
SANOFI-AVENTIS, S.A. 
Ctra. C-35 (La Batlloria-Hostalric), km. 63.09 
17404 Riells i Viabrea (Girona) – Spain 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Zentiva, k.s. 
Tél/Tel: +32 280 86 420 
PV-Belgium@zentiva.com 
 

Lietuva 
Zentiva, k.s. 
Tel: +370 52152025 
PV-Lithuania@zentiva.com 

България 
Zentiva, k.s. 
Тел: + 359 2 805 72 08 
PV-Bulgaria@zentiva.com 
 

Luxembourg/Luxemburg 
Zentiva, k.s. 
Tél/Tel: +352 208 82330 
PV-Luxembourg@zentiva.com 

Česká republika 
Zentiva, k.s. 
Tel: +420 267 241 111 
PV-Czech-Republic@zentiva.com 

Magyarország 
Zentiva, k.s. 
Tel.: +36 165 55 722 
PV-Hungary@zentiva.com 

Danmark 
Zentiva, k.s. 
Tlf: +45 787 68 400 
PV-Denmark@zentiva.com 
 

Malta 
Zentiva, k.s. 
Tel: +356 277 82 052 
PV-Malta@zentiva.com 

Deutschland 
Zentiva Pharma GmbH  
Tel: +49 (0) 800 53 53 010 
PV-Germany@zentiva.com 
 

Nederland 
Zentiva, k.s. 
Tel: +31 202 253 638 
PV-Netherlands@zentiva.com 

Eesti 
Zentiva, k.s. 
Tel: +372 52 70308 
PV-Estonia@zentiva.com 
 

Norge 
Zentiva, k.s. 
Tlf: +47 219 66 203 
PV-Norway@zentiva.com 

Ελλάδα 
Zentiva, k.s. 
Τηλ: +30 211 198 7510 
PV-Greece@zentiva.com 
 

Österreich 
Zentiva, k.s. 
Tel: +43 720 778 877 
PV-Austria@zentiva.com 

España 
Zentiva, k.s. 
Tel: +34 931 815 250 
PV-Spain@zentiva.com 
 

Polska 
Zentiva Polska Sp. z o.o. 
Tel: + 48 22 375 92 00 
PV-Poland@zentiva.com 

France 
Zentiva France 
Tél: +33 (0) 800 089 219  
PV-France@zentiva.com 
 

Portugal 
Zentiva Portugal, Lda 
Tel: +351210601360 
PV-Portugal@zentiva.com 

Hrvatska 
Zentiva, k.s. 
Tel: +385 155 17 772 
PV-Croatia@zentiva.com 

România 
S.C. ZENTIVA S.A. 
Tel: +40 021 317 31 36 
PV-Romania@zentiva.com 



 133 

 
Ireland 
Zentiva, k.s. 
Tel: +353 766 803 944 
PV-Ireland@zentiva.com 
 

 
Slovenija 
Zentiva, k.s. 
Tel: +386 360 00 408 
PV-Slovenia@zentiva.com 

Ísland 
Zentiva, k.s. 
Sími: +354 539 0650 
PV-Iceland@zentiva.com 
 

Slovenská republika 
Zentiva, a.s. 
Tel: +421 2 3918 3010 
PV-Slovakia@zentiva.com 

Italia 
Zentiva Italia S.r.l. 
 +39-02-38598801 
PV-Italy@zentiva.com 

Suomi/Finland 
Zentiva, k.s. 
Puh/Tel: +358 942 598 648 
PV-Finland@zentiva.com 
 

Κύπρος 
Zentiva, k.s. 
Τηλ: +357 240 30 144 
PV-Cyprus@zentiva.com 
 

Sverige 
Zentiva, k.s. 
Tel: +46 840 838 822 
PV-Sweden@zentiva.com 

Latvija 
Zentiva, k.s. 
Tel: +371 67893939 
PV-Latvia@zentiva.com 

United Kingdom 
Zentiva Pharma UK Limited 
Tel: +44 (0) 845 372 7101 
PV-United-Kingdom@zentiva.com 

