Irbesartan Hydrochlorothiazide BMS

1

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide BMS 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: 
Each tablet contains 26.65 mg of lactose (as lactose monohydrate). 
 
For a 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 
 
Irbesartan Hydrochlorothiazide BMS 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 BMS 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 BMS 300 mg/12.5 mg may be administered in patients 
insufficiently controlled by irbesartan 300 mg or by Irbesartan Hydrochlorothiazide 
BMS 150 mg/12.5 mg. 

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

 
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended. 
When necessary, Irbesartan Hydrochlorothiazide BMS may be administered with another 
antihypertensive medicinal product (see section 4.5). 
 
Renal impairment: due to the hydrochlorothiazide component, Irbesartan Hydrochlorothiazide BMS 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). 
 

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Hepatic impairment: Irbesartan Hydrochlorothiazide BMS 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 BMS is necessary in patients with mild to 
moderate hepatic impairment (see section 4.3). 
 
Elderly patients: no dosage adjustment of Irbesartan Hydrochlorothiazide BMS is necessary in elderly 
patients. 
 
Paediatric patients: Irbesartan Hydrochlorothiazide BMS is not recommended for use in children and 
adolescents due to a lack of data on safety and efficacy. 
 
4.3 Contraindications 
 
 Hypersensitivity to the active substances, to any of the excipients (see 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 

 
4.4 Special warnings and precautions for use 
 
Hypotension - Volume-depleted patients: Irbesartan Hydrochlorothiazide BMS 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 BMS. 
 
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 BMS, a 
similar effect should be anticipated. 
 
Renal impairment and kidney transplantation: when Irbesartan Hydrochlorothiazide BMS 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 BMS in patients with a recent kidney transplantation. Irbesartan 
Hydrochlorothiazide BMS should not be used in patients with severe renal impairment (creatinine 
clearance < 30 ml/min) (see section 4.3). Thiazide diuretic-associated azotemia may occur in patients 
with impaired renal function. No dosage adjustment is necessary in patients with renal impairment 
whose creatinine clearance is ≥ 30 ml/min. However, in patients with mild to moderate renal 
impairment (creatinine clearance ≥ 30 ml/min but < 60 ml/min) this fixed dose combination should be 
administered with caution. 
 
Hepatic impairment: thiazides should be used with caution in patients with impaired hepatic function 
or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate 
hepatic coma. There is no clinical experience with Irbesartan Hydrochlorothiazide BMS 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 BMS is not recommended. 

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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 BMS, 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 BMS 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 BMS (see 
section 4.5). 
There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatraemia. Chloride 
deficit is generally mild and usually does not require treatment. 
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of 
serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia 
may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out 
tests for parathyroid function. 
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in 
hypomagnaesemia. 
 
Lithium: the combination of lithium and Irbesartan Hydrochlorothiazide BMS is not recommended 
(see section 4.5). 
 
Anti-doping test: hydrochlorothiazide contained in this medicinal product could produce a positive 
analytic result in an anti-doping test. 
 
General: in patients whose vascular tone and renal function depend predominantly on the activity of 
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or 
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting 
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated 
with acute hypotension, azotemia, oliguria, or rarely acute renal failure. As with any antihypertensive 
agent, excessive blood pressure decrease in patients with ischemic cardiopathy or ischemic 
cardiovascular disease could result in a myocardial infarction or stroke. 
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of 
allergy or bronchial asthma, but are more likely in patients with such a history. 
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide 
diuretics. 
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If 
photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-
administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the 
sun or to artificial UVA. 

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Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. 
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be 
changed to alternative antihypertensive treatments which have an established safety profile for use in 
pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, 
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). 
 
Lactose: this medicinal product contains lactose. Patients with rare hereditary problems of galactose 
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this 
medicinal product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Other antihypertensive agents: the antihypertensive effect of Irbesartan Hydrochlorothiazide BMS 
may be increased with the concomitant use of other antihypertensive agents. Irbesartan and 
hydrochlorothiazide (at doses up to 300 mg irbesartan/25 mg hydrochlorothiazide) have been safely 
administered with other antihypertensive agents including calcium channel blockers and 
beta-adrenergic blockers. Prior treatment with high dose diuretics may result in volume depletion and 
a risk of hypotension when initiating therapy with irbesartan with or without thiazide diuretics unless 
the volume depletion is corrected first (see section 4.4). 
 
Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during 
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects 
have been very rarely reported with irbesartan so far. Furthermore, renal clearance of lithium is 
reduced by thiazides so the risk of lithium toxicity could be increased with Irbesartan 
Hydrochlorothiazide BMS. Therefore, the combination of lithium and Irbesartan Hydrochlorothiazide 
BMS 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 BMS is administered with medicinal 
products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics). 
 
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered 
simultaneously with non-steroidal anti- inflammatory drugs (i.e. selective COX-2 inhibitors, 
acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect 
may occur. 
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an 
increased risk of worsening of renal function, including possible acute renal failure, and an increase in 
serum potassium, especially in patients with poor pre-existing renal function. The combination should 
be administered with caution, especially in the elderly. Patients should be adequately hydrated and 
consideration should be given to monitoring renal function after initiation of concomitant therapy, and 
periodically thereafter. 
 
Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan 
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser 

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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; 
 
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be increased; 
 
Digitalis glycosides: thiazide induced hypokalaemia or hypomagnaesemia favour the onset of 
digitalis-induced cardiac arrhythmias (see section 4.4); 
 
Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory drug 
may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients; 
 
Pressor amines (e.g. noradrenaline): the effect of pressor amines may be decreased, but not 
sufficiently to preclude their use; 
 
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): the effect of nondepolarizing skeletal 
muscle relaxants may be potentiated by hydrochlorothiazide; 
 
Antigout medicinal products: dosage adjustments of antigout medicinal products may be necessary as 
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or 
sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence 
of hypersensitivity reactions to allopurinol; 
 
Calcium salts: thiazide diuretics may increase serum calcium levels due to decreased excretion. If 
calcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be 
prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly; 
 
Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by 
thiazides. Anticholinergic agents (e.g. atropine, beperiden) may increase the bioavailability of 
thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides 
may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal 
excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their 
myelosuppressive effects. 
 
4.6 Pregnancy and lactation 
 
Pregnancy: 
 
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The 
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 
and 4.4). 
 
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 

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cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II 
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued 
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative 
antihypertensive treatments which have an established safety profile for use in pregnancy. When 
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, 
alternative therapy should be started. 
 
Exposure to AIIRA therapy during the second and third trimesters is known to induce human 
fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal 
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see 
sections 4.3 and 4.4). 
 
Thiazides cross the placental barrier and appear in cord blood. They may cause a decrease in placental 
perfusion, foetal electrolyte disturbances and possibly other reactions that have occurred in the adults. 
Cases of neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported with maternal 
thiazide therapy. Since Irbesartan Hydrochlorothiazide BMS contains hydrochlorothiazide, it is not 
recommended during the first trimester of pregnancy. A switch to a suitable alternative treatment 
should be carried out in advance of a planned pregnancy. 
 
Lactation: 
 
Because no information is available regarding the use of Irbesartan Hydrochlorothiazide BMS during 
breast-feeding, Irbesartan Hydrochlorothiazide BMS is not recommended and alternative treatments 
with better established safety profiles during breast-feeding are preferable, especially while nursing a 
newborn or preterm infant. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed. Based on its 
pharmacodynamic properties, Irbesartan Hydrochlorothiazide BMS is unlikely to affect this ability. 
When driving vehicles or operating machines, it should be taken into account that occasionally 
dizziness or weariness may occur during treatment of hypertension. 
 
4.8 Undesirable effects 
 
Irbesartan/hydrochlorothiazide combination: 
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled 
trials in which 898 hypertensive patients received various doses (range: 37.5 mg/6.25 mg to 
300 mg/25 mg irbesartan/hydrochlorothiazide). 
 
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* 

Common: increases in blood urea nitrogen (BUN), 
creatinine and creatine kinase 

Investigations: 

Uncommon: decreases in serum potassium and 
sodium 

Cardiac disorders: Uncommon: syncope, hypotension, tachycardia, 
oedema 

Common: dizziness Nervous system disorders: 
Uncommon: orthostatic dizziness 

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

Not known: cough 

Common: nausea/vomiting 
Uncommon: diarrhoea 

Gastrointestinal disorders: 

Not known: dyspepsia, dysgeusia 
Common: abnormal urination Renal and urinary disorders: 
Not known: impaired renal function including 

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

Uncommon: swelling extremity Musculoskeletal and connective 
tissue disorders: Not known: arthralgia, myalgia 
Metabolism and nutrition 
disorders: 

Not known: hyperkalaemia 

Vascular disorders: Uncommon: flushing 
General disorders and 
administration site conditions: 

Common: fatigue 

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

Hepatobiliary disorders: Not known: hepatitis, abnormal liver function 
Reproductive system and breast 
disorders: 

Uncommon: sexual dysfunction, libido changes 

* Frequency for adverse reactions detected by spontaneous reports is described as “not known” 
 
Additional information on individual components: in addition to the adverse reactions listed above for 
the combination product, other adverse reactions previously reported with one of the individual 
components may be potential adverse reactions with Irbesartan Hydrochlorothiazide BMS. Tables 2 
and 3 below detail the adverse reactions reported with the individual components of Irbesartan 
Hydrochlorothiazide BMS. 
 
Table 2: Adverse reactions reported with the use of irbesartan alone 
General disorders and 
administration site conditions: 

Uncommon: chest pain 

 
Table 3: Adverse reactions (regardless of relationship to medicinal product) 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 
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 

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Skin and subcutaneous tissue 
disorders: 

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

Musculoskeletal and connective 
tissue disorders: 

Not known: weakness, muscle spasm 

Vascular disorders: Not known: postural hypotension 
General disorders and 
administration site conditions: 

Not known: fever 

Hepatobiliary disorders: Not known: jaundice (intrahepatic cholestatic 
jaundice) 

Psychiatric disorders: Not known: depression, sleep disturbances 
 
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may 
increase when titrating the hydrochlorothiazide. 
 
4.9 Overdose 
 
No specific information is available on the treatment of overdose with Irbesartan Hydrochlorothiazide 
BMS. 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. 
 
Irbesartan Hydrochlorothiazide BMS is a combination of an angiotensin-II receptor antagonist, 
irbesartan, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an 
additive antihypertensive effect, reducing blood pressure to a greater degree than either component 
alone. 
 
Irbesartan is a potent, orally active, selective angiotensin-II receptor (AT1 subtype) antagonist. It is 
expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source 
or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors 
results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma 

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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 BMS 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 BMS 150 mg/12.5 mg and 
Irbesartan Hydrochlorothiazide BMS 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 BMS, 
rebound hypertension has not been seen with either irbesartan or hydrochlorothiazide. 
 
The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality has 
not been studied. Epidemiological studies have shown that long term treatment with 
hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity. 
 
There is no difference in response to Irbesartan Hydrochlorothiazide BMS, 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 

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administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the 
antihypertensive response in black patients approaches that of non-black patients. 
 
Efficacy and safety of Irbesartan Hydrochlorothiazide BMS as initial therapy for severe hypertension 
(defined as SeDBP ≥ 110 mmHg) was evaluated in a multicenter, randomized, double-blind, active-
controlled, 8-week, parallel-arm study. A total of 697 patients were randomized in a 2:1 ratio to either 
irbesartan/hydrochlorothiazide 150 mg/12.5 mg or to irbesartan 150 mg and systematically 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. 
 
5.2 Pharmacokinetic properties 
 
Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the 
pharmacokinetics of either medicinal product. 
 
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for 
their activity. Following oral administration of Irbesartan Hydrochlorothiazide BMS, the absolute oral 
bioavailability is 60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does 
not affect the bioavailability of Irbesartan Hydrochlorothiazide BMS. Peak plasma concentration 
occurs at 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for hydrochlorothiazide. 
 
Plasma protein binding of irbesartan is approximately 96%, with negligible binding to cellular blood 
components. The volume of distribution for irbesartan is 53-93 litres. Hydrochlorothiazide is 68% 
protein-bound in the plasma, and its apparent volume of distribution is 0.83-1.14 l/kg. 
 
Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. 
A less than proportional increase in oral absorption at doses beyond 600 mg was observed; the 
mechanism for this is unknown. The total body and renal clearance are 157-176 and 3.0-3.5 ml/min, 
respectively. The terminal elimination half-life of irbesartan is 11-15 hours. Steady-state plasma 
concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited 
accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily dosing. In a study, 
somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. 
However, there was no difference in the half-life and accumulation of irbesartan. No dosage 
adjustment is necessary in female patients. Irbesartan AUC and Cmax values were also somewhat 
greater in elderly subjects (≥ 65 years) than those of young subjects (18-40 years). However the 
terminal half-life was not significantly altered. No dosage adjustment is necessary in elderly patients. 
The mean plasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hours. 
 

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Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma 
radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via 
glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide 
(approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the 
cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. Irbesartan and its 
metabolites are eliminated by both biliary and renal pathways. After either oral or intravenous 
administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the 
remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. 
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidneys. At least 61% of the 
oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not 
the blood-brain barrier, and is excreted in breast milk. 
 
Renal impairment: in patients with renal impairment or those undergoing haemodialysis, the 
pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by 
haemodialysis. In patients with creatinine clearance < 20 ml/min, the elimination half-life of 
hydrochlorothiazide was reported to increase to 21 hours. 
 
Hepatic impairment: in patients with mild to moderate cirrhosis, the pharmacokinetic parameters of 
irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic 
impairment. 
 
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. 
 

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Irbesartan: there was no evidence of abnormal systemic or target organ toxicity at clinically relevant 
doses. In non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and 
≥ 100 mg/kg/day in macaques) caused a reduction of red blood cell parameters (erythrocytes, 
haemoglobin, haematocrit). At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidneys 
(such as interstitial nephritis, tubular distention, basophilic tubules, increased plasma concentrations of 
urea and creatinine) were induced by irbesartan in the rat and the macaque and are considered 
secondary to the hypotensive effects of the medicinal product which led to decreased renal perfusion. 
Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at 
≥ 90 mg/kg/day, in macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused 
by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the 
hyperplasia/hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. 
There was no evidence of mutagenicity, clastogenicity or carcinogenicity. 
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, 
hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, 
abortion or early resorption was noted at doses causing significant maternal toxicity, including 
mortality. No teratogenic effects were observed in the rat or rabbit. 
 
Hydrochlorothiazide: although equivocal evidence for a genotoxic or carcinogenic effect was found in 
some experimental models, the extensive human experience with hydrochlorothiazide has failed to 
show an association between its use and an increase in neoplasms. 
 
 
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. 
 
