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IRBESARTAN AND HYDROCHLOROTHIAZIDE MILPHARM 150 MG/ 12.5 MG FILM-COATED TABLETS
Active substance(s): HYDROCHLOROTHIAZIDE / IRBESARTAN
NAME OF THE MEDICINAL PRODUCT
Irbesartan and Hydrochlorothiazide Milpharm 150 mg/ 12.5 mg film-coated tablets
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 150 mg of irbesartan and 12.5 mg of
Each film-coated tablet contains 131.85 mg of lactose monohydrate.
For a full list of excipients, see section 6.1.
Peach coloured film-coated biconvex oval shaped tablets, debossed with “H 35” on
one side and plain on other side. The size is 14 mm X 7.6 mm.
Treatment of essential hypertension.
This fixed dose combination is indicated in adult patients whose blood pressure is not
controlled on irbesartan or hydrochlorothiazide alone (see section 5.1).
Posology and method of administration
Irbesartan/ Hydrochlorothiazide can be taken once daily, with or without food.
Dose titration with the individual components (i.e. irbesartan and
hydrochlorothiazide) may be
When clinically appropriate direct change from monotherapy to the fixed
combinations may be considered:
Irbesartan/ Hydrochlorothiazide 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 300 mg/12.5 mg may be administered in
patients insufficiently controlled by irbesartan 300 mg or by Irbesartan/
Hydrochlorothiazide 150 mg/12.5 mg.
Irbesartan/ Hydrochlorothiazide 300 mg/25 mg may be administered in
patients insufficiently controlled by Irbesartan/ Hydrochlorothiazide 300
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily
are not recommended. When necessary, Irbesartan/ Hydrochlorothiazide
may be administered with another antihypertensive medicinal product (see
Renal impairment: due to the hydrochlorothiazide component, Irbesartan/
Hydrochlorothiazide is not recommended for patients with severe renal
dysfunction (creatinine clearance < 30 ml/min). Loop diuretics are preferred to
thiazides in this population. No dosage adjustment is necessary in patients
with renal impairment whose renal creatinine clearance is ≥ 30 ml/min (see
sections 4.3 and 4.4).
Hepatic impairment: Irbesartan/ Hydrochlorothiazide 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 is necessary in patients with mild to moderate
hepatic impairment (see section 4.3).
Elderly patients: no dosage adjustment of Irbesartan/ Hydrochlorothiazide is
necessary in elderly patients.
Paediatric population: Irbesartan + Hydrochlorothiazide is not recommended
for use in children and adolescents because the safety and efficacy have not
been established. No data are available.
Method of administration
For oral use.
• Hypersensitivity to the active substances, to any of the excipients (see
section 6.1), or to other sulfonamide-derived substances
(hydrochlorothiazide is a sulfonamide-derived substance)
Severe renal impairment (creatinine clearance < 30 ml/min)
Refractory hypokalaemia, hypercalcaemia
Second and third trimesters of pregnancy (see sections 4.4 and 4.6)
Severe hepatic impairment, biliary cirrhosis and cholestasis
Special warnings and precautions for use
Hypotension - Volume-depleted patients: Irbesartan/ Hydrochlorothiazide has
been rarely associated with symptomatic hypotension in hypertensive patients
without other risk factors for hypotension. Symptomatic hypotension may be
expected to occur in patients who are volume and/or sodium depleted by
vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such
conditions should be corrected before initiating therapy with Irbesartan/
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
receptor antagonists. While this is not documented with Irbesartan/
Hydrochlorothiazide, a similar effect should be anticipated.
Renal impairment and kidney transplantation: when Irbesartan/
Hydrochlorothiazide 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 in patients with a recent kidney
transplantation. Irbesartan/ Hydrochlorothiazide 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
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 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,
Primary aldosteronism: patients with primary aldosteronism generally
will not respond to
antihypertensive medicinal products acting through inhibition of the
Therefore, the use of Irbesartan/ Hydrochlorothiazide is not
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,
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 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 (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
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 is not
recommended (see section 4.5).
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.
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.
Interaction with other medicinal products and other forms of interaction
Other antihypertensive agents: the antihypertensive effect of Irbesartan/
Hydrochlorothiazide 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. Therefore, the combination of lithium and
Irbesartan/ Hydrochlorothiazide is not recommended (see section 4.4). If the
combination proves necessary, careful monitoring of serum lithium levels is
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 is administered with medicinal products affected by
serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are
administered simultaneously with non-steroidal anti- inflammatory drugs (i.e.
selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective
NSAIDs), attenuation of the antihypertensive effect may occur. As with ACE
inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may
lead to an increased risk of worsening of renal function, including possible
acute renal failure, and an increase in serum potassium, especially in patients
with poor pre-existing renal function. The combination should be administered
with caution, especially in the elderly. Patients should be adequately hydrated
and consideration should be given to monitoring renal function after initiation
of concomitant therapy, and periodically thereafter.