  
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/ 



 134 

Package leaflet: Information for the patient 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/25 mg film-coated tablets 

irbesartan/hydrochlorothiazide 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
▪ Keep this leaflet. You may need to read it again. 
▪ If you have any further questions, ask your doctor or pharmacist. 
▪ This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
▪ If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Irbesartan Hydrochlorothiazide Zentiva is and what it is used for 
2. What you need to know before you take Irbesartan Hydrochlorothiazide Zentiva 
3. How to take Irbesartan Hydrochlorothiazide Zentiva 
4. Possible side effects 
5. How to store Irbesartan Hydrochlorothiazide Zentiva 
6. Contents of the pack and other information 
 
 
1. What Irbesartan Hydrochlorothiazide Zentiva is and what it is used for 
 
Irbesartan Hydrochlorothiazide Zentiva is a combination of two active substances, irbesartan and 
hydrochlorothiazide. 
Irbesartan belongs to a group of medicines known as angiotensin-II receptor antagonists. 
Angiotensin-II is a substance produced in the body that binds to receptors in blood vessels causing 
them to tighten. This results in an increase in blood pressure. Irbesartan prevents the binding of 
angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. 
Hydrochlorothiazide is one of a group of medicines (called thiazide diuretics) that causes increased 
urine output and so causes a lowering of blood pressure. 
The two active ingredients in Irbesartan Hydrochlorothiazide Zentiva work together to lower blood 
pressure further than if either was given alone. 
 
Irbesartan Hydrochlorothiazide Zentiva is used to treat high blood pressure, when treatment with 
irbesartan or hydrochlorothiazide alone did not provide adequate control of your blood pressure. 
 
 
2. What you need to know before you take Irbesartan Hydrochlorothiazide Zentiva 
 
Do not take Irbesartan Hydrochlorothiazide Zentiva 
▪ if you are allergic to irbesartan or any of the other ingredients of this medicine (listed in 

section 6) 
▪ if you are allergic  to hydrochlorothiazide or any other sulfonamide-derived medicines 
▪ if you are more than 3 months pregnant. (It is also better to avoid Irbesartan 

Hydrochlorothiazide Zentiva in early pregnancy – see pregnancy section) 
▪ if you have severe liver or kidney problems 
▪ if you have difficulty in producing urine 
▪ if your doctor determines that you have persistently high calcium or low potassium levels in your 

blood 
▪ if you have diabetes or impaired kidney function and you are treated with a blood pressure 

lowering medicine containing aliskiren. 
 
 



 135 

Warnings and precautions 
Talk to your doctor before taking Irbesartan Hydrochlorothiazide Zentiva and if any of the following 
apply to you: 
▪ if you get excessive vomiting or diarrhoea 
▪ if you suffer from kidney problems or have a kidney transplant 
▪ if you suffer from heart problems 
▪ if you suffer from liver problems 
▪ if you suffer from diabetes 
▪ if you suffer from lupus erythematosus (also known as lupus or SLE) 
▪ if you suffer from primary aldosteronism (a condition related to high production of the 

hormone aldosterone, which causes sodium retention and, in turn, an increase in blood pressure) 
▪ if you are taking  any of the following medicines used to treat high blood pressure: 

o an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have 
diabetes-related kidney problems. 

o aliskiren. 
▪ if you have had skin cancer or if you develop an unexpected skin lesion during the treatment. 

Treatment with hydrochlorothiazide, particularly long term use with high doses, may increase the 
risk of some types of skin and lip cancer (non-melanoma skin cancer). Protect your skin from sun 
exposure and UV rays while taking Karvezide. 

 
Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. 
potassium) in your blood at regular intervals. 
 
See also information under the heading “Do not take Irbesartan Hydrochlorothiazide Zentiva”. 
 
You must tell your doctor if you think you are (or might become) pregnant. Irbesartan 
Hydrochlorothiazide Zentiva is not recommended in early pregnancy, and must not be taken if you are 
more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see 
pregnancy section). 
 