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; 1 blister card of 14 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 28 tablets; 2 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 tablets; 4 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 98 tablets; 7 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 x 1 tablets; 7 blister cards of 8 x 1 tablets each in PVC/PVDC/Aluminium perforated 
unit dose blisters. 
 
Not all pack sizes may be marketed. 

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6.6 Special precautions for disposal 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH - United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/369/001-005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 January 2007 
Date of latest renewal: 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this product is available on the website of the European Medicines Agency 
(EMEA) http://www.emea.europa.eu/ 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide BMS 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: 
Each tablet contains 65.8 mg of lactose (as lactose monohydrate). 
 
For a 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 
 
Irbesartan Hydrochlorothiazide BMS 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 BMS 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 BMS 300 mg/12.5 mg may be administered in patients 
insufficiently controlled by irbesartan 300 mg or by Irbesartan Hydrochlorothiazide 
BMS 150 mg/12.5 mg. 

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

 
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended. 
When necessary, Irbesartan Hydrochlorothiazide BMS may be administered with another 
antihypertensive medicinal product (see section 4.5). 
 
Renal impairment: due to the hydrochlorothiazide component, Irbesartan Hydrochlorothiazide BMS 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). 
 

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Hepatic impairment: Irbesartan Hydrochlorothiazide BMS 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 BMS is necessary in patients with mild to 
moderate hepatic impairment (see section 4.3). 
 
Elderly patients: no dosage adjustment of Irbesartan Hydrochlorothiazide BMS is necessary in elderly 
patients. 
 
Paediatric patients: Irbesartan Hydrochlorothiazide BMS is not recommended for use in children and 
adolescents due to a lack of data on safety and efficacy. 
 
4.3 Contraindications 
 
 Hypersensitivity to the active substances, to any of the excipients (see 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 

 
4.4 Special warnings and precautions for use 
 
Hypotension - Volume-depleted patients: Irbesartan Hydrochlorothiazide BMS 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 BMS. 
 
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 BMS, a 
similar effect should be anticipated. 
 
Renal impairment and kidney transplantation: when Irbesartan Hydrochlorothiazide BMS 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 BMS in patients with a recent kidney transplantation. Irbesartan 
Hydrochlorothiazide BMS should not be used in patients with severe renal impairment (creatinine 
clearance < 30 ml/min) (see section 4.3). Thiazide diuretic-associated azotemia may occur in patients 
with impaired renal function. No dosage adjustment is necessary in patients with renal impairment 
whose creatinine clearance is ≥ 30 ml/min. However, in patients with mild to moderate renal 
impairment (creatinine clearance ≥ 30 ml/min but < 60 ml/min) this fixed dose combination should be 
administered with caution. 
 
Hepatic impairment: thiazides should be used with caution in patients with impaired hepatic function 
or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate 
hepatic coma. There is no clinical experience with Irbesartan Hydrochlorothiazide BMS 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 BMS is not recommended. 

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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 BMS, 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 BMS 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 BMS (see 
section 4.5). 
There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatraemia. Chloride 
deficit is generally mild and usually does not require treatment. 
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of 
serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia 
may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out 
tests for parathyroid function. 
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in 
hypomagnaesemia. 
 
Lithium: the combination of lithium and Irbesartan Hydrochlorothiazide BMS is not recommended 
(see section 4.5). 
 
Anti-doping test: hydrochlorothiazide contained in this medicinal product could produce a positive 
analytic result in an anti-doping test. 
 
General: in patients whose vascular tone and renal function depend predominantly on the activity of 
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or 
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting 
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated 
with acute hypotension, azotemia, oliguria, or rarely acute renal failure. As with any antihypertensive 
agent, excessive blood pressure decrease in patients with ischemic cardiopathy or ischemic 
cardiovascular disease could result in a myocardial infarction or stroke. 
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of 
allergy or bronchial asthma, but are more likely in patients with such a history. 
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide 
diuretics. 
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If 
photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-
administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the 
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Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. 
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be 
changed to alternative antihypertensive treatments which have an established safety profile for use in 
pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, 
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). 
 
Lactose: this medicinal product contains lactose. Patients with rare hereditary problems of galactose 
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this 
medicinal product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Other antihypertensive agents: the antihypertensive effect of Irbesartan Hydrochlorothiazide BMS 
may be increased with the concomitant use of other antihypertensive agents. Irbesartan and 
hydrochlorothiazide (at doses up to 300 mg irbesartan/25 mg hydrochlorothiazide) have been safely 
administered with other antihypertensive agents including calcium channel blockers and 
beta-adrenergic blockers. Prior treatment with high dose diuretics may result in volume depletion and 
a risk of hypotension when initiating therapy with irbesartan with or without thiazide diuretics unless 
the volume depletion is corrected first (see section 4.4). 
 
Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during 
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects 
have been very rarely reported with irbesartan so far. Furthermore, renal clearance of lithium is 
reduced by thiazides so the risk of lithium toxicity could be increased with Irbesartan 
Hydrochlorothiazide BMS. Therefore, the combination of lithium and Irbesartan Hydrochlorothiazide 
BMS 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 BMS is administered with medicinal 
products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics). 
 
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered 
simultaneously with non-steroidal anti- inflammatory drugs (i.e. selective COX-2 inhibitors, 
acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect 
may occur. 
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an 
increased risk of worsening of renal function, including possible acute renal failure, and an increase in 
serum potassium, especially in patients with poor pre-existing renal function. The combination should 
be administered with caution, especially in the elderly. Patients should be adequately hydrated and 
consideration should be given to monitoring renal function after initiation of concomitant therapy, and 
periodically thereafter. 
 
Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan 
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser 

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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; 
 
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be increased; 
 
Digitalis glycosides: thiazide induced hypokalaemia or hypomagnaesemia favour the onset of 
digitalis-induced cardiac arrhythmias (see section 4.4); 
 
Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory drug 
may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients; 
 
Pressor amines (e.g. noradrenaline): the effect of pressor amines may be decreased, but not 
sufficiently to preclude their use; 
 
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): the effect of nondepolarizing skeletal 
muscle relaxants may be potentiated by hydrochlorothiazide; 
 
Antigout medicinal products: dosage adjustments of antigout medicinal products may be necessary as 
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or 
sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence 
of hypersensitivity reactions to allopurinol; 
 
Calcium salts: thiazide diuretics may increase serum calcium levels due to decreased excretion. If 
calcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be 
prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly; 
 
Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by 
thiazides. Anticholinergic agents (e.g. atropine, beperiden) may increase the bioavailability of 
thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides 
may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal 
excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their 
myelosuppressive effects. 
 
4.6 Pregnancy and lactation 
 
Pregnancy: 
 
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The 
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 
and 4.4). 
 
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 

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cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II 
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued 
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative 
antihypertensive treatments which have an established safety profile for use in pregnancy. When 
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, 
alternative therapy should be started. 
 
Exposure to AIIRA therapy during the second and third trimesters is known to induce human 
fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal 
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see 
sections 4.3 and 4.4). 
 
Thiazides cross the placental barrier and appear in cord blood. They may cause a decrease in placental 
perfusion, foetal electrolyte disturbances and possibly other reactions that have occurred in the adults. 
Cases of neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported with maternal 
thiazide therapy. Since Irbesartan Hydrochlorothiazide BMS contains hydrochlorothiazide, it is not 
recommended during the first trimester of pregnancy. A switch to a suitable alternative treatment 
should be carried out in advance of a planned pregnancy. 
 
Lactation: 
 
Because no information is available regarding the use of Irbesartan Hydrochlorothiazide BMS during 
breast-feeding, Irbesartan Hydrochlorothiazide BMS is not recommended and alternative treatments 
with better established safety profiles during breast-feeding are preferable, especially while nursing a 
newborn or preterm infant. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed. Based on its 
pharmacodynamic properties, Irbesartan Hydrochlorothiazide BMS is unlikely to affect this ability. 
When driving vehicles or operating machines, it should be taken into account that occasionally 
dizziness or weariness may occur during treatment of hypertension. 
 
4.8 Undesirable effects 
 
Irbesartan/hydrochlorothiazide combination: 
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled 
trials in which 898 hypertensive patients received various doses (range: 37.5 mg/6.25 mg to 
300 mg/25 mg irbesartan/hydrochlorothiazide). 
 
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* 

Common: increases in blood urea nitrogen (BUN), 
creatinine and creatine kinase 

Investigations: 

Uncommon: decreases in serum potassium and 
sodium 

Cardiac disorders: Uncommon: syncope, hypotension, tachycardia, 
oedema 

Common: dizziness Nervous system disorders: 
Uncommon: orthostatic dizziness 

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

Not known: cough 

Common: nausea/vomiting 
Uncommon: diarrhoea 

Gastrointestinal disorders: 

Not known: dyspepsia, dysgeusia 
Common: abnormal urination Renal and urinary disorders: 
Not known: impaired renal function including 

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

Uncommon: swelling extremity Musculoskeletal and connective 
tissue disorders: Not known: arthralgia, myalgia 
Metabolism and nutrition 
disorders: 

Not known: hyperkalaemia 

Vascular disorders: Uncommon: flushing 
General disorders and 
administration site conditions: 

Common: fatigue 

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

Hepatobiliary disorders: Not known: hepatitis, abnormal liver function 
Reproductive system and breast 
disorders: 

Uncommon: sexual dysfunction, libido changes 

* Frequency for adverse reactions detected by spontaneous reports is described as “not known” 
 
Additional information on individual components: in addition to the adverse reactions listed above for 
the combination product, other adverse reactions previously reported with one of the individual 
components may be potential adverse reactions with Irbesartan Hydrochlorothiazide BMS. Tables 2 
and 3 below detail the adverse reactions reported with the individual components of Irbesartan 
Hydrochlorothiazide BMS. 
 
Table 2: Adverse reactions reported with the use of irbesartan alone 
General disorders and 
administration site conditions: 

Uncommon: chest pain 

 
Table 3: Adverse reactions (regardless of relationship to medicinal product) 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 
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 

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Skin and subcutaneous tissue 
disorders: 

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

Musculoskeletal and connective 
tissue disorders: 

Not known: weakness, muscle spasm 

Vascular disorders: Not known: postural hypotension 
General disorders and 
administration site conditions: 

Not known: fever 

Hepatobiliary disorders: Not known: jaundice (intrahepatic cholestatic 
jaundice) 

Psychiatric disorders: Not known: depression, sleep disturbances 
 
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may 
increase when titrating the hydrochlorothiazide. 
 
4.9 Overdose 
 
No specific information is available on the treatment of overdose with Irbesartan Hydrochlorothiazide 
BMS. 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. 
 
Irbesartan Hydrochlorothiazide BMS is a combination of an angiotensin-II receptor antagonist, 
irbesartan, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an 
additive antihypertensive effect, reducing blood pressure to a greater degree than either component 
alone. 
 
Irbesartan is a potent, orally active, selective angiotensin-II receptor (AT1 subtype) antagonist. It is 
expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source 
or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors 
results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma 

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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 BMS 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 BMS 150 mg/12.5 mg and 
Irbesartan Hydrochlorothiazide BMS 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 BMS, 
rebound hypertension has not been seen with either irbesartan or hydrochlorothiazide. 
 
The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality has 
not been studied. Epidemiological studies have shown that long term treatment with 
hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity. 
 
There is no difference in response to Irbesartan Hydrochlorothiazide BMS, 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 

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administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the 
antihypertensive response in black patients approaches that of non-black patients. 
 
Efficacy and safety of Irbesartan Hydrochlorothiazide BMS as initial therapy for severe hypertension 
(defined as SeDBP ≥ 110 mmHg) was evaluated in a multicenter, randomized, double-blind, active-
controlled, 8-week, parallel-arm study. A total of 697 patients were randomized in a 2:1 ratio to either 
irbesartan/hydrochlorothiazide 150 mg/12.5 mg or to irbesartan 150 mg and systematically 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. 
 
5.2 Pharmacokinetic properties 
 
Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the 
pharmacokinetics of either medicinal product. 
 
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for 
their activity. Following oral administration of Irbesartan Hydrochlorothiazide BMS, the absolute oral 
bioavailability is 60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does 
not affect the bioavailability of Irbesartan Hydrochlorothiazide BMS. Peak plasma concentration 
occurs at 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for hydrochlorothiazide. 
 
Plasma protein binding of irbesartan is approximately 96%, with negligible binding to cellular blood 
components. The volume of distribution for irbesartan is 53-93 litres. Hydrochlorothiazide is 68% 
protein-bound in the plasma, and its apparent volume of distribution is 0.83-1.14 l/kg. 
 
Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. 
A less than proportional increase in oral absorption at doses beyond 600 mg was observed; the 
mechanism for this is unknown. The total body and renal clearance are 157-176 and 3.0-3.5 ml/min, 
respectively. The terminal elimination half-life of irbesartan is 11-15 hours. Steady-state plasma 
concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited 
accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily dosing. In a study, 
somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. 
However, there was no difference in the half-life and accumulation of irbesartan. No dosage 
adjustment is necessary in female patients. Irbesartan AUC and Cmax values were also somewhat 
greater in elderly subjects (≥ 65 years) than those of young subjects (18-40 years). However the 
terminal half-life was not significantly altered. No dosage adjustment is necessary in elderly patients. 
The mean plasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hours. 
 

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Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma 
radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via 
glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide 
(approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the 
cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. Irbesartan and its 
metabolites are eliminated by both biliary and renal pathways. After either oral or intravenous 
administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the 
remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. 
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidneys. At least 61% of the 
oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not 
the blood-brain barrier, and is excreted in breast milk. 
 
Renal impairment: in patients with renal impairment or those undergoing haemodialysis, the 
pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by 
haemodialysis. In patients with creatinine clearance < 20 ml/min, the elimination half-life of 
hydrochlorothiazide was reported to increase to 21 hours. 
 
Hepatic impairment: in patients with mild to moderate cirrhosis, the pharmacokinetic parameters of 
irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic 
impairment. 
 
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. 
 

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Irbesartan: there was no evidence of abnormal systemic or target organ toxicity at clinically relevant 
doses. In non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and 
≥ 100 mg/kg/day in macaques) caused a reduction of red blood cell parameters (erythrocytes, 
haemoglobin, haematocrit). At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidneys 
(such as interstitial nephritis, tubular distention, basophilic tubules, increased plasma concentrations of 
urea and creatinine) were induced by irbesartan in the rat and the macaque and are considered 
secondary to the hypotensive effects of the medicinal product which led to decreased renal perfusion. 
Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at 
≥ 90 mg/kg/day, in macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused 
by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the 
hyperplasia/hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. 
There was no evidence of mutagenicity, clastogenicity or carcinogenicity. 
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, 
hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, 
abortion or early resorption was noted at doses causing significant maternal toxicity, including 
mortality. No teratogenic effects were observed in the rat or rabbit. 
 