Additional information on irbesartan interactions: in clinical studies, the
pharmacokinetic of irbesartan is not affected by hydrochlorothiazide.
Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by
glucuronidation. No significant pharmacokinetic or pharmacodynamic
interactions were observed when irbesartan was coadministered with warfarin,
a medicinal product metabolised by CYP2C9. The effects of CYP2C9
inducers such as rifampicin on the pharmacokinetic of irbesartan have not
been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of irbesartan.
Additional information on hydrochlorothiazide interactions: when
administered concurrently, the following medicinal products may interact
with thiazide diuretics:
Alcohol: potentiation of orthostatic hypotension may occur;
Antidiabetic medicinal products (oral agents and insulins): dosage
adjustment of the antidiabetic medicinal product may be required (see
Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is
impaired in the presence of anionic exchange resins. Irbesartan/
Hydrochlorothiazide should be taken at least one hour before or four hours
after these medications;
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may
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
Antigout medicinal products: dosage adjustments of antigout medicinal
products may be necessary as hydrochlorothiazide may raise the level of
serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be
necessary. Co-administration of thiazide diuretics may increase the incidence
of hypersensitivity reactions to allopurinol;
Calcium salts: thiazide diuretics may increase serum calcium levels due to
decreased excretion. If calcium supplements or calcium sparing medicinal
products (e.g. vitamin D therapy) must be prescribed, serum calcium levels
should be monitored and calcium dosage adjusted accordingly;
Carbamazepine: concomitant use of carbamazepine and hydrochlorothiazide
has been associated with the risk of symptomatic hyponatraemia. Electrolytes
should be monitored during concomitant use. If possible, another class of
diuretics should be used;
Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide
may be enhanced by thiazides. Anticholinergic agents (e.g. atropine,
beperiden) may increase the bioavailability of thiazide-type diuretics by
decreasing gastrointestinal motility and stomach emptying rate. Thiazides
may increase the risk of adverse effects caused by amantadine. Thiazides may
reduce the renal excretion of cytotoxic medicinal products (e.g.
cyclophosphamide, methotrexate) and potentiate their myelosuppressive
Fertility, pregnancy and lactation
The use of AIIRAs is not recommended during the first trimester of pregnancy
(see section 4.4). The use of AIIRAs is contraindicated during the second and
third trimesters of pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following
exposure to ACE inhibitors during the first trimester of pregnancy has not
been conclusive; however a small increase in risk cannot be excluded. Whilst
there is no controlled epidemiological data on the risk with Angiotensin II
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs.
Unless continued AIIRA therapy is considered essential, patients planning
pregnancy should be changed to alternative antihypertensive treatments which
have an established safety profile for use in pregnancy. When pregnancy is
diagnosed, treatment with AIIRAs should be stopped immediately, and, if
appropriate, alternative therapy should be started.
Exposure to AIIRA therapy during the second and third trimesters is known to
induce human 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).
There is limited experience with hydrochlorothiazide during pregnancy,
especially during the first trimester. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Based on the pharmacological
mechanism of action of hydrochlorothiazide its use during the second and
third trimester may compromise foeto-placental perfusion and may cause
foetal and neonatal effects like icterus, disturbance of electrolyte balance and
Hydrochlorothiazide should not be used for gestational oedema, gestational
hypertension or preeclampsia due to the risk of decreased plasma volume and
placental hypoperfusion, without a beneficial effect on the course of the
Hydrochlorothiazide should not be used for essential hypertension in pregnant
women except in rare situations where no other treatment could be used.
Because no information is available regarding the use of Irbesartan/
Hydrochlorothiazide during breast-feeding, Irbesartan/ Hydrochlorothiazide is
not recommended and alternative treatments with better established safety
profiles during breast-feeding are preferable, especially while nursing a
newborn or preterm infant.
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in
high doses causing intense diuresis can inhibit the milk production. The use of
Irbesartan + Hydrochlorothiazide during breast feeding is not recommended. If
Irbesartan + Hydrochlorothiazide is used during breast feeding, doses should
be kept as low as possible.
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 is unlikely to affect this ability. When driving vehicles or
operating machines, it should be taken into account that occasionally dizziness
or weariness may occur during treatment of hypertension.