You should also tell your doctor: 

 if you are on a low-salt diet 
▪ if you have signs such as abnormal thirst, dry mouth, general weakness, drowsiness, muscle 

pain or cramps, nausea, vomiting, or an abnormally fast heart beat which may indicate an 
excessive effect of hydrochlorothiazide (contained in Irbesartan Hydrochlorothiazide Zentiva) 

▪ if you experience an increased sensitivity of the skin to the sun with symptoms of sunburn (such 
as redness, itching, swelling, blistering) occurring more quickly than normal 

 if you are going to have an operation (surgery) or be given anaesthetics  
▪ if you have changes in your vision or pain in one or both of your eyes while taking Irbesartan 

Hydrochlorothiazide Zentiva. This could be a sign that you are developing glaucoma, increased 
pressure in your eye(s). You should discontinue Irbesartan Hydrochlorothiazide Zentiva treatment 
and seek medical attention. 

 
The hydrochlorothiazide contained in this medicine could produce a positive result in an anti-doping 
test. 
 
Children and adolescents 
Irbesartan Hydrochlorothiazide Zentiva should not be given to children and adolescents 
(under 18 years). 
 
 
Other medicines and Irbesartan Hydrochlorothiazide Zentiva 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 



 136 

Diuretic agents such as the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide Zentiva 
may have an effect on other medicines. Preparations containing lithium should not be taken with 
Irbesartan Hydrochlorothiazide Zentiva without close supervision by your doctor. 
 
Your doctor may need to change your dose and/or to take other precautions: 
 If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do 
not take Irbesartan Hydrochlorothiazide Zentiva” and “Warnings and precautions”). 
You may need to have blood checks if you take: 
▪ potassium supplements 
▪ salt substitutes containing potassium 
▪ potassium sparing medicines or other diuretics (water tablets) 
▪ some laxatives 
▪ medicines for the treatment of gout 
▪ therapeutic vitamin D supplements 
▪ medicines to control heart rhythm 
▪ medicines for diabetes (oral agents or insulins)  
▪ carbamazepine (a medicine for the treatment of epilepsy). 
 
It is also important to tell your doctor if you are taking other medicines to reduce your blood pressure, 
steroids, medicines to treat cancer, pain killers, arthritis medicines, or colestyramine and colestipol 
resins for lowering blood cholesterol. 
 
Irbesartan Hydrochlorothiazide Zentiva with food and drink 
Irbesartan Hydrochlorothiazide Zentiva can be taken with or without food. 
 
Due to the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide Zentiva, if you drink 
alcohol while on treatment with this medicine, you may have an increased feeling of dizziness on 
standing up, specially when getting up from a sitting position. 
 
Pregnancy, breast-feeding and fertility 
Pregnancy 
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally 
advise you to stop taking Irbesartan Hydrochlorothiazide Zentiva before you become pregnant or as 
soon as you know you are pregnant and will advise you to take another medicine instead of Irbesartan 
Hydrochlorothiazide Zentiva. Irbesartan Hydrochlorothiazide Zentiva is not recommended in early 
pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to 
your baby if used after the third month of pregnancy. 
 
Breast-feeding 
Tell your doctor if you are breast-feeding or about to start breast-feeding. Irbesartan 
Hydrochlorothiazide Zentiva is not recommended for mothers who are breast-feeding, and your doctor 
may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, 
or was born prematurely. 
 
Driving and using machines 
Irbesartan Hydrochlorothiazide Zentiva is unlikely to affect your ability to drive or use machines. 
However, occasionally dizziness or weariness may occur during treatment of high blood pressure. If 
you experience these, talk to your doctor before attempting to drive or use machines. 
 
Irbesartan Hydrochlorothiazide Zentiva contains lactose. If you have been told by your doctor that 
you have an intolerance to some sugars (e.g. lactose), contact your doctor before taking this medicinal 
product. 
 
 



 137 

3. How to take Irbesartan Hydrochlorothiazide Zentiva 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Dosage 
The recommended dose of Irbesartan Hydrochlorothiazide Zentiva is one tablet a day. Irbesartan 
Hydrochlorothiazide Zentiva will usually be prescribed by your doctor when your previous treatment 
did not reduce your blood pressure enough. Your doctor will instruct you how to switch from the 
previous treatment to Irbesartan Hydrochlorothiazide Zentiva. 
 
