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IRBESARTAN AND HYDROCHLOROTHIAZIDE MILPHARM 300 MG/ 25 MG FILM-COATED TABLETS

Active substance(s): HYDROCHLOROTHIAZIDE / IRBESARTAN / HYDROCHLOROTHIAZIDE / IRBESARTAN / HYDROCHLOROTHIAZIDE / IRBESARTAN

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Irbesartan and Hydrochlorothiazide Milpharm 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 256.50 mg of lactose monohydrate.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet.
Pink coloured film-coated biconvex oval shaped tablets, debossed with “H 37” on one
side and plain on other side. The size is 17.7 mm X 9.6 mm.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment of essential hypertension.
This fixed dose combination is indicated in adult patients whose blood pressure is not
adequately
controlled on irbesartan or hydrochlorothiazide alone (see section 5.1).

4.2

Posology and method of administration
Posology
Irbesartan/ Hydrochlorothiazide 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 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
mg/12.5 mg.

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
section 4.5).
Special Populations
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.

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)



Severe renal impairment (creatinine clearance < 30 ml/min)



Refractory hypokalaemia, hypercalcaemia



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/ Hydrochlorothiazide.
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, 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 with caution.





4.4

Second and third trimesters of pregnancy (see sections 4.4 and 4.6)

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, 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 is not recommended.
Metabolic and endocrine effects: thiazide therapy may impair glucose tolerance. In
diabetic patients
dosage adjustments of insulin or oral hypoglycemic agents may be required. Latent
diabetes mellitus
may become manifest during thiazide therapy.
Increases in cholesterol and triglyceride levels have been associated with thiazide
diuretic therapy;
however at the 12.5 mg dose contained in Irbesartan/ Hydrochlorothiazide, 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
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 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 readministration of the diuretic is deemed necessary, it is recommended to protect
exposed areas to the sun or to artificial UVA.
Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated
during pregnancy. Unless continued AIIRA therapy is considered essential, patients
planning pregnancy should be changed to alternative antihypertensive treatments
which have an established safety profile for use in pregnancy. When pregnancy is
diagnosed, treatment with AIIRAs should be stopped immediately, and, if
appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Lactose: this medicinal product contains lactose. Patients with rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption should not take this medicinal product.

4.5

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 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 is
administered with medicinal products affected by serum potassium disturbances (e.g.
digitalis glycosides, antiarrhythmics).
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are
administered simultaneously with non-steroidal anti- inflammatory drugs (i.e.
selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective
NSAIDs), attenuation of the antihypertensive effect may occur. As with ACE
inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an
increased risk of worsening of renal function, including possible acute renal failure,
and an increase in serum potassium, especially in patients with poor pre-existing renal
function. The combination should be administered with caution, especially in the
elderly. Patients should be adequately hydrated and consideration should be given to
monitoring renal function after initiation of concomitant therapy, and periodically
thereafter.
Additional information on irbesartan interactions: in clinical studies, the
pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartan is
mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No
significant pharmacokinetic or pharmacodynamic interactions were observed when
irbesartan was coadministered with warfarin, a medicinal product metabolised by
CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic
of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not
altered by co-administration of irbesartan.
Additional information on hydrochlorothiazide interactions: when administered
concurrently, the following medicinal products may interact with thiazide diuretics:
Alcohol: potentiation of orthostatic hypotension may occur;

Antidiabetic medicinal products (oral agents and insulins): dosage adjustment of the
antidiabetic medicinal product may be required (see section 4.4);
Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is impaired
in the presence of anionic exchange resins. Irbesartan/ Hydrochlorothiazide should be
taken at least one hour before or four hours after these medications;
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be
increased;
Digitalis glycosides: thiazide induced hypokalaemia or hypomagnaesemia favour the
onset of digitalis-induced cardiac arrhythmias (see section 4.4);
Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal antiinflammatory drug may reduce the diuretic, natriuretic and antihypertensive effects of
thiazide diuretics in some patients;
Pressor amines (e.g. noradrenaline): the effect of pressor amines may be decreased,
but not sufficiently to preclude their use;
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): the effect of
nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide;
Antigout medicinal products: dosage adjustments of antigout medicinal products may
be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase
in dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of
thiazide diuretics may increase the incidence of hypersensitivity reactions to
allopurinol;
Calcium salts: thiazide diuretics may increase serum calcium levels due to decreased
excretion. If calcium supplements or calcium sparing medicinal products (e.g. vitamin
D therapy) must be prescribed, serum calcium levels should be monitored and
calcium dosage adjusted accordingly;
Carbamazepine: concomitant use of carbamazepine and hydrochlorothiazide has been
associated with the risk of symptomatic hyponatraemia. Electrolytes should be
monitored during concomitant use. If possible, another class of diuretics should be
used;
Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be
enhanced by thiazides. Anticholinergic agents (e.g. atropine, beperiden) may increase
the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility
and stomach emptying rate. Thiazides may increase the risk of adverse effects caused
by amantadine. Thiazides may reduce the renal excretion of cytotoxic medicinal

products (e.g. cyclophosphamide, methotrexate) and potentiate their
myelosuppressive effects.