Hydrochlorothiazide: although equivocal evidence for a genotoxic or carcinogenic effect was found in 
some experimental models, the extensive human experience with hydrochlorothiazide has failed to 
show an association between its use and an increase in neoplasms. 
 
 
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. 
 
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; 1 blister card of 14 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 28 tablets; 2 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 tablets; 4 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 98 tablets; 7 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 x 1 tablets; 7 blister cards of 8 x 1 tablets each in PVC/PVDC/Aluminium perforated 
unit dose blisters. 
 
Not all pack sizes may be marketed. 

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6.6 Special precautions for disposal 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH - United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/369/006-010 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 January 2007 
Date of latest renewal: 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this product is available on the website of the European Medicines Agency 
(EMEA) http://www.emea.europa.eu/ 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide BMS 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: 
Each film-coated tablet contains 38.5 mg of lactose (as lactose monohydrate). 
 
For a 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 
 
Irbesartan Hydrochlorothiazide BMS 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 BMS 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 BMS 300 mg/12.5 mg may be administered in patients 
insufficiently controlled by irbesartan 300 mg or by Irbesartan Hydrochlorothiazide 
BMS 150 mg/12.5 mg. 

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

 
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended. 
When necessary, Irbesartan Hydrochlorothiazide BMS may be administered with another 
antihypertensive medicinal product (see section 4.5). 
 
Renal impairment: due to the hydrochlorothiazide component, Irbesartan Hydrochlorothiazide BMS 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). 
 

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Hepatic impairment: Irbesartan Hydrochlorothiazide BMS 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 BMS is necessary in patients with mild to 
moderate hepatic impairment (see section 4.3). 
 
Elderly patients: no dosage adjustment of Irbesartan Hydrochlorothiazide BMS is necessary in elderly 
patients. 
 
Paediatric patients: Irbesartan Hydrochlorothiazide BMS is not recommended for use in children and 
adolescents due to a lack of data on safety and efficacy. 
 
4.3 Contraindications 
 
 Hypersensitivity to the active substances, to any of the excipients (see 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 

 
4.4 Special warnings and precautions for use 
 
Hypotension - Volume-depleted patients: Irbesartan Hydrochlorothiazide BMS 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 BMS. 
 
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 BMS, a 
similar effect should be anticipated. 
 
Renal impairment and kidney transplantation: when Irbesartan Hydrochlorothiazide BMS 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 BMS in patients with a recent kidney transplantation. Irbesartan 
Hydrochlorothiazide BMS should not be used in patients with severe renal impairment (creatinine 
clearance < 30 ml/min) (see section 4.3). Thiazide diuretic-associated azotemia may occur in patients 
with impaired renal function. No dosage adjustment is necessary in patients with renal impairment 
whose creatinine clearance is ≥ 30 ml/min. However, in patients with mild to moderate renal 
impairment (creatinine clearance ≥ 30 ml/min but < 60 ml/min) this fixed dose combination should be 
administered with caution. 
 
Hepatic impairment: thiazides should be used with caution in patients with impaired hepatic function 
or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate 
hepatic coma. There is no clinical experience with Irbesartan Hydrochlorothiazide BMS 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 BMS is not recommended. 

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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 BMS, 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 BMS 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 BMS (see 
section 4.5). 
There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatraemia. Chloride 
deficit is generally mild and usually does not require treatment. 
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of 
serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia 
may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out 
tests for parathyroid function. 
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in 
hypomagnaesemia. 
 
Lithium: the combination of lithium and Irbesartan Hydrochlorothiazide BMS is not recommended 
(see section 4.5). 
 
Anti-doping test: hydrochlorothiazide contained in this medicinal product could produce a positive 
analytic result in an anti-doping test. 
 
General: in patients whose vascular tone and renal function depend predominantly on the activity of 
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or 
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting 
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated 
with acute hypotension, azotemia, oliguria, or rarely acute renal failure. As with any antihypertensive 
agent, excessive blood pressure decrease in patients with ischemic cardiopathy or ischemic 
cardiovascular disease could result in a myocardial infarction or stroke. 
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of 
allergy or bronchial asthma, but are more likely in patients with such a history. 
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide 
diuretics. 
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If 
photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-
administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the 
sun or to artificial UVA. 

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Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. 
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be 
changed to alternative antihypertensive treatments which have an established safety profile for use in 
pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, 
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). 
 
Lactose: this medicinal product contains lactose. Patients with rare hereditary problems of galactose 
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this 
medicinal product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Other antihypertensive agents: the antihypertensive effect of Irbesartan Hydrochlorothiazide BMS 
may be increased with the concomitant use of other antihypertensive agents. Irbesartan and 
hydrochlorothiazide (at doses up to 300 mg irbesartan/25 mg hydrochlorothiazide) have been safely 
administered with other antihypertensive agents including calcium channel blockers and 
beta-adrenergic blockers. Prior treatment with high dose diuretics may result in volume depletion and 
a risk of hypotension when initiating therapy with irbesartan with or without thiazide diuretics unless 
the volume depletion is corrected first (see section 4.4). 
 
Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during 
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects 
have been very rarely reported with irbesartan so far. Furthermore, renal clearance of lithium is 
reduced by thiazides so the risk of lithium toxicity could be increased with Irbesartan 
Hydrochlorothiazide BMS. Therefore, the combination of lithium and Irbesartan Hydrochlorothiazide 
BMS 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 BMS is administered with medicinal 
products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics). 
 
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered 
simultaneously with non-steroidal anti- inflammatory drugs (i.e. selective COX-2 inhibitors, 
acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect 
may occur. 
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an 
increased risk of worsening of renal function, including possible acute renal failure, and an increase in 
serum potassium, especially in patients with poor pre-existing renal function. The combination should 
be administered with caution, especially in the elderly. Patients should be adequately hydrated and 
consideration should be given to monitoring renal function after initiation of concomitant therapy, and 
periodically thereafter. 
 
Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan 
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser 

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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; 
 
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be increased; 
 
Digitalis glycosides: thiazide induced hypokalaemia or hypomagnaesemia favour the onset of 
digitalis-induced cardiac arrhythmias (see section 4.4); 
 
Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory drug 
may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients; 
 
Pressor amines (e.g. noradrenaline): the effect of pressor amines may be decreased, but not 
sufficiently to preclude their use; 
 
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): the effect of nondepolarizing skeletal 
muscle relaxants may be potentiated by hydrochlorothiazide; 
 
Antigout medicinal products: dosage adjustments of antigout medicinal products may be necessary as 
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or 
sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence 
of hypersensitivity reactions to allopurinol; 
 
Calcium salts: thiazide diuretics may increase serum calcium levels due to decreased excretion. If 
calcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be 
prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly; 
 
Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by 
thiazides. Anticholinergic agents (e.g. atropine, beperiden) may increase the bioavailability of 
thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides 
may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal 
excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their 
myelosuppressive effects. 
 
4.6 Pregnancy and lactation 
 
Pregnancy: 
 
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The 
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 
and 4.4). 
 
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 

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cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II 
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued 
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative 
antihypertensive treatments which have an established safety profile for use in pregnancy. When 
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, 
alternative therapy should be started. 
 
Exposure to AIIRA therapy during the second and third trimesters is known to induce human 
fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal 
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see 
sections 4.3 and 4.4). 
 
Thiazides cross the placental barrier and appear in cord blood. They may cause a decrease in placental 
perfusion, foetal electrolyte disturbances and possibly other reactions that have occurred in the adults. 
Cases of neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported with maternal 
thiazide therapy. Since Irbesartan Hydrochlorothiazide BMS contains hydrochlorothiazide, it is not 
recommended during the first trimester of pregnancy. A switch to a suitable alternative treatment 
should be carried out in advance of a planned pregnancy. 
 
Lactation: 
 
Because no information is available regarding the use of Irbesartan Hydrochlorothiazide BMS during 
breast-feeding, Irbesartan Hydrochlorothiazide BMS is not recommended and alternative treatments 
with better established safety profiles during breast-feeding are preferable, especially while nursing a 
newborn or preterm infant. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed. Based on its 
pharmacodynamic properties, Irbesartan Hydrochlorothiazide BMS is unlikely to affect this ability. 
When driving vehicles or operating machines, it should be taken into account that occasionally 
dizziness or weariness may occur during treatment of hypertension. 
 
4.8 Undesirable effects 
 
Irbesartan/hydrochlorothiazide combination: 
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled 
trials in which 898 hypertensive patients received various doses (range: 37.5 mg/6.25 mg to 
300 mg/25 mg irbesartan/hydrochlorothiazide). 
 
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* 

Common: increases in blood urea nitrogen (BUN), 
creatinine and creatine kinase 

Investigations: 

Uncommon: decreases in serum potassium and sodium 
Cardiac disorders: Uncommon: syncope, hypotension, tachycardia, oedema 

Common: dizziness 
Uncommon: orthostatic dizziness 

Nervous system disorders: 

Not known: headache 

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

Not known: cough 

Common: nausea/vomiting 
Uncommon: diarrhoea 

Gastrointestinal disorders: 

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

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

Uncommon: swelling extremity Musculoskeletal and connective 
tissue disorders: Not known: arthralgia, myalgia 
Metabolism and nutrition 
disorders: 

Not known: hyperkalaemia 

Vascular disorders: Uncommon: flushing 
General disorders and 
administration site conditions: 

Common: fatigue 

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

Hepatobiliary disorders: Not known: hepatitis, abnormal liver function 
Reproductive system and breast 
disorders: 

Uncommon: sexual dysfunction, libido changes 

* Frequency for adverse reactions detected by spontaneous reports is described as “not known” 
 
Additional information on individual components: in addition to the adverse reactions listed above for 
the combination product, other adverse reactions previously reported with one of the individual 
components may be potential adverse reactions with Irbesartan Hydrochlorothiazide BMS. Tables 2 
and 3 below detail the adverse reactions reported with the individual components of Irbesartan 
Hydrochlorothiazide BMS. 
 
Table 2: Adverse reactions reported with the use of irbesartan alone 
General disorders and 
administration site conditions: 

Uncommon: chest pain 

 
Table 3: Adverse reactions (regardless of relationship to medicinal product) 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 
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 

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cutaneous lupus erythematosus, photosensitivity 
reactions, rash, urticaria 

Musculoskeletal and connective 
tissue disorders: 

Not known: weakness, muscle spasm 

Vascular disorders: Not known: postural hypotension 
General disorders and 
administration site conditions: 

Not known: fever 

Hepatobiliary disorders: Not known: jaundice (intrahepatic cholestatic jaundice) 
Psychiatric disorders: Not known: depression, sleep disturbances 
 
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may 
increase when titrating the hydrochlorothiazide. 
 
4.9 Overdose 
 
No specific information is available on the treatment of overdose with Irbesartan Hydrochlorothiazide 
BMS. 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. 
 
Irbesartan Hydrochlorothiazide BMS is a combination of an angiotensin-II receptor antagonist, 
irbesartan, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an 
additive antihypertensive effect, reducing blood pressure to a greater degree than either component 
alone. 
 
Irbesartan is a potent, orally active, selective angiotensin-II receptor (AT1 subtype) antagonist. It is 
expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source 
or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors 
results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma 
aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at 
the recommended doses in patients without risk of electrolyte imbalance (see sections 4.4 and 4.5). 
Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also 
degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its 
activity. 

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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 BMS 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 BMS 150 mg/12.5 mg and 
Irbesartan Hydrochlorothiazide BMS 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 BMS, 
rebound hypertension has not been seen with either irbesartan or hydrochlorothiazide. 
 
The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality has 
not been studied. Epidemiological studies have shown that long term treatment with 
hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity. 
 
There is no difference in response to Irbesartan Hydrochlorothiazide BMS, regardless of age or 
gender. As is the case with other medicinal products that affect the renin-angiotensin system, black 
hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is 
administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the 
antihypertensive response in black patients approaches that of non-black patients. 
 
Efficacy and safety of Irbesartan Hydrochlorothiazide BMS as initial therapy for severe hypertension 
(defined as SeDBP ≥ 110 mmHg) was evaluated in a multicenter, randomized, double-blind, active-

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

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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: 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. 

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Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at 
≥ 90 mg/kg/day, in macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused 
by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the 
hyperplasia/hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. 
There was no evidence of mutagenicity, clastogenicity or carcinogenicity. 
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, 
hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, 
abortion or early resorption was noted at doses causing significant maternal toxicity, including 
mortality. No teratogenic effects were observed in the rat or rabbit. 
 
Hydrochlorothiazide: although equivocal evidence for a genotoxic or carcinogenic effect was found in 
some experimental models, the extensive human experience with hydrochlorothiazide has failed to 
show an association between its use and an increase in neoplasms. 
 
 
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. 
 
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; 1 blister card of 14 film-coated tablets in PVC/PVDC/Aluminium 
blisters. 
Cartons of 28 film-coated tablets; 2 blister cards of 14 film-coated tablets in PVC/PVDC/Aluminium 
blisters. 
Cartons of 56 film-coated tablets; 4 blister cards of 14 film-coated tablets in PVC/PVDC/Aluminium 
blisters. 

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Cartons of 84 film-coated tablets; 6 blister cards of 14 film-coated tablets in PVC/PVDC/Aluminium 
blisters. 
Cartons of 98 film-coated tablets; 7 blister cards of 14 film-coated tablets in PVC/PVDC/Aluminium 
blisters. 
Cartons of 56 x 1 film-coated tablets; 7 blister cards of 8 x 1 film-coated tablets each in 
PVC/PVDC/Aluminium perforated unit dose blisters. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH - United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/369/011-016 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 January 2007 
Date of latest renewal: 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this product is available on the website of the European Medicines Agency 
(EMEA) http://www.emea.europa.eu/ 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide BMS 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: 
Each film-coated tablet contains 89.5 mg of lactose (as lactose monohydrate). 
 
For a 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 
 
Irbesartan Hydrochlorothiazide BMS 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 BMS 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 BMS 300 mg/12.5 mg may be administered in patients 
insufficiently controlled by irbesartan 300 mg or by Irbesartan Hydrochlorothiazide 
BMS 150 mg/12.5 mg. 

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

 
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended. 
When necessary, Irbesartan Hydrochlorothiazide BMS may be administered with another 
antihypertensive medicinal product (see section 4.5). 
 
Renal impairment: due to the hydrochlorothiazide component, Irbesartan Hydrochlorothiazide BMS 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). 
 

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Hepatic impairment: Irbesartan Hydrochlorothiazide BMS 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 BMS is necessary in patients with mild to 
moderate hepatic impairment (see section 4.3). 
 
Elderly patients: no dosage adjustment of Irbesartan Hydrochlorothiazide BMS is necessary in elderly 
patients. 
 