Method of administration 
Irbesartan Hydrochlorothiazide Zentiva is for oral use. Swallow the tablets with a sufficient amount of 
fluid (e.g. one glass of water). You can take Irbesartan Hydrochlorothiazide Zentiva with or without 
food. Try to take your daily dose at about the same time each day. It is important that you continue to 
take Irbesartan Hydrochlorothiazide Zentiva until your doctor tells you otherwise. 
 
The maximal blood pressure lowering effect should be reached 6-8 weeks after beginning treatment. 
 
If you take more Irbesartan Hydrochlorothiazide Zentiva than you should 
If you accidentally take too many tablets, contact your doctor immediately. 
 
Children should not take Irbesartan Hydrochlorothiazide Zentiva 
Irbesartan Hydrochlorothiazide Zentiva should not be given to children under 18 years of age. If a 
child swallows some tablets, contact your doctor immediately. 
 
If you forget to take Irbesartan Hydrochlorothiazide Zentiva 
If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to 
make up for a forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
Some of these effects may be serious and may require medical attention. 
 
Rare cases of allergic skin reactions (rash, urticaria), as well as localised swelling of the face, lips 
and/or tongue have been reported in patients taking irbesartan. 
If you get any of the above symptoms or get short of breath, stop taking Irbesartan 
Hydrochlorothiazide Zentiva and contact your doctor immediately. 
 
The frequency of the side effects listed below is defined using the following convention: 
Common: may affect up to 1 in 10 people 
Uncommon: may affect up to 1 in 100 people 
 
Side effects reported in clinical studies for patients treated with Irbesartan Hydrochlorothiazide 
Zentiva were: 
 
Common side effects (may affect up to 1 in 10 people): 
▪ nausea/vomiting 
▪ abnormal urination 
▪ fatigue 
▪ dizziness (including when getting up from a lying or sitting position) 



 138 

▪ blood tests may show raised levels of an enzyme that measures the muscle and heart function 
(creatine kinase) or raised levels of substances that measure kidney function (blood urea nitrogen, 
creatinine). 

If any of these side effects causes you problems, talk to your doctor. 
 
Uncommon side effects ( may affect up to 1 in 100 people): 
▪ diarrhoea 
▪ low blood pressure 
▪ fainting 
▪ heart rate increased 
▪ flushing 
▪ swelling 
▪ sexual dysfunction (problems with sexual performance) 
▪ blood tests may show lowered levels of potassium and sodium in your blood. 
If any of these side effects causes you problems, talk to your doctor. 
 
Side effects reported since the launch of Irbesartan Hydrochlorothiazide Zentiva 
Some undesirable effects have been reported since marketing of Irbesartan Hydrochlorothiazide 
Zentiva. Undesirable effects where the frequency is not known are: headache, ringing in the ears, 
cough, taste disturbance, indigestion, pain in joints and muscles, liver function abnormal and impaired 
kidney function, increased level of potassium in your blood and allergic reactions such as rash, hives, 
swelling of the face, lips, mouth, tongue or throat. Uncommon cases of jaundice (yellowing of the skin 
and/or whites of the eyes) have also been reported. 
 
As for any combination of two active substances, side effects associated with each individual 
component cannot be excluded. 
 
Side effects associated with irbesartan alone 
In addition to the side effects listed above, chest pain, severe allergic reactions (anaphylactic shock) 
and decrease in te number of platelets (a blood cell essential for the clotting of the blood) have also 
been reported. 
 