4.6

Fertility, pregnancy and lactation
Pregnancy:
Irbesartan
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).
Hydrochlorothiazide
There is limited experience with hydrochlorothiazide during pregnancy,
especially during the first trimester. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Based on the pharmacological
mechanism of action of hydrochlorothiazide its use during the second and
third trimester may compromise foeto-placental perfusion and may cause
foetal and neonatal effects like icterus, disturbance of electrolyte balance and
thrombocytopenia.
Hydrochlorothiazide should not be used for gestational oedema, gestational
hypertension or preeclampsia due to the risk of decreased plasma volume and
placental hypoperfusion, without a beneficial effect on the course of the
disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant
women except in rare situations where no other treatment could be used.

Breast-feeding:
Irbesartan
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
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.

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 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.

Undesirable effects
Irbesartan/hydrochlorothiazide combination: Among 898 hypertensive patients who
received various doses of irbesartan/hydrochlorothiazide (range: 37.5 mg/6.25 mg to
300 mg/25 mg) in placebo-controlled trials, 29.5% of the patients experienced
adverse reactions. The most commonly reported ADRs were dizziness (5.6%), fatigue
(4.9%), nausea/vomiting (1.8%), and abnormal urination (1.4%). In addition,
increases in blood urea nitrogen (BUN) (2.3%), creatine kinase (1.7%) and creatinine
(1.1%) were also commonly observed in the trials.
Table 1 gives the adverse reactions observed from spontaneous reporting and in
placebo-controlled trials.
The frequency of adverse reactions listed below is defined using the following
convention: very common ( 1/10); common ( 1/100 to < 1/10); uncommon (
1/1,000 to < 1/100); rare ( 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within
each frequency grouping, undesirable effects are presented in order of decreasing
seriousness.









4.8

Table 1: Adverse Reactions in Placebo-Controlled Trials and Spontaneous Reports
Investigations:

Common:

increases in blood
urea nitrogen

(BUN), creatinine
and creatine
kinase
Uncommon:

decreases in
serum potassium
and sodium

Cardiac disorders:

Uncommon:

syncope,
hypotension,
tachycardia,
oedema

Nervous system
disorders:

Common:

dizziness

Uncommon:

orthostatic
dizziness

Not known:

headache

Ear and labyrinth
disorders:

Not known:

tinnitus

Respiratory, thoracic
and mediastinal
disorders:

Not known:

cough

Gastrointestinal
disorders:

Common:

nausea/vomiting

Uncommon:

diarrhoea

Not known:

dyspepsia,
dysgeusia

Common:

abnormal
urination

Not known:

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

Uncommon:

swelling
extremity

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

Not known:

cases of

Renal and urinary
disorders:

Musculoskeletal and
connective tissue
disorders:

disorders:

hypersensitivity
reactions such as
angioedema, rash,
urticaria

Hepatobiliary
disorders:

Uncommon

jaundice

Not known:

angioedema, rash,
urticaria hepatitis,
abnormal liver
function

Reproductive system
and breast disorders

Uncommon:

sexual
dysfunction,
libido changes

Additional information on individual components: in addition to the adverse reactions
listed above for the combination product, other adverse reactions previously reported
with one of the individual components may be potential adverse reactions with
Irbesartan/ Hydrochlorothiazide. Tables 2 and 3 below detail the adverse reactions
reported with the individual components of Irbesartan/ Hydrochlorothiazide.
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/agranulocyt
osis, haemolytic
anaemia, leucopenia,
thrombocytopenia

Nervous system
disorders:

Not
known:

vertigo, paraesthesia,
light-headedness,
restlessness

Eye disorders:

Not

transient blurred vision,

known:

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
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. 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 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-angiotensinaldosterone 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 placebocorrected 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 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 12 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, 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 reninangiotensin 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 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, 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.

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. 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
Sodium Starch Glycolate (Type A)
Povidone K30

Silica Colloidal Anhydrous
Talc
Sodium stearyl fumarate
Tablet coat:
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol 4000
Iron oxide red (E172)
Iron oxide black (E172)

6.2

Incompatibilities
Not applicable

6.3

Shelf life
2 years.

6.4

Special precautions for storage
Store below 30˚C.

6.5

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.
Pack size:
Blister pack: 1, 14, 28, 30, 56, 90, 98, 100 & 500 tablets
Bottle pack: 30 & 90 tablets
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
Milpharm Limited
Ares Block
Odyssey Business Park
West End Road
Ruislip HA4 6QD
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 16363/0305

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
13/09/2012

10

DATE OF REVISION OF THE TEXT
13/09/2012

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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