Paediatric patients: Irbesartan Hydrochlorothiazide BMS is not recommended for use in children and 
adolescents due to a lack of data on safety and efficacy. 
 
4.3 Contraindications 
 
 Hypersensitivity to the active substances, to any of the excipients (see 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 

 
4.4 Special warnings and precautions for use 
 
Hypotension - Volume-depleted patients: Irbesartan Hydrochlorothiazide BMS 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 BMS. 
 
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 BMS, a 
similar effect should be anticipated. 
 
Renal impairment and kidney transplantation: when Irbesartan Hydrochlorothiazide BMS 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 BMS in patients with a recent kidney transplantation. Irbesartan 
Hydrochlorothiazide BMS should not be used in patients with severe renal impairment (creatinine 
clearance < 30 ml/min) (see section 4.3). Thiazide diuretic-associated azotemia may occur in patients 
with impaired renal function. No dosage adjustment is necessary in patients with renal impairment 
whose creatinine clearance is ≥ 30 ml/min. However, in patients with mild to moderate renal 
impairment (creatinine clearance ≥ 30 ml/min but < 60 ml/min) this fixed dose combination should be 
administered with caution. 
 
Hepatic impairment: thiazides should be used with caution in patients with impaired hepatic function 
or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate 
hepatic coma. There is no clinical experience with Irbesartan Hydrochlorothiazide BMS 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 BMS is not recommended. 

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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 BMS, 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 BMS 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 BMS (see 
section 4.5). 
There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatraemia. Chloride 
deficit is generally mild and usually does not require treatment. 
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of 
serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia 
may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out 
tests for parathyroid function. 
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in 
hypomagnaesemia. 
 
Lithium: the combination of lithium and Irbesartan Hydrochlorothiazide BMS is not recommended 
(see section 4.5). 
 
Anti-doping test: hydrochlorothiazide contained in this medicinal product could produce a positive 
analytic result in an anti-doping test. 
 
General: in patients whose vascular tone and renal function depend predominantly on the activity of 
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or 
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting 
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated 
with acute hypotension, azotemia, oliguria, or rarely acute renal failure. As with any antihypertensive 
agent, excessive blood pressure decrease in patients with ischemic cardiopathy or ischemic 
cardiovascular disease could result in a myocardial infarction or stroke. 
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of 
allergy or bronchial asthma, but are more likely in patients with such a history. 
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide 
diuretics. 
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If 
photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-
administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the 
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Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. 
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be 
changed to alternative antihypertensive treatments which have an established safety profile for use in 
pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, 
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). 
 
Lactose: this medicinal product contains lactose. Patients with rare hereditary problems of galactose 
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this 
medicinal product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Other antihypertensive agents: the antihypertensive effect of Irbesartan Hydrochlorothiazide BMS 
may be increased with the concomitant use of other antihypertensive agents. Irbesartan and 
hydrochlorothiazide (at doses up to 300 mg irbesartan/25 mg hydrochlorothiazide) have been safely 
administered with other antihypertensive agents including calcium channel blockers and 
beta-adrenergic blockers. Prior treatment with high dose diuretics may result in volume depletion and 
a risk of hypotension when initiating therapy with irbesartan with or without thiazide diuretics unless 
the volume depletion is corrected first (see section 4.4). 
 
Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during 
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects 
have been very rarely reported with irbesartan so far. Furthermore, renal clearance of lithium is 
reduced by thiazides so the risk of lithium toxicity could be increased with Irbesartan 
Hydrochlorothiazide BMS. Therefore, the combination of lithium and Irbesartan Hydrochlorothiazide 
BMS 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 BMS is administered with medicinal 
products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics). 
 
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered 
simultaneously with non-steroidal anti- inflammatory drugs (i.e. selective COX-2 inhibitors, 
acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect 
may occur. 
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an 
increased risk of worsening of renal function, including possible acute renal failure, and an increase in 
serum potassium, especially in patients with poor pre-existing renal function. The combination should 
be administered with caution, especially in the elderly. Patients should be adequately hydrated and 
consideration should be given to monitoring renal function after initiation of concomitant therapy, and 
periodically thereafter. 
 
Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan 
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser 

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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; 
 
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be increased; 
 
Digitalis glycosides: thiazide induced hypokalaemia or hypomagnaesemia favour the onset of 
digitalis-induced cardiac arrhythmias (see section 4.4); 
 
Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory drug 
may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients; 
 
Pressor amines (e.g. noradrenaline): the effect of pressor amines may be decreased, but not 
sufficiently to preclude their use; 
 
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): the effect of nondepolarizing skeletal 
muscle relaxants may be potentiated by hydrochlorothiazide; 
 
Antigout medicinal products: dosage adjustments of antigout medicinal products may be necessary as 
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or 
sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence 
of hypersensitivity reactions to allopurinol; 
 
Calcium salts: thiazide diuretics may increase serum calcium levels due to decreased excretion. If 
calcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be 
prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly; 
 
Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by 
thiazides. Anticholinergic agents (e.g. atropine, beperiden) may increase the bioavailability of 
thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides 
may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal 
excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their 
myelosuppressive effects. 
 
4.6 Pregnancy and lactation 
 
Pregnancy: 
 
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The 
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 
and 4.4). 
 
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 

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cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II 
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued 
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative 
antihypertensive treatments which have an established safety profile for use in pregnancy. When 
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, 
alternative therapy should be started. 
 
Exposure to AIIRA therapy during the second and third trimesters is known to induce human 
fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal 
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see 
sections 4.3 and 4.4). 
 
Thiazides cross the placental barrier and appear in cord blood. They may cause a decrease in placental 
perfusion, foetal electrolyte disturbances and possibly other reactions that have occurred in the adults. 
Cases of neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported with maternal 
thiazide therapy. Since Irbesartan Hydrochlorothiazide BMS contains hydrochlorothiazide, it is not 
recommended during the first trimester of pregnancy. A switch to a suitable alternative treatment 
should be carried out in advance of a planned pregnancy. 
 
Lactation: 
 
Because no information is available regarding the use of Irbesartan Hydrochlorothiazide BMS during 
breast-feeding, Irbesartan Hydrochlorothiazide BMS is not recommended and alternative treatments 
with better established safety profiles during breast-feeding are preferable, especially while nursing a 
newborn or preterm infant. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed. Based on its 
pharmacodynamic properties, Irbesartan Hydrochlorothiazide BMS is unlikely to affect this ability. 
When driving vehicles or operating machines, it should be taken into account that occasionally 
dizziness or weariness may occur during treatment of hypertension. 
 
4.8 Undesirable effects 
 
Irbesartan/hydrochlorothiazide combination: 
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled 
trials in which 898 hypertensive patients received various doses (range: 37.5 mg/6.25 mg to 
300 mg/25 mg irbesartan/hydrochlorothiazide). 
 
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* 

Common: increases in blood urea nitrogen (BUN), 
creatinine and creatine kinase 

Investigations: 

Uncommon: decreases in serum potassium and sodium 
Cardiac disorders: Uncommon: syncope, hypotension, tachycardia, oedema 

Common: dizziness 
Uncommon: orthostatic dizziness 

Nervous system disorders: 

Not known: headache 

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

Not known: cough 

Common: nausea/vomiting 
Uncommon: diarrhoea 

Gastrointestinal disorders: 

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

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

Uncommon: swelling extremity Musculoskeletal and connective 
tissue disorders: Not known: arthralgia, myalgia 
Metabolism and nutrition 
disorders: 

Not known: hyperkalaemia 

Vascular disorders: Uncommon: flushing 
General disorders and 
administration site conditions: 

Common: fatigue 

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

Hepatobiliary disorders: Not known: hepatitis, abnormal liver function 
Reproductive system and breast 
disorders: 

Uncommon: sexual dysfunction, libido changes 

* Frequency for adverse reactions detected by spontaneous reports is described as “not known” 
 
Additional information on individual components: in addition to the adverse reactions listed above for 
the combination product, other adverse reactions previously reported with one of the individual 
components may be potential adverse reactions with Irbesartan Hydrochlorothiazide BMS. Tables 2 
and 3 below detail the adverse reactions reported with the individual components of Irbesartan 
Hydrochlorothiazide BMS. 
 
Table 2: Adverse reactions reported with the use of irbesartan alone 
General disorders and 
administration site conditions: 

Uncommon: chest pain 

 
Table 3: Adverse reactions (regardless of relationship to medicinal product) 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 
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 

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cutaneous lupus erythematosus, photosensitivity 
reactions, rash, urticaria 

Musculoskeletal and connective 
tissue disorders: 

Not known: weakness, muscle spasm 

Vascular disorders: Not known: postural hypotension 
General disorders and 
administration site conditions: 

Not known: fever 

Hepatobiliary disorders: Not known: jaundice (intrahepatic cholestatic jaundice) 
Psychiatric disorders: Not known: depression, sleep disturbances 
 
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may 
increase when titrating the hydrochlorothiazide. 
 
4.9 Overdose 
 
No specific information is available on the treatment of overdose with Irbesartan Hydrochlorothiazide 
BMS. 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. 
 
Irbesartan Hydrochlorothiazide BMS is a combination of an angiotensin-II receptor antagonist, 
irbesartan, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an 
additive antihypertensive effect, reducing blood pressure to a greater degree than either component 
alone. 
 
Irbesartan is a potent, orally active, selective angiotensin-II receptor (AT1 subtype) antagonist. It is 
expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source 
or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors 
results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma 
aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at 
the recommended doses in patients without risk of electrolyte imbalance (see sections 4.4 and 4.5). 
Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also 
degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its 
activity. 

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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 BMS 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 BMS 150 mg/12.5 mg and 
Irbesartan Hydrochlorothiazide BMS 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 BMS, 
rebound hypertension has not been seen with either irbesartan or hydrochlorothiazide. 
 
The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality has 
not been studied. Epidemiological studies have shown that long term treatment with 
hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity. 
 
There is no difference in response to Irbesartan Hydrochlorothiazide BMS, regardless of age or 
gender. As is the case with other medicinal products that affect the renin-angiotensin system, black 
hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is 
administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the 
antihypertensive response in black patients approaches that of non-black patients. 
 
Efficacy and safety of Irbesartan Hydrochlorothiazide BMS as initial therapy for severe hypertension 
(defined as SeDBP ≥ 110 mmHg) was evaluated in a multicenter, randomized, double-blind, active-

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

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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: 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. 

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Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at 
≥ 90 mg/kg/day, in macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused 
by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the 
hyperplasia/hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. 
There was no evidence of mutagenicity, clastogenicity or carcinogenicity. 
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, 
hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, 
abortion or early resorption was noted at doses causing significant maternal toxicity, including 
mortality. No teratogenic effects were observed in the rat or rabbit. 
 
Hydrochlorothiazide: although equivocal evidence for a genotoxic or carcinogenic effect was found in 
some experimental models, the extensive human experience with hydrochlorothiazide has failed to 
show an association between its use and an increase in neoplasms. 
 
 
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. 
 
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; 1 blister card of 14 film-coated tablets in PVC/PVDC/Aluminium 
blisters. 
Cartons of 28 film-coated tablets; 2 blister cards of 14 film-coated tablets in PVC/PVDC/Aluminium 
blisters. 
Cartons of 56 film-coated tablets; 4 blister cards of 14 film-coated tablets in PVC/PVDC/Aluminium 
blisters. 

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Cartons of 84 film-coated tablets; 6 blister cards of 14 film-coated tablets in PVC/PVDC/Aluminium 
blisters. 
Cartons of 98 film-coated tablets; 7 blister cards of 14 film-coated tablets in PVC/PVDC/Aluminium 
blisters. 
Cartons of 56 x 1 film-coated tablets; 7 blister cards of 8 x 1 film-coated tablets each in 
PVC/PVDC/Aluminium perforated unit dose blisters. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH - United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/369/017-022 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 January 2007 
Date of latest renewal: 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this product is available on the website of the European Medicines Agency 
(EMEA) http://www.emea.europa.eu/ 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide BMS 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: 
Each film-coated tablet contains 53.3 mg of lactose (as lactose monohydrate). 
 
For a 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 
 
Irbesartan Hydrochlorothiazide BMS 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 BMS 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 BMS 300 mg/12.5 mg may be administered in patients 
insufficiently controlled by irbesartan 300 mg or by Irbesartan Hydrochlorothiazide 
BMS 150 mg/12.5 mg. 

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

 
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended. 
When necessary, Irbesartan Hydrochlorothiazide BMS may be administered with another 
antihypertensive medicinal product (see section 4.5). 
 
Renal impairment: due to the hydrochlorothiazide component, Irbesartan Hydrochlorothiazide BMS 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). 
 

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Hepatic impairment: Irbesartan Hydrochlorothiazide BMS 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 BMS is necessary in patients with mild to 
moderate hepatic impairment (see section 4.3). 
 
Elderly patients: no dosage adjustment of Irbesartan Hydrochlorothiazide BMS is necessary in elderly 
patients. 
 
Paediatric patients: Irbesartan Hydrochlorothiazide BMS is not recommended for use in children and 
adolescents due to a lack of data on safety and efficacy. 
 
4.3 Contraindications 
 
 Hypersensitivity to the active substances, to any of the excipients (see 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 

 
4.4 Special warnings and precautions for use 
 
Hypotension - Volume-depleted patients: Irbesartan Hydrochlorothiazide BMS 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 BMS. 
 
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 BMS, a 
similar effect should be anticipated. 
 
Renal impairment and kidney transplantation: when Irbesartan Hydrochlorothiazide BMS 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 BMS in patients with a recent kidney transplantation. Irbesartan 
Hydrochlorothiazide BMS should not be used in patients with severe renal impairment (creatinine 
clearance < 30 ml/min) (see section 4.3). Thiazide diuretic-associated azotemia may occur in patients 
with impaired renal function. No dosage adjustment is necessary in patients with renal impairment 
whose creatinine clearance is ≥ 30 ml/min. However, in patients with mild to moderate renal 
impairment (creatinine clearance ≥ 30 ml/min but < 60 ml/min) this fixed dose combination should be 
administered with caution. 
 
Hepatic impairment: thiazides should be used with caution in patients with impaired hepatic function 
or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate 
hepatic coma. There is no clinical experience with Irbesartan Hydrochlorothiazide BMS 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 BMS is not recommended. 

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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 BMS, 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 BMS 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 BMS (see 
section 4.5). 
There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatraemia. Chloride 
deficit is generally mild and usually does not require treatment. 
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of 
serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia 
may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out 
tests for parathyroid function. 
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in 
hypomagnaesemia. 
 
Lithium: the combination of lithium and Irbesartan Hydrochlorothiazide BMS is not recommended 
(see section 4.5). 
 
Anti-doping test: hydrochlorothiazide contained in this medicinal product could produce a positive 
analytic result in an anti-doping test. 
 