Side effects associated with hydrochlorothiazide alone 
Loss of appetite; stomach irritation; stomach cramps; constipation; jaundice (yellowing of the skin 
and/or whites of the eyes); inflammation of the pancreas characterised by severe upper stomach pain, 
often with nausea and vomiting; sleep disorders; depression; blurred vision; lack of white blood cells, 
which can result in frequent infections, fever; decrease in the number of platelets (a blood cell 
essential for the clotting of the blood), decreased number of red blood cells (anaemia) characterised by 
tiredness, headaches, being short of breath when exercising, dizziness and looking pale; kidney 
disease; lung problems including pneumonia or build-up of fluid in the lungs; increased sensitivity of 
the skin to the sun; inflammation of blood vessels; a skin disease characterized by the peeling of the 
skin all over the body; cutaneous lupus erythematosus, which is identified by a rash that may appear 
on the face, neck, and scalp; allergic reactions; weakness and muscle spasm; altered heart rate; reduced 
blood pressure after a change in body position; swelling of the salivary glands; high sugar levels in the 
blood; sugar in the urine; increases in some kinds of blood fat; high uric acid levels in the blood, 
which may cause gout. 
Not known (frequency cannot be estimated from the available data): skin and lip cancer (non-
melanoma skin cancer) 
 
It is known that side effects associated with hydrochlorothiazide may increase with higher doses of 
hydrochlorothiazide. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 



 139 

 
 
 
5. How to store Irbesartan Hydrochlorothiazide Zentiva 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and on the blister after 
EXP. The expiry date refers to the last day of that month. 
 
Do not store above 30°C. 
 
Store in the original package in order to protect from moisture. 
 
Do not throw awy any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Irbesartan Hydrochlorothiazide Zentiva contains 
▪ The active substances are irbesartan and hydrochlorothiazide. Each film-coated tablet of 

Irbesartan Hydrochlorothiazide Zentiva 300 mg/25 mg contains 300 mg irbesartan and 25 mg 
hydrochlorothiazide. 

▪ The other ingredients are lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, hypromellose, silicon dioxide, magnesium stearate, titanium dioxide, macrogol 3350, 
red, yellow and black ferric oxides, pregelatinized starch, carnauba wax. Please see section 2 
“Irbesartan Hydrochlorothiazide Zentiva contains lactose”. 

 
What Irbesartan Hydrochlorothiazide Zentiva looks like and contents of the pack 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/25 mg film-coated tablets are pink, biconvex, oval-
shaped, with a heart debossed on one side and the number 2788 engraved on the other side. 
 
Irbesartan Hydrochlorothiazide Zentiva 300 mg/25 mg film-coated tablets are supplied in blister packs 
of 14, 28, 30, 56, 84, 90 or 98 film-coated tablets. Unit dose blister packs of 56 x 1 film-coated tablet 
for delivery in hospitals are also available. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
Manufacturer 
SANOFI WINTHROP INDUSTRIE 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex - France 
 
CHINOIN PRIVATE CO. LTD. 
Lévai u.5. 
2112 Veresegyház - Hungary 
 



 140 

SANOFI WINTHROP INDUSTRIE 
30-36 Avenue Gustave Eiffel 
37100 Tours - France 
 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Zentiva, k.s. 
Tél/Tel: +32 280 86 420 
PV-Belgium@zentiva.com 
 

Lietuva 
Zentiva, k.s. 
Tel: +370 52152025 
PV-Lithuania@zentiva.com 

България 
Zentiva, k.s. 
Тел: + 359 2 805 72 08 
PV-Bulgaria@zentiva.com 
 

Luxembourg/Luxemburg 
Zentiva, k.s. 
Tél/Tel: +352 208 82330 
PV-Luxembourg@zentiva.com 

Česká republika 
Zentiva, k.s. 
Tel: +420 267 241 111 
PV-Czech-Republic@zentiva.com 

Magyarország 
Zentiva, k.s. 
Tel.: +36 165 55 722 
PV-Hungary@zentiva.com 

Danmark 
Zentiva, k.s. 
Tlf: +45 787 68 400 
PV-Denmark@zentiva.com 
 

Malta 
Zentiva, k.s. 
Tel: +356 277 82 052 
PV-Malta@zentiva.com 

Deutschland 
Zentiva Pharma GmbH  
Tel: +49 (0) 800 53 53 010 
PV-Germany@zentiva.com 
 