Irbesartan/hydrochlorothiazide combination: Among 898 hypertensive patients
who received various doses of irbesartan/hydrochlorothiazide (range: 37.5
mg/6.25 mg to 300 mg/25 mg) in placebo-controlled trials, 29.5% of the
patients experienced adverse reactions. The most commonly reported ADRs
were dizziness (5.6%), fatigue (4.9%), nausea/vomiting (1.8%), and abnormal
urination (1.4%). In addition, increases in blood urea nitrogen (BUN) (2.3%),
creatine kinase (1.7%) and creatinine (1.1%) were also commonly observed in
Table 1 gives the adverse reactions observed from spontaneous reporting
and in placebo-controlled trials.
The frequency of adverse reactions listed below is defined using the following
convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon
(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).
Within each frequency grouping, undesirable effects are presented in order of
Table 1: Adverse Reactions in Placebo-Controlled Trials and Spontaneous
Nervous system disorders:
increases in blood urea
nitrogen (BUN), creatinine
and creatine kinase
decreases in serum
potassium and sodium
Ear and labyrinth
Respiratory, thoracic and
Metabolism and nutrition
General disorders and
Immune system disorders:
Renal and urinary
impaired renal function
including isolated cases of
renal failure in patients at
risk (see section 4.4)
cases of hypersensitivity
reactions such as
angioedema, rash, urticaria
angioedema, rash, urticaria
hepatitis, abnormal liver
sexual dysfunction, libido
Reproductive system and
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. Tables 2 and 3 below
detail the adverse reactions reported with the individual components of
Table 2: Adverse reactions reported with the use of irbesartan alone
General disorders and
Table 3: Adverse reactions (regardless of relationship to medicinal product)
reported with the use of hydrochlorothiazide alone
(including hypokalaemia and
hyponatraemia, see section
Blood and lymphatic
Nervous system disorders:
Respiratory, thoracic and
Renal and urinary
Skin and subcutaneous
General disorders and
increases in cholesterol and
aplastic anaemia, bone
vertigo, paraesthesia, lightheadedness, restlessness
transient blurred vision,
respiratory distress (including
pneumonitis and pulmonary
gastric irritation, sialadenitis,
loss of appetite
interstitial nephritis, renal
anaphylactic reactions, toxic
necrotizing angitis (vasculitis,
reactivation of cutaneous
weakness, muscle spasm
The dose dependent adverse events of hydrochlorothiazide (particularly
electrolyte disturbances) may increase when titrating the hydrochlorothiazide.
No specific information is available on the treatment of overdose with
Irbesartan/ Hydrochlorothiazide. The patient should be closely monitored, and
the treatment should be symptomatic and supportive. Management depends on
the time since ingestion and the severity of the symptoms. Suggested measures
include induction of emesis and/or gastric lavage. Activated charcoal may be
useful in the treatment of overdose. Serum electrolytes and creatinine should
be monitored frequently. If hypotension occurs, the patient should be placed in
a supine position, with salt and volume replacements given quickly.
The most likely manifestations of irbesartan overdose are expected to be
hypotension and tachycardia; bradycardia might also occur.
Overdose with hydrochlorothiazide is associated with electrolyte depletion
(hypokalaemia, hypochloremia, hyponatraemia) and dehydration resulting
from excessive diuresis. The most common signs and symptoms of overdose
are nausea and somnolence. Hypokalaemia may result in muscle spasms
and/or accentuate cardiac arrhythmias associated with the concomitant use of
digitalis glycosides or certain anti-arrhythmic medicinal products.
Irbesartan is not removed by haemodialysis. The degree to which
hydrochlorothiazide is removed by haemodialysis has not been established.
Pharmacotherapeutic group: angiotensin-II antagonists and diuretics
ATC code: C09DA04.
Irbesartan/ Hydrochlorothiazide is a combination of an angiotensin-II receptor
antagonist, irbesartan, and a thiazide diuretic, hydrochlorothiazide. The
combination of these ingredients has an additive antihypertensive effect,
reducing blood pressure to a greater degree than either component alone.
Irbesartan is a potent, orally active, selective angiotensin-II receptor (AT1
subtype) antagonist. It is expected to block all actions of angiotensin-II
mediated by the AT1 receptor, regardless of the source or route of synthesis of
angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors
results in increases in plasma renin levels and angiotensin-II levels, and a
decrease in plasma aldosterone concentration. Serum potassium levels are not
significantly affected by irbesartan alone at the recommended doses in patients
without risk of electrolyte imbalance (see sections 4.4 and 4.5). Irbesartan
does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II
and also degrades bradykinin into inactive metabolites. Irbesartan does not
require metabolic activation for its activity.
Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive
effect of thiazide diuretics is not fully known. Thiazides affect the renal
tubular mechanisms of electrolyte reabsorption, directly increasing excretion
of sodium and chloride in approximately equivalent amounts. The diuretic
action of hydrochlorothiazide reduces plasma volume, increases plasma renin
activity, increases aldosterone secretion, with consequent increases in urinary
potassium and bicarbonate loss, and decreases in serum potassium.