General: in patients whose vascular tone and renal function depend predominantly on the activity of 
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or 
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting 
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated 
with acute hypotension, azotemia, oliguria, or rarely acute renal failure. As with any antihypertensive 
agent, excessive blood pressure decrease in patients with ischemic cardiopathy or ischemic 
cardiovascular disease could result in a myocardial infarction or stroke. 
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of 
allergy or bronchial asthma, but are more likely in patients with such a history. 
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide 
diuretics. 
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If 
photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-
administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the 
sun or to artificial UVA. 

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Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. 
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be 
changed to alternative antihypertensive treatments which have an established safety profile for use in 
pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, 
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). 
 
Lactose: this medicinal product contains lactose. Patients with rare hereditary problems of galactose 
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this 
medicinal product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Other antihypertensive agents: the antihypertensive effect of Irbesartan Hydrochlorothiazide BMS 
may be increased with the concomitant use of other antihypertensive agents. Irbesartan and 
hydrochlorothiazide (at doses up to 300 mg irbesartan/25 mg hydrochlorothiazide) have been safely 
administered with other antihypertensive agents including calcium channel blockers and 
beta-adrenergic blockers. Prior treatment with high dose diuretics may result in volume depletion and 
a risk of hypotension when initiating therapy with irbesartan with or without thiazide diuretics unless 
the volume depletion is corrected first (see section 4.4). 
 
Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during 
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects 
have been very rarely reported with irbesartan so far. Furthermore, renal clearance of lithium is 
reduced by thiazides so the risk of lithium toxicity could be increased with Irbesartan 
Hydrochlorothiazide BMS. Therefore, the combination of lithium and Irbesartan Hydrochlorothiazide 
BMS 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 BMS is administered with medicinal 
products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics). 
 
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered 
simultaneously with non-steroidal anti- inflammatory drugs (i.e. selective COX-2 inhibitors, 
acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect 
may occur. 
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an 
increased risk of worsening of renal function, including possible acute renal failure, and an increase in 
serum potassium, especially in patients with poor pre-existing renal function. The combination should 
be administered with caution, especially in the elderly. Patients should be adequately hydrated and 
consideration should be given to monitoring renal function after initiation of concomitant therapy, and 
periodically thereafter. 
 
Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan 
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser 

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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; 
 
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be increased; 
 
Digitalis glycosides: thiazide induced hypokalaemia or hypomagnaesemia favour the onset of 
digitalis-induced cardiac arrhythmias (see section 4.4); 
 
Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory drug 
may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients; 
 
Pressor amines (e.g. noradrenaline): the effect of pressor amines may be decreased, but not 
sufficiently to preclude their use; 
 
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): the effect of nondepolarizing skeletal 
muscle relaxants may be potentiated by hydrochlorothiazide; 
 
Antigout medicinal products: dosage adjustments of antigout medicinal products may be necessary as 
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or 
sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence 
of hypersensitivity reactions to allopurinol; 
 
Calcium salts: thiazide diuretics may increase serum calcium levels due to decreased excretion. If 
calcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be 
prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly; 
 
Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by 
thiazides. Anticholinergic agents (e.g. atropine, beperiden) may increase the bioavailability of 
thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides 
may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal 
excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their 
myelosuppressive effects. 
 
4.6 Pregnancy and lactation 
 
Pregnancy: 
 
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The 
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 
and 4.4). 
 
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 

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cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II 
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued 
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative 
antihypertensive treatments which have an established safety profile for use in pregnancy. When 
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, 
alternative therapy should be started. 
 
Exposure to AIIRA therapy during the second and third trimesters is known to induce human 
fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal 
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see 
sections 4.3 and 4.4). 
 
Thiazides cross the placental barrier and appear in cord blood. They may cause a decrease in placental 
perfusion, foetal electrolyte disturbances and possibly other reactions that have occurred in the adults. 
Cases of neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported with maternal 
thiazide therapy. Since Irbesartan Hydrochlorothiazide BMS contains hydrochlorothiazide, it is not 
recommended during the first trimester of pregnancy. A switch to a suitable alternative treatment 
should be carried out in advance of a planned pregnancy. 
 
Lactation: 
 
Because no information is available regarding the use of Irbesartan Hydrochlorothiazide BMS during 
breast-feeding, Irbesartan Hydrochlorothiazide BMS is not recommended and alternative treatments 
with better established safety profiles during breast-feeding are preferable, especially while nursing a 
newborn or preterm infant. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed. Based on its 
pharmacodynamic properties, Irbesartan Hydrochlorothiazide BMS is unlikely to affect this ability. 
When driving vehicles or operating machines, it should be taken into account that occasionally 
dizziness or weariness may occur during treatment of hypertension. 
 
4.8 Undesirable effects 
 
Irbesartan/hydrochlorothiazide combination: 
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled 
trials in which 898 hypertensive patients received various doses (range: 37.5 mg/6.25 mg to 
300 mg/25 mg irbesartan/hydrochlorothiazide). 
 
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* 

Common: increases in blood urea nitrogen (BUN), 
creatinine and creatine kinase 

Investigations: 

Uncommon: decreases in serum potassium and sodium 
Cardiac disorders: Uncommon: syncope, hypotension, tachycardia, oedema 

Common: dizziness 
Uncommon: orthostatic dizziness 

Nervous system disorders: 

Not known: headache 

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

Not known: cough 

Common: nausea/vomiting 
Uncommon: diarrhoea 

Gastrointestinal disorders: 

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

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

Uncommon: swelling extremity Musculoskeletal and connective 
tissue disorders: Not known: arthralgia, myalgia 
Metabolism and nutrition 
disorders: 

Not known: hyperkalaemia 

Vascular disorders: Uncommon: flushing 
General disorders and 
administration site conditions: 

Common: fatigue 

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

Hepatobiliary disorders: Not known: hepatitis, abnormal liver function 
Reproductive system and breast 
disorders: 

Uncommon: sexual dysfunction, libido changes 

* Frequency for adverse reactions detected by spontaneous reports is described as “not known” 
 
Additional information on individual components: in addition to the adverse reactions listed above for 
the combination product, other adverse reactions previously reported with one of the individual 
components may be potential adverse reactions with Irbesartan Hydrochlorothiazide BMS. Tables 2 
and 3 below detail the adverse reactions reported with the individual components of Irbesartan 
Hydrochlorothiazide BMS. 
 
Table 2: Adverse reactions reported with the use of irbesartan alone 
General disorders and 
administration site conditions: 

Uncommon: chest pain 

 
Table 3: Adverse reactions (regardless of relationship to medicinal product) 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 
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 

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cutaneous lupus erythematosus, photosensitivity 
reactions, rash, urticaria 

Musculoskeletal and connective 
tissue disorders: 

Not known: weakness, muscle spasm 

Vascular disorders: Not known: postural hypotension 
General disorders and 
administration site conditions: 

Not known: fever 

Hepatobiliary disorders: Not known: jaundice (intrahepatic cholestatic jaundice) 
Psychiatric disorders: Not known: depression, sleep disturbances 
 
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may 
increase when titrating the hydrochlorothiazide. 
 
4.9 Overdose 
 
No specific information is available on the treatment of overdose with Irbesartan Hydrochlorothiazide 
BMS. 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. 
 
Irbesartan Hydrochlorothiazide BMS is a combination of an angiotensin-II receptor antagonist, 
irbesartan, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an 
additive antihypertensive effect, reducing blood pressure to a greater degree than either component 
alone. 
 
Irbesartan is a potent, orally active, selective angiotensin-II receptor (AT1 subtype) antagonist. It is 
expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source 
or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors 
results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma 
aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at 
the recommended doses in patients without risk of electrolyte imbalance (see sections 4.4 and 4.5). 
Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also 
degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its 
activity. 

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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 BMS 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 BMS 150 mg/12.5 mg and 
Irbesartan Hydrochlorothiazide BMS 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 BMS, 
rebound hypertension has not been seen with either irbesartan or hydrochlorothiazide. 
 
The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality has 
not been studied. Epidemiological studies have shown that long term treatment with 
hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity. 
 
There is no difference in response to Irbesartan Hydrochlorothiazide BMS, regardless of age or 
gender. As is the case with other medicinal products that affect the renin-angiotensin system, black 
hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is 
administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the 
antihypertensive response in black patients approaches that of non-black patients. 
 
Efficacy and safety of Irbesartan Hydrochlorothiazide BMS as initial therapy for severe hypertension 
(defined as SeDBP ≥ 110 mmHg) was evaluated in a multicenter, randomized, double-blind, active-

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

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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: 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. 

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Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at 
≥ 90 mg/kg/day, in macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused 
by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the 
hyperplasia/hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. 
There was no evidence of mutagenicity, clastogenicity or carcinogenicity. 
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, 
hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, 
abortion or early resorption was noted at doses causing significant maternal toxicity, including 
mortality. No teratogenic effects were observed in the rat or rabbit. 
 
Hydrochlorothiazide: although equivocal evidence for a genotoxic or carcinogenic effect was found in 
some experimental models, the extensive human experience with hydrochlorothiazide has failed to 
show an association between its use and an increase in neoplasms. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Lactose monohydrate 
Microcrystalline cellulose 
Croscarmellose sodium 
Pregelatinized 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 
 
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; 1 blister card of 14 film-coated tablets in PVC/PVDC/Aluminium 
blisters. 
Cartons of 28 film-coated tablets; 2 blister cards of 14 film-coated tablets in PVC/PVDC/Aluminium 
blisters. 
Cartons of 56 film-coated tablets; 4 blister cards of 14 film-coated tablets in PVC/PVDC/Aluminium 
blisters. 

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Cartons of 84 film-coated tablets; 6 blister cards of 14 film-coated tablets in PVC/PVDC/Aluminium 
blisters. 
Cartons of 98 film-coated tablets; 7 blister cards of 14 film-coated tablets in PVC/PVDC/Aluminium 
blisters. 
Cartons of 56 x 1 film-coated tablets; 7 blister cards of 8 x 1 film-coated tablets each in 
PVC/PVDC/Aluminium perforated unit dose blisters. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH - United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/369/023-028 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 January 2007 
Date of latest renewal: 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this product is available on the website of the European Medicines Agency 
(EMEA) http://www.emea.europa.eu/ 
 

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ANNEX II 
 

A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR 
BATCH RELEASE 

 
B. CONDITIONS OF THE MARKETING AUTHORISATION 

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A. MANUFACTURING AUTHORISATION HOLDERS 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 
 
Sanofi-Synthelabo Limited 
Edgefield Avenue 
Fawdon 
Newcastle Upon Tyne 
Tyne & Wear NE3 3TT 
United Kingdom 
 
Chinoin Private Co. Ltd. 
Lévai u.5. 
2112 Veresegyhaz 
Hungary 
 
Sanofi Winthrop Industrie 
30-36, avenue Gustave Eiffel 
37100 Tours 
France 
 
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 OF THE MARKETING AUTHORISATION 
 
 CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON 

THE MARKETING AUTHORISATION HOLDER 
 
Medicinal product subject to medical prescription 
 
 CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
Not applicable. 
 
 OTHER CONDITIONS 

 
The PSUR cycle of Irbesartan Hydrochlorothiazide BMS is aligned with the cross-referred product, 
KARVEZIDE, until otherwise specified. 
 
Pharmacovigilance system 
The MAH must ensure that the system of pharmacovigilance, as described in version 3.0 presented in 
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and 
whilst the product is on the market. 
 

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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

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A. LABELLING 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide BMS 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. 
 
 
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 REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight 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. 
 
 

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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 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH - United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/369/001 - 14 tablets 
EU/1/06/369/002 - 28 tablets 
EU/1/06/369/003 - 56 tablets 
EU/1/06/369/004 - 56 x 1 tablets 
EU/1/06/369/005 - 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 BMS 150 mg/12.5 mg 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide BMS 150 mg/12.5 mg tablets 
irbesartan/hydrochlorothiazide 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
 
 
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: 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide BMS 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. 
 
 
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 REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight 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. 
 
 

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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 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH - United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/369/006 - 14 tablets 
EU/1/06/369/007 - 28 tablets 
EU/1/06/369/008 - 56 tablets 
EU/1/06/369/009 - 56 x 1 tablets 
EU/1/06/369/010 - 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 BMS 300 mg/12.5 mg 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide BMS 300 mg/12.5 mg tablets 
irbesartan/hydrochlorothiazide 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
 
 
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: 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide BMS 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. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
56 tablets 
56 x 1 tablets 
84 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 REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight 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. 
 

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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 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH - United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/369/011 - 14 tablets 
EU/1/06/369/012 - 28 tablets 
EU/1/06/369/013 - 56 tablets 
EU/1/06/369/014 - 56 x 1 tablets 
EU/1/06/369/015 - 84 tablets 
EU/1/06/369/016 - 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 BMS 150 mg/12.5 mg 

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

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide BMS 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. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
56 tablets 
56 x 1 tablets 
84 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 REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight 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. 
 

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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 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH - United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/369/017 - 14 tablets 
EU/1/06/369/018 - 28 tablets 
EU/1/06/369/019 - 56 tablets 
EU/1/06/369/020 - 56 x 1 tablets 
EU/1/06/369/021 - 84 tablets 
EU/1/06/369/022 - 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 BMS 300 mg/12.5 mg 

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

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Hydrochlorothiazide BMS 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. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
56 tablets 
56 x 1 tablets 
84 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 REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight 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. 
 

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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 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH - United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/369/023 - 14 tablets 
EU/1/06/369/024 - 28 tablets 
EU/1/06/369/025 - 56 tablets 
EU/1/06/369/026 - 56 x 1 tablets 
EU/1/06/369/027 - 84 tablets 
EU/1/06/369/028 - 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 BMS 300 mg/25 mg 

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

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B. PACKAGE LEAFLET 

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PACKAGE LEAFLET: INFORMATION FOR THE USER 
Irbesartan Hydrochlorothiazide BMS 150 mg/12.5 mg tablets 

irbesartan/hydrochlorothiazide 
 
Read all of this leaflet carefully before you start taking this medicine. 
 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. Do not pass it on to others. It may harm them, even 

if their symptoms are the same as yours. 
 If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 

please tell your doctor or pharmacist. 
 
In this leaflet: 
1. What Irbesartan Hydrochlorothiazide BMS is and what it is used for 
2. Before you take Irbesartan Hydrochlorothiazide BMS 
3. How to take Irbesartan Hydrochlorothiazide BMS 
4. Possible side effects 
5. How to store Irbesartan Hydrochlorothiazide BMS 
6. Further information 
 
 
1. WHAT IRBESARTAN HYDROCHLOROTHIAZIDE BMS IS AND WHAT IT IS USED 
FOR 
 
Irbesartan Hydrochlorothiazide BMS 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 BMS work together to lower blood 
pressure further than if either was given alone. 
 