Nederland 
Zentiva, k.s. 
Tel: +31 202 253 638 
PV-Netherlands@zentiva.com 

Eesti 
Zentiva, k.s. 
Tel: +372 52 70308 
PV-Estonia@zentiva.com 
 

Norge 
Zentiva, k.s. 
Tlf: +47 219 66 203 
PV-Norway@zentiva.com 

Ελλάδα 
Zentiva, k.s. 
Τηλ: +30 211 198 7510 
PV-Greece@zentiva.com 
 

Österreich 
Zentiva, k.s. 
Tel: +43 720 778 877 
PV-Austria@zentiva.com 

España 
Zentiva, k.s. 
Tel: +34 931 815 250 
PV-Spain@zentiva.com 
 

Polska 
Zentiva Polska Sp. z o.o. 
Tel: + 48 22 375 92 00 
PV-Poland@zentiva.com 

France 
Zentiva France 
Tél: +33 (0) 800 089 219  
PV-France@zentiva.com 
 

Portugal 
Zentiva Portugal, Lda 
Tel: +351210601360 
PV-Portugal@zentiva.com 

Hrvatska 
Zentiva, k.s. 
Tel: +385 155 17 772 
PV-Croatia@zentiva.com 

România 
S.C. ZENTIVA S.A. 
Tel: +40 021 317 31 36 
PV-Romania@zentiva.com 



 141 

 
Ireland 
Zentiva, k.s. 
Tel: +353 766 803 944 
PV-Ireland@zentiva.com 
 

 
Slovenija 
Zentiva, k.s. 
Tel: +386 360 00 408 
PV-Slovenia@zentiva.com 

Ísland 
Zentiva, k.s. 
Sími: +354 539 0650 
PV-Iceland@zentiva.com 
 

Slovenská republika 
Zentiva, a.s. 
Tel: +421 2 3918 3010 
PV-Slovakia@zentiva.com 

Italia 
Zentiva Italia S.r.l. 
 +39-02-38598801 
PV-Italy@zentiva.com 

Suomi/Finland 
Zentiva, k.s. 
Puh/Tel: +358 942 598 648 
PV-Finland@zentiva.com 
 

Κύπρος 
Zentiva, k.s. 
Τηλ: +357 240 30 144 
PV-Cyprus@zentiva.com 
 

Sverige 
Zentiva, k.s. 
Tel: +46 840 838 822 
PV-Sweden@zentiva.com 

Latvija 
Zentiva, k.s. 
Tel: +371 67893939 
PV-Latvia@zentiva.com 

United Kingdom 
Zentiva Pharma UK Limited 
Tel: +44 (0) 845 372 7101 
PV-United-Kingdom@zentiva.com 

  
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/  



 142 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Annex IV 

Scientific conclusions  



 143 

Scientific conclusions  

Sartan-containing medicinal products are important treatment options of serious or potentially 

serious conditions such as hypertension or certain heart or kidney diseases. Efficacy and safety of 

sartan-containing medicines in these indications are per se well-established and are not questioned 

in this referral. The key issue of this referral concerns the detection of N-nitrosamine (esp. NDMA 

and/or NDEA) contaminations in sartans, the resulting potential long-term risk to patients and 

measures to minimise as much as possible these contaminations. 

Nitrosamines are chemically simple molecules and can be formed in pharmaceutical manufacturing 

steps whenever there is a presence of a secondary (or tertiary) amines and nitrites, usually in 

acidic conditions. This is the background to the current referral procedure. However, it should be 

noted that nitrosamines can also be formed in many other situations, including in biological 

processes.  

NDMA and NDEA are two of the most potent mutagenic carcinogens known. As soon as the 

problem of nitrosamine-contamination became known, immediate, precautionary measures were 

taken by competent authorities across the EU such as recalls of affected batches from pharmacies. 

Initially, this was only necessary for valsartan containing APIs from few manufacturers but later 

also for some other sartans with a tetrazole ring. 

Assessment of the excess risk of cancer  

The impact of NDMA and NDEA on human health is currently only extrapolated from animal 

studies. However, as the DNA damage mechanisms documented in these studies are also relevant 

in humans and in vitro data in human cells are not significantly different from those in animal cells, 

it is prudent to assume that effects seen in animals may also occur in humans after exposure to 

sufficiently large amounts of these nitrosamines.  