Presumably through blockade of the renin-angiotensin-aldosterone system, coadministration 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-tomoderate 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 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 150 mg/12.5 mg and Irbesartan/ Hydrochlorothiazide 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 longterm follow-up studies, the effect of irbesartan/hydrochlorothiazide was
maintained for over one year. Although not specifically studied with the
Irbesartan/ Hydrochlorothiazide, 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,
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
Efficacy and safety of Irbesartan/ Hydrochlorothiazide 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
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,
Concomitant administration of hydrochlorothiazide and
irbesartan has no effect on the pharmacokinetics of either
Irbesartan and hydrochlorothiazide are orally active agents and do not require
biotransformation for their activity. Following oral administration of
Irbesartan/ Hydrochlorothiazide, the absolute oral bioavailability is 60-80%
and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does
not affect the bioavailability of Irbesartan/ Hydrochlorothiazide. Peak plasma
concentration occurs at 1.5-2 hours after oral administration for irbesartan
and 1-2.5 hours for hydrochlorothiazide.
Plasma protein binding of irbesartan is approximately 96%, with negligible
binding to cellular blood components. The volume of distribution for
irbesartan is 53-93 litres. Hydrochlorothiazide is 68% protein-bound in the
plasma, and its apparent volume of distribution is 0.83-1.14 l/kg.
Irbesartan exhibits linear and dose proportional pharmacokinetics over the
dose range of 10 to 600 mg. A less than proportional increase in oral
absorption at doses beyond 600 mg was observed; the mechanism for this is
unknown. The total body and renal clearance are 157-176 and 3.0-3.5 ml/min,
respectively. The terminal elimination half-life of irbesartan is 11-15 hours.
Steady-state plasma concentrations are attained within 3 days after initiation of
a once-daily dosing regimen. Limited accumulation of irbesartan (< 20%) is
observed in plasma upon repeated once-daily dosing. In a study, somewhat
higher plasma concentrations of irbesartan were observed in female
hypertensive patients. However, there was no difference in the half-life and
accumulation of irbesartan. No dosage adjustment is necessary in female
patients. Irbesartan AUC and Cmax values were also somewhat greater in
elderly subjects (≥ 65 years) than those of young subjects (18-40 years).
However the terminal half-life was not significantly altered. No dosage
adjustment is necessary in elderly patients. The mean plasma half-life of
hydrochlorothiazide reportedly ranges from 5-15 hours.
Following oral or intravenous administration of 14C irbesartan, 80-85% of the
circulating plasma radioactivity is attributable to unchanged irbesartan.
Irbesartan is metabolised by the liver via glucuronide conjugation and
oxidation. The major circulating metabolite is irbesartan glucuronide
(approximately 6%). In vitro studies indicate that irbesartan is primarily
oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has
negligible effect. Irbesartan and its metabolites are eliminated by both biliary
and renal pathways. After either oral or intravenous administration of 14C
irbesartan, about 20% of the radioactivity is recovered in the urine, and the
remainder in the faeces. Less than 2% of the dose is excreted in the urine as
unchanged irbesartan. Hydrochlorothiazide is not metabolized but is
eliminated rapidly by the kidneys. At least 61% of the oral dose is eliminated
unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not
the blood-brain barrier, and is excreted in breast milk.
Renal impairment: in patients with renal impairment or those undergoing
haemodialysis, the pharmacokinetic parameters of irbesartan are not
significantly altered. Irbesartan is not removed by haemodialysis. In
patients with creatinine clearance < 20 ml/min, the elimination half-life of
hydrochlorothiazide was reported to increase to 21 hours.
Hepatic impairment: in patients with mild to moderate cirrhosis, the
pharmacokinetic parameters of irbesartan are not significantly altered. Studies
have not been performed in patients with severe hepatic impairment.
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,
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
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
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
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
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.
List of excipients
Sodium Starch Glycolate (Type A)
Silica Colloidal Anhydrous
Sodium stearyl fumarate
Titanium dioxide (E171)
Iron oxide yellow (E172)
Iron oxide red (E172)
Special precautions for storage
Store below 30˚C.
Nature and contents of container
Tablets are available in Polyamide/Aluminium/PVC/Aluminium blister pack
and white opaque HDPE bottle with white opaque polypropylene closure pack.
Blister pack: 1, 14, 28, 30, 56, 90, 98, 100 & 500 tablets
Bottle pack: 30 & 90 tablets
Not all pack sizes may be marketed.
Special precautions for disposal
Any unused product or waste material should be disposed of in accordance
with local requirements.
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MARKETING AUTHORISATION NUMBER(S)
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
DATE OF REVISION OF THE TEXT
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