Irbesartan Hydrochlorothiazide BMS is used to treat high blood pressure, when treatment with 
irbesartan or hydrochlorothiazide alone did not provide adequate control of your blood pressure. 
 
 
2. BEFORE YOU TAKE IRBESARTAN HYDROCHLOROTHIAZIDE BMS 
 
Do not take Irbesartan Hydrochlorothiazide BMS 
 if you are allergic (hypersensitive) to irbesartan or any of the other ingredients of Irbesartan 

Hydrochlorothiazide BMS  
 if you are allergic (hypersensitive) to hydrochlorothiazide or any other sulfonamide-derived 

medicines 
 if you are more than 3 months pregnant. (It is also better to avoid Irbesartan 

Hydrochlorothiazide BMS 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 
 
Irbesartan Hydrochlorothiazide BMS should not be given to children and adolescents (under 18 years). 
 
Take special care with Irbesartan Hydrochlorothiazide BMS 
Tell your doctor if any of the following apply to you: 

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 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). 

 
You must tell your doctor if you think you are (or might become) pregnant. Irbesartan 
Hydrochlorothiazide BMS 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 BMS) 

 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 
 
The hydrochlorothiazide contained in this medicine could produce a positive result in an anti-doping 
test. 
 
Using other medicines 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription. 
 
Diuretic agents such as the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide BMS 
may have an effect on other medicines. Preparations containing lithium should not be taken with 
Irbesartan Hydrochlorothiazide BMS without close supervision by your doctor. 
 
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) 

 
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 or arthritis medicines. 
 
Taking Irbesartan Hydrochlorothiazide BMS with food and drink 
Irbesartan Hydrochlorothiazide BMS can be taken with or without food. 
 
Due to the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide BMS, 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. 
 

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Pregnancy and breast-feeding 
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 BMS 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 BMS. Irbesartan Hydrochlorothiazide BMS 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 BMS 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 
No studies on the effects on the ability to drive and use machines have been performed. Irbesartan 
Hydrochlorothiazide BMS 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. 
 
Important information about some of the ingredients of Irbesartan Hydrochlorothiazide BMS 
Irbesartan Hydrochlorothiazide BMS 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 medicine. 
 
 
3. HOW TO TAKE IRBESARTAN HYDROCHLOROTHIAZIDE BMS 
 
Always take Irbesartan Hydrochlorothiazide BMS exactly as your doctor has told you. You should 
check with your doctor or pharmacist if you are not sure. 
 
Dosage 
The usual dose of Irbesartan Hydrochlorothiazide BMS is one or two tablets a day. Irbesartan 
Hydrochlorothiazide BMS 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 BMS. 
 
Method of administration 
Irbesartan Hydrochlorothiazide BMS is for oral use. Swallow the tablets with a sufficient amount of 
fluid (e.g. one glass of water). You can take Irbesartan Hydrochlorothiazide BMS 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 BMS 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 BMS than you should 
If you accidentally take too many tablets, contact your doctor immediately. 
 
Children should not take Irbesartan Hydrochlorothiazide BMS 
Irbesartan Hydrochlorothiazide BMS 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 BMS 
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 product, ask your doctor or pharmacist. 

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4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, Irbesartan Hydrochlorothiazide BMS 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 BMS and contact your doctor immediately. 
 
Side effects reported in clinical studies for patients treated with Irbesartan Hydrochlorothiazide BMS 
were: 
 
Common side effects (affect 1 to 10 users in 100)  
 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 (affect 1 to 10 users in 1,000)  
 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 BMS 
The frequency of these effects is not known. These undesirable effects 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. 
 
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 has 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 

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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. 
 
It is known that side effects associated with hydrochlorothiazide may increase with higher doses of 
hydrochlorothiazide. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor or pharmacist. 
 
 
5. HOW TO STORE IRBESARTAN HYDROCHLOROTHIAZIDE BMS 
 
Keep out of the reach and sight of children. 
 
Do not use Irbesartan Hydrochlorothiazide BMS 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. 
 
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to 
dispose of medicines no longer required. These measures will help to protect the environment. 
 
 
6. FURTHER INFORMATION 
 
What Irbesartan Hydrochlorothiazide BMS contains 
 The active substances are irbesartan and hydrochlorothiazide. Each tablet of Irbesartan 

Hydrochlorothiazide BMS 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). 

 
What Irbesartan Hydrochlorothiazide BMS looks like and contents of the pack 
Irbesartan Hydrochlorothiazide BMS 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 BMS 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 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH - United Kingdom 
 
Manufacturer 
SANOFI WINTHROP INDUSTRIE 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex - France 

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SANOFI SYNTHELABO LIMITED 
Edgefield Avenue - Fawdon 
Newcastle Upon Tyne, Tyne & Wear NE3 3TT - United Kingdom 
 
CHINOIN PRIVATE CO. LTD. 
Lévai u.5. 
2112 Veresegyház - Hungary 
 
SANOFI WINTHROP INDUSTRIE 
30-36 Avenue Gustave Eiffel 
37100 Tours - France 

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For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
Belgique/België/Belgien 
BRISTOL-MYERS SQUIBB BELGIUM S.A./N.V. 
Tél/Tel: + 32 2 352 76 11 
 

Luxembourg/Luxemburg 
BRISTOL-MYERS SQUIBB BELGIUM S.A./N.V. 
Tél/Tel: + 32 2 352 76 11 
 

България 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Teл.: + 359 800 12 400 
 

Magyarország 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel.: + 36 1 301 9700 
 

Česká republika 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 420 221 016 111 
 

Malta 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Danmark 
BRISTOL-MYERS SQUIBB 
Tlf: + 45 45 93 05 06 
 

Nederland 
BRISTOL-MYERS SQUIBB BV 
Tel: + 31 34 857 42 22 
 

Deutschland 
BRISTOL-MYERS SQUIBB GMBH & CO. KGAA 
Tel: + 49 89 121 42-0 
 

Norge 
BRISTOL-MYERS SQUIBB NORWAY LTD 
Tlf: + 47 67 55 53 50 
 

Eesti 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 372 6827 400 
 

Österreich 
BRISTOL-MYERS SQUIBB GESMBH 
Tel: + 43 1 60 14 30 
 
 

Ελλάδα 
BRISTOL-MYERS SQUIBB A.E. 
Τηλ: + 30 210 6074300 
 

Polska 
BRISTOL-MYERS SQUIBB POLSKA SP. Z O.O. 
Tel.: + 48 22 5796666 
 

España 
BRISTOL-MYERS SQUIBB, S.A. 
Tel: + 34 91 456 53 00 
 
 

Portugal 
BRISTOL-MYERS SQUIBB FARMACÊUTICA 
PORTUGUESA, S.A. 
Tel: + 351 21 440 70 00 
 

France 
BRISTOL-MYERS SQUIBB SARL 
Tél: + 33 (0)810 410 500 
 
 

România 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 40 (0)21 272 16 00 
 

Ireland 
BRISTOL-MYERS SQUIBB PHARMACEUTICALS LTD
Tel: + 353 (1 800) 749 749 
 

Slovenija 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 386 1 236 47 00 
 

Ísland 
VISTOR HF 
Sími: + 354 535 7000 
 

Slovenská republika 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 421 2 59298411  
 

Italia 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Suomi/Finland 
OY BRISTOL-MYERS SQUIBB (FINLAND) AB 
Puh/Tel: + 358 9 251 21 230 
 

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Κύπρος 
ΑΚΗΣ ΠΑΝΑΓΙΩΤΟΥ & ΥΙΟΣ Ε.Π.Ε. 
Τηλ: + 357 22 677038 
 

Sverige 
BRISTOL-MYERS SQUIBB AB 
Tel: + 46 8 704 71 00 
 

Latvija 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 371 67 50 21 85 
 

United Kingdom 
BRISTOL-MYERS SQUIBB PHARMACEUTICALS LTD
Tel: + 44 (0800) 731 1736 
 
 

Lietuva 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 370 5 2790 762 
 

 

 

This leaflet was last approved in 
 
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web 
site: http://www.emea.europa.eu/ 
 

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PACKAGE LEAFLET: INFORMATION FOR THE USER 
Irbesartan Hydrochlorothiazide BMS 300 mg/12.5 mg tablets 

irbesartan/hydrochlorothiazide 
 
Read all of this leaflet carefully before you start taking this medicine. 
 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. Do not pass it on to others. It may harm them, even 

if their symptoms are the same as yours. 
 If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 

please tell your doctor or pharmacist. 
 
In this leaflet: 
1. What Irbesartan Hydrochlorothiazide BMS is and what it is used for 
2. Before you take Irbesartan Hydrochlorothiazide BMS 
3. How to take Irbesartan Hydrochlorothiazide BMS 
4. Possible side effects 
5. How to store Irbesartan Hydrochlorothiazide BMS 
6. Further information 
 
 
1. WHAT IRBESARTAN HYDROCHLOROTHIAZIDE BMS IS AND WHAT IT IS USED 
FOR 
 
Irbesartan Hydrochlorothiazide BMS 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 BMS work together to lower blood 
pressure further than if either was given alone. 
 
Irbesartan Hydrochlorothiazide BMS is used to treat high blood pressure, when treatment with 
irbesartan or hydrochlorothiazide alone did not provide adequate control of your blood pressure. 
 
 
2. BEFORE YOU TAKE IRBESARTAN HYDROCHLOROTHIAZIDE BMS 
 
Do not take Irbesartan Hydrochlorothiazide BMS 
 if you are allergic (hypersensitive) to irbesartan or any of the other ingredients of Irbesartan 

Hydrochlorothiazide BMS  
 if you are allergic (hypersensitive) to hydrochlorothiazide or any other sulfonamide-derived 

medicines 
 if you are more than 3 months pregnant. (It is also better to avoid Irbesartan 

Hydrochlorothiazide BMS 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 
 
Irbesartan Hydrochlorothiazide BMS should not be given to children and adolescents (under 18 years). 
 
Take special care with Irbesartan Hydrochlorothiazide BMS 
Tell your doctor if any of the following apply to you: 

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 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). 

 
You must tell your doctor if you think you are (or might become) pregnant. Irbesartan 
Hydrochlorothiazide BMS 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 BMS) 

 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 
 
The hydrochlorothiazide contained in this medicine could produce a positive result in an anti-doping 
test. 
 
Using other medicines 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription. 
 
Diuretic agents such as the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide BMS 
may have an effect on other medicines. Preparations containing lithium should not be taken with 
Irbesartan Hydrochlorothiazide BMS without close supervision by your doctor. 
 
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) 

 
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 or arthritis medicines. 
 
Taking Irbesartan Hydrochlorothiazide BMS with food and drink 
Irbesartan Hydrochlorothiazide BMS can be taken with or without food. 
 
Due to the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide BMS, 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. 
 

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Pregnancy and breast-feeding 
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 BMS 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 BMS. Irbesartan Hydrochlorothiazide BMS 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 BMS 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 
No studies on the effects on the ability to drive and use machines have been performed. Irbesartan 
Hydrochlorothiazide BMS 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. 
 
Important information about some of the ingredients of Irbesartan Hydrochlorothiazide BMS 
Irbesartan Hydrochlorothiazide BMS 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 medicine. 
 
 
3. HOW TO TAKE IRBESARTAN HYDROCHLOROTHIAZIDE BMS 
 
Always take Irbesartan Hydrochlorothiazide BMS exactly as your doctor has told you. You should 
check with your doctor or pharmacist if you are not sure. 
 
Dosage 
The usual dose of Irbesartan Hydrochlorothiazide BMS is one tablet a day. Irbesartan 
Hydrochlorothiazide BMS 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 BMS. 
 
Method of administration 
Irbesartan Hydrochlorothiazide BMS is for oral use. Swallow the tablets with a sufficient amount of 
fluid (e.g. one glass of water). You can take Irbesartan Hydrochlorothiazide BMS 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 BMS 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 BMS than you should 
If you accidentally take too many tablets, contact your doctor immediately. 
 
Children should not take Irbesartan Hydrochlorothiazide BMS 
Irbesartan Hydrochlorothiazide BMS 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 BMS 
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 product, ask your doctor or pharmacist. 

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4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, Irbesartan Hydrochlorothiazide BMS 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 BMS and contact your doctor immediately. 
 
Side effects reported in clinical studies for patients treated with Irbesartan Hydrochlorothiazide BMS 
were: 
 
Common side effects (affect 1 to 10 users in 100)  
 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 (affect 1 to 10 users in 1,000)  
 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 BMS 
The frequency of these effects is not known. These undesirable effects 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. 
 
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 has 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 

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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. 
 
It is known that side effects associated with hydrochlorothiazide may increase with higher doses of 
hydrochlorothiazide. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor or pharmacist. 
 
 
5. HOW TO STORE IRBESARTAN HYDROCHLOROTHIAZIDE BMS 
 
Keep out of the reach and sight of children. 
 
Do not use Irbesartan Hydrochlorothiazide BMS 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. 
 
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to 
dispose of medicines no longer required. These measures will help to protect the environment. 
 
 
6. FURTHER INFORMATION 
 
What Irbesartan Hydrochlorothiazide BMS contains 
 The active substances are irbesartan and hydrochlorothiazide. Each tablet of Irbesartan 

Hydrochlorothiazide BMS 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). 