In addition to NDMA and NDEA, other N-nitrosamines have been detected in a few sartan-

containing medicinal products. Risks resulting from multiple exposures are considered to add up in 

patients as mutagenic carcinogens are currently considered as summation toxins. 

The ICH M7(R1) guideline sets out principles for determining limits for mutagenic / DNA-reactive 

impurities. The determination of an acceptable intake (AI) is based on extrapolation of carcinogenic 

risk from rodent carcinogenicity data, as the dose resulting in one cancer case among 100,000 

individuals exposed for a life-time to the impurity. N-nitrosamines belong to a “cohort of concern” 

compounds in this guideline. For these reasons, N-nitrosamine impurities in pharmaceuticals such 

as sartans intended for long-term use should be reduced as much as possible. 

A full risk assessment for patients previously exposed to NDMA and/or NDEA impurities in sartans, 

especially valsartan which was found to contain the highest nitrosamine contamination, is not 

possible as the real extent of exposure of patients is unknown. For an individual risk assessment, 

data on the exact drug products and batches used by each individual patient would be necessary. 

Thus, the risk assessment is based on a potential worst case scenario, which would be a partially 

combined exposure to the highest levels of NDEA for 4 years (2011 – 2015) and to NDMA for 6 

years (2012 – 2018) reported from a sartan, resulting in a cumulative theoretical excess cancer 

risk of 29.5:100,000 or 1:3390 (0.029%) when extrapolated from the available rat studies 

according to ICH M7(R1). Compared to the lifetime cancer risk in the European population of 

approximately 50%, this additional risk is considered to be very low.  

 



 144 

 

Considerations on monitoring of exposed patients 

The above stated very small theoretical risk has to be balanced against the risks of potential 

measures to monitor patients such as colonoscopy or gastroscopy which may exceed the 

theoretical excess cancer risk. For example, a recent review has estimated risks of perforation of 4 

per 10,000 (95% confidence interval, 2-5) and major haemorrhage of 8 per 10,000 (95% 

confidence interval, 5-14) with screening colonoscopy. In addition, advancing age, comorbidity and 

use of anticoagulants were found to be strongly associated with both gastrointestinal and non-

gastrointestinal complications. Furthermore, the target organ(s) of NDMA/NDEA toxicity in humans 

are still not sufficiently clear.  

For these reasons, CHMP could not identify cancer screening methods that patients would benefit 

from.  

 

Measures to mitigate the risk 

Appropriate regulatory actions (such as quarantine or batch recalls) have been taken where 

relevant. 

Additional measures are needed to minimise prospectively the reoccurrence of such contamination. 

Based on all available data, the CHMP requires the following: 

1. Obligatory risk assessments to be performed for manufacturing processes of the drug 

substances in order to evaluate the theoretical risk of N-nitrosamine formation and contamination 

2. Modifying manufacturing processes, where necessary, to minimise contamination as much as 

possible. 

3. Implement a control strategy to detect and control N-nitrosamine impurities in the API (or 

intermediate, if justified). 

Specifically, CHMP considered that NDMA and NDEA limits should be as low as technically possible. 

In this regard, a limit of quantification of 0.03 ppm for NDMA and NDEA would be achievable 

according to the available data on analytical methods. This limit is considered a sufficiently robust 

threshold for APIs that can technically be reached. In comparison to the daily intake levels 

calculated based on ICH M7(R1) using non-clinical toxicology, it is possible to generate additional 

safety factors ranging from 2.73 – 27.3 for NDMA and 10.0 – 100 for NDEA, by defining 0.03 ppm 

as the common technical target limit for NDEA and NDMA in tetrazole sartan APIs. The underlying 

concept of the proposed approach is to keep the amount of N-nitrosamine impurities as low as 

possible, irrespective of the type of sartan or dose. 