 
What Irbesartan Hydrochlorothiazide BMS looks like and contents of the pack 
Irbesartan Hydrochlorothiazide BMS 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 BMS 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 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH - United Kingdom 
 
Manufacturer 
SANOFI WINTHROP INDUSTRIE 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex - France 

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SANOFI SYNTHELABO LIMITED 
Edgefield Avenue - Fawdon 
Newcastle Upon Tyne, Tyne & Wear NE3 3TT - United Kingdom 
 
CHINOIN PRIVATE CO. LTD. 
Lévai u.5. 
2112 Veresegyház - Hungary 
 
SANOFI WINTHROP INDUSTRIE 
30-36 Avenue Gustave Eiffel 
37100 Tours - France 

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For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
Belgique/België/Belgien 
BRISTOL-MYERS SQUIBB BELGIUM S.A./N.V. 
Tél/Tel: + 32 2 352 76 11 
 

Luxembourg/Luxemburg 
BRISTOL-MYERS SQUIBB BELGIUM S.A./N.V. 
Tél/Tel: + 32 2 352 76 11 
 

България 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Teл.: + 359 800 12 400 
 

Magyarország 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel.: + 36 1 301 9700 
 

Česká republika 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 420 221 016 111 
 

Malta 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Danmark 
BRISTOL-MYERS SQUIBB 
Tlf: + 45 45 93 05 06 
 

Nederland 
BRISTOL-MYERS SQUIBB BV 
Tel: + 31 34 857 42 22 
 

Deutschland 
BRISTOL-MYERS SQUIBB GMBH & CO. KGAA 
Tel: + 49 89 121 42-0 
 

Norge 
BRISTOL-MYERS SQUIBB NORWAY LTD 
Tlf: + 47 67 55 53 50 
 

Eesti 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 372 6827 400 
 

Österreich 
BRISTOL-MYERS SQUIBB GESMBH 
Tel: + 43 1 60 14 30 
 
 

Ελλάδα 
BRISTOL-MYERS SQUIBB A.E. 
Τηλ: + 30 210 6074300 
 

Polska 
BRISTOL-MYERS SQUIBB POLSKA SP. Z O.O. 
Tel.: + 48 22 5796666 
 

España 
BRISTOL-MYERS SQUIBB, S.A. 
Tel: + 34 91 456 53 00 
 
 

Portugal 
BRISTOL-MYERS SQUIBB FARMACÊUTICA 
PORTUGUESA, S.A. 
Tel: + 351 21 440 70 00 
 

France 
BRISTOL-MYERS SQUIBB SARL 
Tél: + 33 (0)810 410 500 
 
 

România 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 40 (0)21 272 16 00 
 

Ireland 
BRISTOL-MYERS SQUIBB PHARMACEUTICALS LTD
Tel: + 353 (1 800) 749 749 
 

Slovenija 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 386 1 236 47 00 
 

Ísland 
VISTOR HF 
Sími: + 354 535 7000 
 

Slovenská republika 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 421 2 59298411  
 

Italia 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Suomi/Finland 
OY BRISTOL-MYERS SQUIBB (FINLAND) AB 
Puh/Tel: + 358 9 251 21 230 
 

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Κύπρος 
ΑΚΗΣ ΠΑΝΑΓΙΩΤΟΥ & ΥΙΟΣ Ε.Π.Ε. 
Τηλ: + 357 22 677038 
 

Sverige 
BRISTOL-MYERS SQUIBB AB 
Tel: + 46 8 704 71 00 
 

Latvija 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 371 67 50 21 85 
 

United Kingdom 
BRISTOL-MYERS SQUIBB PHARMACEUTICALS LTD
Tel: + 44 (0800) 731 1736 
 
 

Lietuva 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 370 5 2790 762 
 

 

 

This leaflet was last approved in 
 
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web 
site: http://www.emea.europa.eu/ 
 

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PACKAGE LEAFLET: INFORMATION FOR THE USER 
Irbesartan Hydrochlorothiazide BMS 150 mg/12.5 mg film-coated tablets 

irbesartan/hydrochlorothiazide 
 
Read all of this leaflet carefully before you start taking this medicine. 
 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. Do not pass it on to others. It may harm them, even 

if their symptoms are the same as yours. 
 If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 

please tell your doctor or pharmacist. 
 
In this leaflet: 
1. What Irbesartan Hydrochlorothiazide BMS is and what it is used for 
2. Before you take Irbesartan Hydrochlorothiazide BMS 
3. How to take Irbesartan Hydrochlorothiazide BMS 
4. Possible side effects 
5. How to store Irbesartan Hydrochlorothiazide BMS 
6. Further information 
 
 
1. WHAT IRBESARTAN HYDROCHLOROTHIAZIDE BMS IS AND WHAT IT IS USED 

FOR 
 
Irbesartan Hydrochlorothiazide BMS 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 BMS work together to lower blood 
pressure further than if either was given alone. 
 
Irbesartan Hydrochlorothiazide BMS is used to treat high blood pressure, when treatment with 
irbesartan or hydrochlorothiazide alone did not provide adequate control of your blood pressure. 
 
 
2. BEFORE YOU TAKE IRBESARTAN HYDROCHLOROTHIAZIDE BMS 
 
Do not take Irbesartan Hydrochlorothiazide BMS 
 if you are allergic (hypersensitive) to irbesartan or any of the other ingredients of Irbesartan 

Hydrochlorothiazide BMS  
 if you are allergic (hypersensitive) to hydrochlorothiazide or any other sulfonamide-derived 

medicines 
 if you are more than 3 months pregnant. (It is also better to avoid Irbesartan 

Hydrochlorothiazide BMS 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 
 
Irbesartan Hydrochlorothiazide BMS should not be given to children and adolescents (under 18 years). 
 
Take special care with Irbesartan Hydrochlorothiazide BMS 
Tell your doctor if any of the following apply to you: 

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 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). 

 
You must tell your doctor if you think you are (or might become) pregnant. Irbesartan 
Hydrochlorothiazide BMS 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 BMS) 

 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 
 
The hydrochlorothiazide contained in this medicine could produce a positive result in an anti-doping 
test. 
 
Using other medicines 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription. 
 
Diuretic agents such as the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide BMS 
may have an effect on other medicines. Preparations containing lithium should not be taken with 
Irbesartan Hydrochlorothiazide BMS without close supervision by your doctor. 
 
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) 

 
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 or arthritis medicines. 
 
Taking Irbesartan Hydrochlorothiazide BMS with food and drink 
Irbesartan Hydrochlorothiazide BMS can be taken with or without food. 
 
Due to the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide BMS, 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. 
 

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Pregnancy and breast-feeding 
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 BMS 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 BMS. Irbesartan Hydrochlorothiazide BMS 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 BMS 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 
No studies on the effects on the ability to drive and use machines have been performed. Irbesartan 
Hydrochlorothiazide BMS 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. 
 
Important information about some of the ingredients of Irbesartan Hydrochlorothiazide BMS 
Irbesartan Hydrochlorothiazide BMS 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 medicine. 
 
 
3. HOW TO TAKE IRBESARTAN HYDROCHLOROTHIAZIDE BMS 
 
Always take Irbesartan Hydrochlorothiazide BMS exactly as your doctor has told you. You should 
check with your doctor or pharmacist if you are not sure. 
 
Dosage 
The usual dose of Irbesartan Hydrochlorothiazide BMS is one or two tablets a day. Irbesartan 
Hydrochlorothiazide BMS 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 BMS. 
 
Method of administration 
Irbesartan Hydrochlorothiazide BMS is for oral use. Swallow the tablets with a sufficient amount of 
fluid (e.g. one glass of water). You can take Irbesartan Hydrochlorothiazide BMS 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 BMS 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 BMS than you should 
If you accidentally take too many tablets, contact your doctor immediately. 
 
Children should not take Irbesartan Hydrochlorothiazide BMS 
Irbesartan Hydrochlorothiazide BMS 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 BMS 
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 product, ask your doctor or pharmacist. 

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4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, Irbesartan Hydrochlorothiazide BMS 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 BMS and contact your doctor immediately. 
 
Side effects reported in clinical studies for patients treated with Irbesartan Hydrochlorothiazide BMS 
were: 
 
Common side effects (affect 1 to 10 users in 100) 
 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 (affect 1 to 10 users in 1,000) 
 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 BMS 
The frequency of these effects is not known. These undesirable effects 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. 
 
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 has 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 

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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. 
 
It is known that side effects associated with hydrochlorothiazide may increase with higher doses of 
hydrochlorothiazide. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor or pharmacist. 
 
 
5. HOW TO STORE IRBESARTAN HYDROCHLOROTHIAZIDE BMS 
 
Keep out of the reach and sight of children. 
 
Do not use Irbesartan Hydrochlorothiazide BMS 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. 
 
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to 
dispose of medicines no longer required. These measures will help to protect the environment. 
 
 
6. FURTHER INFORMATION 
 
What Irbesartan Hydrochlorothiazide BMS contains 
 The active substances are irbesartan and hydrochlorothiazide. Each film-coated tablet of 

Irbesartan Hydrochlorothiazide BMS 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. 

 
What Irbesartan Hydrochlorothiazide BMS looks like and contents of the pack 
Irbesartan Hydrochlorothiazide BMS 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 BMS 150 mg/12.5 mg film-coated tablets are supplied in blister packs 
of 14, 28, 56, 84 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 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH - United Kingdom 
 

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Manufacturer 
SANOFI WINTHROP INDUSTRIE 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex - France 
 
SANOFI SYNTHELABO LIMITED 
Edgefield Avenue - Fawdon 
Newcastle Upon Tyne, Tyne & Wear NE3 3TT - United Kingdom 
 
CHINOIN PRIVATE CO. LTD. 
Lévai u.5. 
2112 Veresegyház - Hungary 
 
SANOFI WINTHROP INDUSTRIE 
30-36 Avenue Gustave Eiffel 
37100 Tours - France 

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For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
Belgique/België/Belgien 
BRISTOL-MYERS SQUIBB BELGIUM S.A./N.V. 
Tél/Tel: + 32 2 352 76 11 
 

Luxembourg/Luxemburg 
BRISTOL-MYERS SQUIBB BELGIUM S.A./N.V. 
Tél/Tel: + 32 2 352 76 11 
 

България 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Teл.: + 359 800 12 400 
 

Magyarország 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel.: + 36 1 301 9700 
 

Česká republika 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 420 221 016 111 
 

Malta 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Danmark 
BRISTOL-MYERS SQUIBB 
Tlf: + 45 45 93 05 06 
 

Nederland 
BRISTOL-MYERS SQUIBB BV 
Tel: + 31 34 857 42 22 
 

Deutschland 
BRISTOL-MYERS SQUIBB GMBH & CO. KGAA 
Tel: + 49 89 121 42-0 
 

Norge 
BRISTOL-MYERS SQUIBB NORWAY LTD 
Tlf: + 47 67 55 53 50 
 

Eesti 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 372 6827 400 
 

Österreich 
BRISTOL-MYERS SQUIBB GESMBH 
Tel: + 43 1 60 14 30 
 
 

Ελλάδα 
BRISTOL-MYERS SQUIBB A.E. 
Τηλ: + 30 210 6074300 
 

Polska 
BRISTOL-MYERS SQUIBB POLSKA SP. Z O.O. 
Tel.: + 48 22 5796666 
 

España 
BRISTOL-MYERS SQUIBB, S.A. 
Tel: + 34 91 456 53 00 
 
 

Portugal 
BRISTOL-MYERS SQUIBB FARMACÊUTICA 
PORTUGUESA, S.A. 
Tel: + 351 21 440 70 00 
 

France 
BRISTOL-MYERS SQUIBB SARL 
Tél: + 33 (0)810 410 500 
 
 

România 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 40 (0)21 272 16 00 
 

Ireland 
BRISTOL-MYERS SQUIBB PHARMACEUTICALS LTD
Tel: + 353 (1 800) 749 749 
 

Slovenija 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 386 1 236 47 00 
 

Ísland 
VISTOR HF 
Sími: + 354 535 7000 
 

Slovenská republika 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 421 2 59298411  
 

Italia 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Suomi/Finland 
OY BRISTOL-MYERS SQUIBB (FINLAND) AB 
Puh/Tel: + 358 9 251 21 230 
 

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Κύπρος 
ΑΚΗΣ ΠΑΝΑΓΙΩΤΟΥ & ΥΙΟΣ Ε.Π.Ε. 
Τηλ: + 357 22 677038 
 

Sverige 
BRISTOL-MYERS SQUIBB AB 
Tel: + 46 8 704 71 00 
 

Latvija 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 371 67 50 21 85 
 

United Kingdom 
BRISTOL-MYERS SQUIBB PHARMACEUTICALS LTD
Tel: + 44 (0800) 731 1736 
 
 

Lietuva 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 370 5 2790 762 
 

 

 

This leaflet was last approved in 
 
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web 
site: http://www.emea.europa.eu/ 

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 111

PACKAGE LEAFLET: INFORMATION FOR THE USER 
Irbesartan Hydrochlorothiazide BMS 300 mg/12.5 mg film-coated tablets 

irbesartan/hydrochlorothiazide 
 
Read all of this leaflet carefully before you start taking this medicine. 
 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. Do not pass it on to others. It may harm them, even 

if their symptoms are the same as yours. 
 If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 

please tell your doctor or pharmacist. 
 
In this leaflet: 
1. What Irbesartan Hydrochlorothiazide BMS is and what it is used for 
2. Before you take Irbesartan Hydrochlorothiazide BMS 
3. How to take Irbesartan Hydrochlorothiazide BMS 
4. Possible side effects 
5. How to store Irbesartan Hydrochlorothiazide BMS 
6. Further information 
 
 
1. WHAT IRBESARTAN HYDROCHLOROTHIAZIDE BMS IS AND WHAT IT IS USED 

FOR 
 
Irbesartan Hydrochlorothiazide BMS 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 BMS work together to lower blood 
pressure further than if either was given alone. 
 
Irbesartan Hydrochlorothiazide BMS is used to treat high blood pressure, when treatment with 
irbesartan or hydrochlorothiazide alone did not provide adequate control of your blood pressure. 
 
 
2. BEFORE YOU TAKE IRBESARTAN HYDROCHLOROTHIAZIDE BMS 
 
Do not take Irbesartan Hydrochlorothiazide BMS 
 if you are allergic (hypersensitive) to irbesartan or any of the other ingredients of Irbesartan 

Hydrochlorothiazide BMS  
 if you are allergic (hypersensitive) to hydrochlorothiazide or any other sulfonamide-derived 

medicines 
 if you are more than 3 months pregnant. (It is also better to avoid Irbesartan 

Hydrochlorothiazide BMS 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 
 
Irbesartan Hydrochlorothiazide BMS should not be given to children and adolescents (under 18 years). 
 
Take special care with Irbesartan Hydrochlorothiazide BMS 
Tell your doctor if any of the following apply to you: 

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 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). 

 
You must tell your doctor if you think you are (or might become) pregnant. Irbesartan 
Hydrochlorothiazide BMS 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 BMS) 

 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 
 
The hydrochlorothiazide contained in this medicine could produce a positive result in an anti-doping 
test. 
 
Using other medicines 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription. 
 
Diuretic agents such as the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide BMS 
may have an effect on other medicines. Preparations containing lithium should not be taken with 
Irbesartan Hydrochlorothiazide BMS without close supervision by your doctor. 
 
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) 

 
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 or arthritis medicines. 
 
Taking Irbesartan Hydrochlorothiazide BMS with food and drink 
Irbesartan Hydrochlorothiazide BMS can be taken with or without food. 
 
Due to the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide BMS, 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. 
 

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Pregnancy and breast-feeding 
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 BMS 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 BMS. Irbesartan Hydrochlorothiazide BMS 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 BMS 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 
No studies on the effects on the ability to drive and use machines have been performed. Irbesartan 
Hydrochlorothiazide BMS 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. 
 
Important information about some of the ingredients of Irbesartan Hydrochlorothiazide BMS 
Irbesartan Hydrochlorothiazide BMS 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 medicine. 
 
 
3. HOW TO TAKE IRBESARTAN HYDROCHLOROTHIAZIDE BMS 
 
Always take Irbesartan Hydrochlorothiazide BMS exactly as your doctor has told you. You should 
check with your doctor or pharmacist if you are not sure. 
 