The limit of 0.03 ppm for NDMA and NDEA will be enforceable after a transitional period of 2 years 

from the notification of the Commission Decision. During this time period, MAHs and manufacturers 

are requested to introduce relevant changes to the manufacturing processes of the drug 

substances, as well as develop appropriate analytical methods while ensuring adequate supply of 

the market for these essential medicinal products. An interim limit based on daily intakes according 

to principles in ICH M7(R1) using toxicology data are set in order to control these impurities in the 

meantime at an acceptable level. These interim limits are based on the maximum daily dose 

authorised in the EU for each of the sartans and therefore vary between them, as outlined in the 

table below: 

 



 145 

 

Drug 

substance 

Max. daily 

dose (mg) 

NDEA   

Limit in ppm 
in API 

NDMA  

 Limit in ppm 
in API 

Valsartan 320 0.082  0.300 

Losartan 150 0.177 0.640 

Olmesartan 40 0.663 2.400 

Irbesartan 300 0.088 0.320 

Candesartan 32 0.820  3.000 

 

Should NDMA and NDEA be detected in parallel in an API batch, this should lead to rejection of the 

respective batch, considering that a combined contamination would translate into a combined risk, 

which may be higher than one additional case of cancer in 100.000 individuals. 

Whilst the measures are focused on NDMA and NDEA, the principles used in this procedure in terms 

of toxicology assessment, control strategy and changes to the manufacturing processes for drug 

substances should be applied by analogy to other nitrosamines. 

In case of identification of other nitrosamines, this should be forthwith reported to the competent 

authorities, together with a toxicology assessment of the impurity, a clinical assessment for the 

exposed patients, a root cause analysis and a corrective action plan (e.g. changes to the 

manufacturing process). 

 

Overall, taking into account the available data assessed in this procedure, the benefit risk balance 

of medicines containing a sartan with a tetrazole ring remains positive subject to the conditions 

imposed. 

 

Grounds for CHMP opinion 

Whereas 

• The CHMP considered the procedure under Article 31 of Directive 2001/83/EC for products 

containing sartans with a tetrazole group (candesartan, irbesartan, losartan, olmesartan, 

valsartan) 

• The CHMP reviewed data on quality regarding the manufacturing processes of sartans with 

a tetrazole group, analytical data including test results and available methods, and 

toxicological data available for the N-nitrosamines found in some of these products. The 

CHMP also carried out a risk assessment for patients previously exposed to NDMA and 

NDEA in sartans and calculated daily intake levels based on the principles of ICH M7(R1) 

which are associated with an additional lifetime risk of 1 in 100,000 patients. 

• Based on the analysis of potential root causes the CHMP considered that all the MAHs 

should perform risk assessment of the manufacturing processes used for the APIs in their 

finished products to evaluate the risk of N-nitrosamine formation and contamination. 

• A two-year transition period) is considered acceptable to change production processes to 

achieve syntheses in which N-nitrosamines are not formed, to adopt analytical methods for 

the control strategy and in order to avoid product shortages.  

• During this period, NDMA and NDEA impurities in the API should be controlled for a 

transition period at limits calculated based on the principles of ICH M7(R1) using validated 

assays 



 146 

• After the transition period, a limit for NDMA and NDEA of maximum 0.03 ppm should be 

implemented, which reflects the lowest quantifiable level based on capability of the 

available analytical methods. 

• In case of detection of other N-nitrosamines this should be forthwith reported to the 

competent authorities, together with a toxicology assessment of the impurity, a clinical 

assessment for the exposed patients, a root cause analysis and a corrective action plan.  

• CHMP could not identify cancer screening methods that patients would benefit from, 

considering the uncertainty of the target organ(s) of NDMA/NDEA toxicity in humans and 

the risks of measures to monitor patients such as colonoscopy or gastroscopy which may 

exceed the theoretical excess cancer risk. 

 

CHMP opinion 

The CHMP, as a consequence, considers that the benefit-risk balance of products containing 

candesartan, irbesartan, losartan, olmesartan, valsartan remains favourable subject to the 

conditions described above. 

Therefore the CHMP recommends the variation to the terms of the marketing authorisations for 

products containing candesartan, irbesartan, losartan, olmesartan, valsartan. 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	Scientific conclusions