Dosage 
The usual dose of Irbesartan Hydrochlorothiazide BMS is one tablet a day. Irbesartan 
Hydrochlorothiazide BMS 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 BMS. 
 
Method of administration 
Irbesartan Hydrochlorothiazide BMS is for oral use. Swallow the tablets with a sufficient amount of 
fluid (e.g. one glass of water). You can take Irbesartan Hydrochlorothiazide BMS 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 BMS 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 BMS than you should 
If you accidentally take too many tablets, contact your doctor immediately. 
 
Children should not take Irbesartan Hydrochlorothiazide BMS 
Irbesartan Hydrochlorothiazide BMS 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 BMS 
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 product, ask your doctor or pharmacist. 

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4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, Irbesartan Hydrochlorothiazide BMS 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 BMS and contact your doctor immediately. 
 
Side effects reported in clinical studies for patients treated with Irbesartan Hydrochlorothiazide BMS 
were: 
 
Common side effects (affect 1 to 10 users in 100) 
 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 (affect 1 to 10 users in 1,000) 
 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 BMS 
The frequency of these effects is not known. These undesirable effects 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. 
 
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 has 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 

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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. 
 
It is known that side effects associated with hydrochlorothiazide may increase with higher doses of 
hydrochlorothiazide. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor or pharmacist. 
 
 
5. HOW TO STORE IRBESARTAN HYDROCHLOROTHIAZIDE BMS 
 
Keep out of the reach and sight of children. 
 
Do not use Irbesartan Hydrochlorothiazide BMS 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. 
 
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to 
dispose of medicines no longer required. These measures will help to protect the environment. 
 
 
6. FURTHER INFORMATION 
 
What Irbesartan Hydrochlorothiazide BMS contains 
 The active substances are irbesartan and hydrochlorothiazide. Each film-coated tablet of 

Irbesartan Hydrochlorothiazide BMS 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. 

 
What Irbesartan Hydrochlorothiazide BMS looks like and contents of the pack 
Irbesartan Hydrochlorothiazide BMS 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 BMS 300 mg/12.5 mg film-coated tablets are supplied in blister packs 
of 14, 28, 56, 84 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 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH - United Kingdom 
 

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Manufacturer 
SANOFI WINTHROP INDUSTRIE 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex - France 
 
SANOFI SYNTHELABO LIMITED 
Edgefield Avenue - Fawdon 
Newcastle Upon Tyne, Tyne & Wear NE3 3TT - United Kingdom 
 
CHINOIN PRIVATE CO. LTD. 
Lévai u.5. 
2112 Veresegyház - Hungary 
 
SANOFI WINTHROP INDUSTRIE 
30-36 Avenue Gustave Eiffel 
37100 Tours - France 

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For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
Belgique/België/Belgien 
BRISTOL-MYERS SQUIBB BELGIUM S.A./N.V. 
Tél/Tel: + 32 2 352 76 11 
 

Luxembourg/Luxemburg 
BRISTOL-MYERS SQUIBB BELGIUM S.A./N.V. 
Tél/Tel: + 32 2 352 76 11 
 

България 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Teл.: + 359 800 12 400 
 

Magyarország 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel.: + 36 1 301 9700 
 

Česká republika 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 420 221 016 111 
 

Malta 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Danmark 
BRISTOL-MYERS SQUIBB 
Tlf: + 45 45 93 05 06 
 

Nederland 
BRISTOL-MYERS SQUIBB BV 
Tel: + 31 34 857 42 22 
 

Deutschland 
BRISTOL-MYERS SQUIBB GMBH & CO. KGAA 
Tel: + 49 89 121 42-0 
 

Norge 
BRISTOL-MYERS SQUIBB NORWAY LTD 
Tlf: + 47 67 55 53 50 
 

Eesti 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 372 6827 400 
 

Österreich 
BRISTOL-MYERS SQUIBB GESMBH 
Tel: + 43 1 60 14 30 
 
 

Ελλάδα 
BRISTOL-MYERS SQUIBB A.E. 
Τηλ: + 30 210 6074300 
 

Polska 
BRISTOL-MYERS SQUIBB POLSKA SP. Z O.O. 
Tel.: + 48 22 5796666 
 

España 
BRISTOL-MYERS SQUIBB, S.A. 
Tel: + 34 91 456 53 00 
 
 

Portugal 
BRISTOL-MYERS SQUIBB FARMACÊUTICA 
PORTUGUESA, S.A. 
Tel: + 351 21 440 70 00 
 

France 
BRISTOL-MYERS SQUIBB SARL 
Tél: + 33 (0)810 410 500 
 
 

România 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 40 (0)21 272 16 00 
 

Ireland 
BRISTOL-MYERS SQUIBB PHARMACEUTICALS LTD
Tel: + 353 (1 800) 749 749 
 

Slovenija 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 386 1 236 47 00 
 

Ísland 
VISTOR HF 
Sími: + 354 535 7000 
 

Slovenská republika 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 421 2 59298411  
 

Italia 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Suomi/Finland 
OY BRISTOL-MYERS SQUIBB (FINLAND) AB 
Puh/Tel: + 358 9 251 21 230 
 

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Κύπρος 
ΑΚΗΣ ΠΑΝΑΓΙΩΤΟΥ & ΥΙΟΣ Ε.Π.Ε. 
Τηλ: + 357 22 677038 
 

Sverige 
BRISTOL-MYERS SQUIBB AB 
Tel: + 46 8 704 71 00 
 

Latvija 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 371 67 50 21 85 
 

United Kingdom 
BRISTOL-MYERS SQUIBB PHARMACEUTICALS LTD
Tel: + 44 (0800) 731 1736 
 
 

Lietuva 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 370 5 2790 762 
 

 

 

This leaflet was last approved in 
 
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web 
site: http://www.emea.europa.eu/ 

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PACKAGE LEAFLET: INFORMATION FOR THE USER 
Irbesartan Hydrochlorothiazide BMS 300 mg/25 mg film-coated tablets 

irbesartan/hydrochlorothiazide 
 
Read all of this leaflet carefully before you start taking this medicine. 
 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. Do not pass it on to others. It may harm them, even 

if their symptoms are the same as yours. 
 If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 

please tell your doctor or pharmacist. 
 
In this leaflet: 
1. What Irbesartan Hydrochlorothiazide BMS is and what it is used for 
2. Before you take Irbesartan Hydrochlorothiazide BMS 
3. How to take Irbesartan Hydrochlorothiazide BMS 
4. Possible side effects 
5. How to store Irbesartan Hydrochlorothiazide BMS 
6. Further information 
 
 
1. WHAT IRBESARTAN HYDROCHLOROTHIAZIDE BMS IS AND WHAT IT IS USED 

FOR 
 
Irbesartan Hydrochlorothiazide BMS 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 BMS work together to lower blood 
pressure further than if either was given alone. 
 
Irbesartan Hydrochlorothiazide BMS is used to treat high blood pressure, when treatment with 
irbesartan or hydrochlorothiazide alone did not provide adequate control of your blood pressure. 
 
 
2. BEFORE YOU TAKE IRBESARTAN HYDROCHLOROTHIAZIDE BMS 
 
Do not take Irbesartan Hydrochlorothiazide BMS 
 if you are allergic (hypersensitive) to irbesartan or any of the other ingredients of Irbesartan 

Hydrochlorothiazide BMS  
 if you are allergic (hypersensitive) to hydrochlorothiazide or any other sulfonamide-derived 

medicines 
 if you are more than 3 months pregnant. (It is also better to avoid Irbesartan 

Hydrochlorothiazide BMS 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 
 
Irbesartan Hydrochlorothiazide BMS should not be given to children and adolescents (under 18 years). 
 
Take special care with Irbesartan Hydrochlorothiazide BMS 
Tell your doctor if any of the following apply to you: 

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 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). 

 
You must tell your doctor if you think you are (or might become) pregnant. Irbesartan 
Hydrochlorothiazide BMS 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 BMS) 

 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 
 
The hydrochlorothiazide contained in this medicine could produce a positive result in an anti-doping 
test. 
 
Using other medicines 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription. 
 
Diuretic agents such as the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide BMS 
may have an effect on other medicines. Preparations containing lithium should not be taken with 
Irbesartan Hydrochlorothiazide BMS without close supervision by your doctor. 
 
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) 

 
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 or arthritis medicines. 
 
Taking Irbesartan Hydrochlorothiazide BMS with food and drink 
Irbesartan Hydrochlorothiazide BMS can be taken with or without food. 
 
Due to the hydrochlorothiazide contained in Irbesartan Hydrochlorothiazide BMS, 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. 
 

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Pregnancy and breast-feeding 
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 BMS 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 BMS. Irbesartan Hydrochlorothiazide BMS 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 BMS 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 
No studies on the effects on the ability to drive and use machines have been performed. Irbesartan 
Hydrochlorothiazide BMS 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. 
 
Important information about some of the ingredients of Irbesartan Hydrochlorothiazide BMS 
Irbesartan Hydrochlorothiazide BMS 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 medicine. 
 
 
3. HOW TO TAKE IRBESARTAN HYDROCHLOROTHIAZIDE BMS 
 
Always take Irbesartan Hydrochlorothiazide BMS exactly as your doctor has told you. You should 
check with your doctor or pharmacist if you are not sure. 
 
Dosage 
The usual dose of Irbesartan Hydrochlorothiazide BMS is one tablet a day. Irbesartan 
Hydrochlorothiazide BMS 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 BMS. 
 
Method of administration 
Irbesartan Hydrochlorothiazide BMS is for oral use. Swallow the tablets with a sufficient amount of 
fluid (e.g. one glass of water). You can take Irbesartan Hydrochlorothiazide BMS 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 BMS 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 BMS than you should 
If you accidentally take too many tablets, contact your doctor immediately. 
 
Children should not take Irbesartan Hydrochlorothiazide BMS 
Irbesartan Hydrochlorothiazide BMS 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 BMS 
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 product, ask your doctor or pharmacist. 

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4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, Irbesartan Hydrochlorothiazide BMS 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 BMS and contact your doctor immediately. 
 
Side effects reported in clinical studies for patients treated with Irbesartan Hydrochlorothiazide BMS 
were: 
 
Common side effects (affect 1 to 10 users in 100) 
 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 (affect 1 to 10 users in 1,000) 
 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 BMS 
The frequency of these effects is not known. These undesirable effects 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. 
 
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 has 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 

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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. 
 
It is known that side effects associated with hydrochlorothiazide may increase with higher doses of 
hydrochlorothiazide. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor or pharmacist. 
 
 
5. HOW TO STORE IRBESARTAN HYDROCHLOROTHIAZIDE BMS 
 
Keep out of the reach and sight of children. 
 
Do not use Irbesartan Hydrochlorothiazide BMS 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. 
 
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to 
dispose of medicines no longer required. These measures will help to protect the environment. 
 
 
6. FURTHER INFORMATION 
 
What Irbesartan Hydrochlorothiazide BMS contains 
 The active substances are irbesartan and hydrochlorothiazide. Each film-coated tablet of 

Irbesartan Hydrochlorothiazide BMS 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. 

 
What Irbesartan Hydrochlorothiazide BMS looks like and contents of the pack 
Irbesartan Hydrochlorothiazide BMS 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 BMS 300 mg/25 mg film-coated tablets are supplied in blister packs of 
14, 28, 56, 84 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 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH - United Kingdom 
 

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Manufacturer 
SANOFI WINTHROP INDUSTRIE 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex - France 
 
SANOFI SYNTHELABO LIMITED 
Edgefield Avenue - Fawdon 
Newcastle Upon Tyne, Tyne & Wear NE3 3TT - United Kingdom 
 
CHINOIN PRIVATE CO. LTD. 
Lévai u.5. 
2112 Veresegyház - Hungary 
 
SANOFI WINTHROP INDUSTRIE 
30-36 Avenue Gustave Eiffel 
37100 Tours - France 

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For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
Belgique/België/Belgien 
BRISTOL-MYERS SQUIBB BELGIUM S.A./N.V. 
Tél/Tel: + 32 2 352 76 11 
 

Luxembourg/Luxemburg 
BRISTOL-MYERS SQUIBB BELGIUM S.A./N.V. 
Tél/Tel: + 32 2 352 76 11 
 

България 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Teл.: + 359 800 12 400 
 

Magyarország 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel.: + 36 1 301 9700 
 

Česká republika 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 420 221 016 111 
 

Malta 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Danmark 
BRISTOL-MYERS SQUIBB 
Tlf: + 45 45 93 05 06 
 

Nederland 
BRISTOL-MYERS SQUIBB BV 
Tel: + 31 34 857 42 22 
 

Deutschland 
BRISTOL-MYERS SQUIBB GMBH & CO. KGAA 
Tel: + 49 89 121 42-0 
 

Norge 
BRISTOL-MYERS SQUIBB NORWAY LTD 
Tlf: + 47 67 55 53 50 
 

Eesti 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 372 6827 400 
 

Österreich 
BRISTOL-MYERS SQUIBB GESMBH 
Tel: + 43 1 60 14 30 
 
 

Ελλάδα 
BRISTOL-MYERS SQUIBB A.E. 
Τηλ: + 30 210 6074300 
 

Polska 
BRISTOL-MYERS SQUIBB POLSKA SP. Z O.O. 
Tel.: + 48 22 5796666 
 

España 
BRISTOL-MYERS SQUIBB, S.A. 
Tel: + 34 91 456 53 00 
 
 

Portugal 
BRISTOL-MYERS SQUIBB FARMACÊUTICA 
PORTUGUESA, S.A. 
Tel: + 351 21 440 70 00 
 

France 
BRISTOL-MYERS SQUIBB SARL 
Tél: + 33 (0)810 410 500 
 
 

România 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 40 (0)21 272 16 00 
 

Ireland 
BRISTOL-MYERS SQUIBB PHARMACEUTICALS LTD
Tel: + 353 (1 800) 749 749 
 

Slovenija 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 386 1 236 47 00 
 

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VISTOR HF 
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Slovenská republika 
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Suomi/Finland 
OY BRISTOL-MYERS SQUIBB (FINLAND) AB 
Puh/Tel: + 358 9 251 21 230 
 

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Κύπρος 
ΑΚΗΣ ΠΑΝΑΓΙΩΤΟΥ & ΥΙΟΣ Ε.Π.Ε. 
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GYÓGYSZERKERESKEDELMI KFT. 
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United Kingdom 
BRISTOL-MYERS SQUIBB PHARMACEUTICALS LTD
Tel: + 44 (0800) 731 1736 
 
 

Lietuva 
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Tel: + 370 5 2790 762 
 

 

 

This leaflet was last approved in 
 
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web 
site: http://www.emea.europa.eu/ 
 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCHRELEASE
	B. CONDITIONS OF THE MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET