United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)
Irbesartan/Hydrochlorothiazide Mylan 300
mg/12.5 mg tablets
Summary of Product Characteristics Updated 06-Sep-2017 | Generics UK T/A Mylan
1. Name of the medicinal product
Irbesartan/Hydrochlorothiazide Mylan 300 mg/12.5 mg tablets
2. Qualitative and quantitative composition
300 mg/12.5 mg tablets
Each tablet contains 300 mg of irbesartan and 12.5 mg of hydrochlorothiazide.
Excipient with known effect
Each tablet contains 120 mg of lactose (as lactose monohydrate).
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
300 mg/12.5 mg tablets
A peach, 0.3400” x 0.7350” (8.64 mm x 18.67 mm) oval, biconvex tablet debossed with “M” on one side
of the tablet and “I34” 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 Mylan can be taken once daily.
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
Irbesartan/Hydrochlorothiazide Mylan 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 Mylan 300 mg/12.5 mg may be administered in patients insufficiently
controlled by irbesartan 300 mg or by Irbesartan/Hydrochlorothiazide Mylan 150 mg/12.5 mg.
Irbesartan/Hydrochlorothiazide Mylan 300 mg/25 mg may be administered in patients insufficiently
controlled by Irbesartan/Hydrochlorothiazide Mylan 300 mg/12.5 mg.
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended.
When necessary, Irbesartan/Hydrochlorothiazide Mylan may be administered with another
antihypertensive medicinal product (see sections 4.3, 4.4, 4.5 and 5.1).
Due to the hydrochlorothiazide component, Irbesartan/Hydrochlorothiazide Mylan 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).
Irbesartan/Hydrochlorothiazide Mylan 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 Mylan is necessary in patients with mild to moderate hepatic
impairment (see section 4.3).
No dosage adjustment of Irbesartan/Hydrochlorothiazide Mylan is necessary in elderly.
Irbesartan/Hydrochlorothiazide Mylan 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.
Irbesartan/Hydrochlorothiazide Mylan may be taken with or without food.
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or to other
sulfonamide-derived substances (hydrochlorothiazide is a sulfonamide-derived substance)
Second and third trimesters of pregnancy (see sections 4.4 and 4.6)
Severe renal impairment (creatinine clearance < 30 ml/min)
Refractory hypokalaemia, hypercalcaemia
Severe hepatic impairment, biliary cirrhosis and cholestasis
The concomitant use of Irbesartan/Hydrochlorothiazide Mylan with aliskiren-containing products is
contraindicated in patients with diabetes mellitus or renal impairment (GFR) < 60 ml/min/1.73 m
sections 4.5 and 5.1).
4.4 Special warnings and precautions for use
Irbesartan/hydrochlorothiazide tablets have 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 Mylan.
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 tablets, a similar effect should be anticipated.
Renal impairment and kidney transplantation:
When Irbesartan/Hydrochlorothiazide Mylan 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 tablets in patients with a recent kidney
transplantation. Irbesartan/Hydrochlorothiazide Mylan should not be used in patients with severe renal
impairment (creatinine clearance < 30 ml/min) (see section 4.3). Thiazide diuretic-associated azotemia
may occur in patients with impaired renal function. No dosage adjustment is necessary in patients with
renal impairment whose creatinine clearance is ≥ 30 ml/min. However, in patients with mild to moderate
renal impairment (creatinine clearance ≥ 30 ml/min but < 60 ml/min) this fixed dose combination should
be administered with caution.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS):
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren
increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal
failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor
blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist
supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with
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 Mylan 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.
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 Mylan tablets 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
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy;
however at the 12.5 mg dose contained in irbesartan/hydrochlorothiazide tablets, minimal or no effects
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide
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 hypochloraemic 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 Mylan 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 Mylan (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
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in
The combination of lithium and Irbesartan/Hydrochlorothiazide Mylan is not recommended (see section
Hydrochlorothiazide contained in this medicinal product could produce a positive analytic result in an
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,
azotaemia, oliguria, or rarely acute renal failure (see section 4.5). As with any antihypertensive agent,
excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic 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
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.
Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless
continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to
alternative antihypertensive treatments which have an established safety profile for use in pregnancy.
When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if
appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Acute Myopia and Secondary Acute Angle-Closure Glaucoma:
Sulfonamide drugs or sulfonamide derivative drugs can cause an idiosyncratic reaction, resulting in
transient myopia and acute angle-closure glaucoma. While hydrochlorothiazide is a sulfonamide, only
isolated cases of acute angle-closure glaucoma have been reported so far with hydrochlorothiazide.
Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours
to weeks of drug initiation.
Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to
discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be
considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-
closure glaucoma may include a history of sulfonamide or penicillin allergy (see section 4.8).
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 Mylan 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).
The combination of Irbesartan/Hydrochlorothiazide Mylan with aliskiren-containing medicinal products
is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment (GFR <60
) and is not recommended in other patients.
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS)
through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated
with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal
function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections
4.3, 4.4 and 5.1).
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 Mylan. Therefore, the
combination of lithium and Irbesartan/Hydrochlorothiazide Mylan 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 Mylan is
administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides,
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
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 Mylan 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 hypomagnesaemia favour the onset of digitalis-
induced cardiac arrhythmias (see section 4.4);
Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory drug may
reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients;
Pressor amines (e.g. noradrenaline): the effect of pressor amines may be decreased, but not sufficiently
to preclude their use;
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): the effect of nondepolarizing skeletal
muscle relaxants may be potentiated by hydrochlorothiazide;
Antigout medicinal products: dosage adjustments of antigout medicinal products may be necessary as
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or
sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence of
hypersensitivity reactions to allopurinol;
Calcium salts: thiazide diuretics may increase serum calcium levels due to decreased excretion. If
calcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be prescribed,
serum calcium levels should be monitored and calcium dosage adjusted accordingly;
Carbamazepine: concomitant use of carbamazepine and hydrochlorothiazide has been associated with the
risk of symptomatic hyponatraemia. Electrolytes should be monitored during concomitant use. If possible,
another class of diuretics should be used
Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by
thiazides. Anticholinergic agents (e.g. atropine, biperiden) 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
Angiotensin II Receptor Antagonists (AIIRAs):
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The use
of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and
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
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
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first
trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the
pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third
trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like
icterus, disturbance of electrolyte balance and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia
due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on
the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare
situations where no other treatment could be used.
Since Irbesartan/Hydrochlorothiazide Mylan 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.
Angiotensin II Receptor Antagonists (AIIRAs):
Because no information is available regarding the use of Irbesartan/Hydrochlorothiazide Mylan during
breast-feeding, Irbesartan/Hydrochlorothiazide Mylan is not recommended and alternative treatments
with better established safety profiles during breast-feeding are preferable, especially while nursing a
newborn or preterm infant.
It is unknown whether irbesartan or its metabolites are excreted in human milk.
Available pharmacodynamics/toxicological data in rats have shown excretion of irbesartan or its
metabolites in milk (for details see 5.3).
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 Mylan during breast
feeding is not recommended. If Irbesartan/Hydrochlorothiazide Mylan is used during breast feeding,
doses should be kept as low as possible.
Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducing the
first signs of parental toxicity (see section 5.3).
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. Based on its
pharmacodynamic properties, Irbesartan/Hydrochlorothiazide Mylan 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
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%), creatinine kinase (1.7%) and creatine (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).
Not known (cannot be estimated from the available data)
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1: Adverse Reactions in Placebo-Controlled Trials and Spontaneous Reports*
Immune system disorders:
cases of hypersensitivity reactions
such as angioedema, rash, urticaria
Metabolism and nutrition disorders
Nervous system disorders:
Ear and labyrinth disorders:
syncope, hypotension, tachycardia,
Respiratory, thoracic and mediastinal
hepatitis, abnormal liver function
Musculoskeletal and connective tissue
Renal and urinary disorders:
impaired renal function including
isolated cases of renal failure in
patients at risk (see section 4.4)
Reproductive system and breast
sexual dysfunction, libido changes
General disorders and administration
increases in blood urea nitrogen
(BUN), creatinine and creatinine
decreases in serum potassium 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 Mylan. Tables 2 and 3 below detail the adverse reactions reported with
the individual components.
Table 2: Adverse reactions reported with the use of irbesartan alone
Blood and lymphatic system disorders:
General disorders and administration site
Table 3: Adverse reactions (regardless of relationship to medicinal product) reported with the use of
Blood and lymphatic system disorders:
aplastic anaemia, bone marrow
haemolytic anaemia, leucopenia,
depression, sleep disturbances
Nervous system disorders:
vertigo, paraesthesia, light-headedness,
transient blurred vision, xanthopsia,
acute myopia and secondary acute
Respiratory, thoracic and mediastinal
respiratory distress (including
pneumonitis and pulmonary oedema)
pancreatitis, anorexia, diarrhoea,
constipation, gastric irritation,
sialadenitis, loss of appetite
jaundice (intrahepatic cholestatic
Skin and subcutaneous tissue disorders:
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
weakness, muscle spasm
Renal and urinary disorders:
interstitial nephritis, renal dysfunction,
General disorders and administration site
electrolyte imbalance (including
hypokalaemia and hyponatraemia, see
section 4.4), hyperuricaemia,
glycosuria, hyperglycaemia, increases
in cholesterol and triglycerides
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may
increase when titrating the hydrochlorothiazide.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are
asked to report any suspected adverse reactions via the internet at www.mhra.gov.uk/yellowcard.
No specific information is available on the treatment of overdose with irbesartan/hydrochlorothiazide
Mylan. 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
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,
hypochloraemia, 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, combinations, ATC code:
Irbesartan/Hydrochlorothiazide Mylan 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 (AT
subtype) antagonist. It is
expected to block all actions of angiotensin II mediated by the AT
receptor, regardless of the source or
route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT
) receptors results
in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma aldosterone
concentration. Serum potassium levels are not significantly affected by irbesartan alone at the
recommended doses in patients without risk of electrolyte imbalance (see sections 4.4 and 4.5). Irbesartan
does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also degrades
bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its activity.
Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive effect of thiazide diuretics
is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly
increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of
hydrochlorothiazide reduces plasma volume, increases plasma renin activity, increases aldosterone
secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum
potassium. Presumably through blockade of the renin-angiotensin-aldosterone system, co-administration
of irbesartan tends to reverse the potassium loss associated with these diuretics. With
hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at about 4 hours, while
the action persists for approximately 6-12 hours.
The combination of hydrochlorothiazide and irbesartan produces dose-related additive reductions in blood
pressure across their therapeutic dose ranges. The addition of 12.5 mg hydrochlorothiazide to 300 mg
irbesartan once daily in patients not adequately controlled on 300 mg irbesartan alone resulted in further
placebo-corrected diastolic blood pressure reductions at trough (24 hours post-dosing) of 6.1 mm Hg. The
combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide resulted in an overall placebo-
subtracted systolic/diastolic reductions of up to 13.6/11.5 mm Hg.
Limited clinical data (7 out of 22 patients) suggest that patients not controlled with the 300 mg/12.5 mg
combination may respond when uptitrated to 300 mg/25 mg. In these patients, an incremental blood
pressure lowering effect was observed for both systolic blood pressure (SBP) and diastolic blood pressure
(DBP) (13.3 and 8.3 mm Hg, respectively).
Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide gave systolic/diastolic mean
placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of 12.9/6.9 mm Hg in
patients with mild-to-moderate hypertension. Peak effects occurred at 3- 6 hours. When assessed by
ambulatory blood pressure monitoring, the combination 150 mg irbesartan and 12.5 mg
hydrochlorothiazide once daily produced consistent reduction in blood pressure over the 24 hours period
with mean 24 hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mm Hg. When measured
by ambulatory blood pressure monitoring, the trough to peak effects of irbesartan/hydrochlorothiazide
150 mg/12.5 mg tablets 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 tablets and
irbesartan/hydrochlorothiazide 300 mg/12.5 mg tablets, 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 tablets, 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 tablets, 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 tablets as initial therapy for severe hypertension
(defined as SeDBP ≥ 110 mmHg) was evaluated in a multicenter, randomized, double-blind, active-
controlled, 8-week, parallel-arm study. A total of 697 patients were randomized in a 2:1 ratio to either
irbesartan/hydrochlorothiazide 150 mg/12.5 mg or to irbesartan 150 mg and systematically forcetitrated
(before assessing the response to the lower dose) after one week to irbesartan/hydrochlorothiazide 300
mg/25 mg or irbesartan 300 mg, respectively.
The study recruited 58% males. The mean age of patients was 52.5 years, 13% were ≥ 65 years of age,
and just 2% were ≥ 75 years of age. Twelve percent (12%) of patients were diabetic, 34% were
hyperlipidemic and the most frequent cardiovascular condition was stable angina pectorisin 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 through 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.
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination
with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in
Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular
disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D
was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and
mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared
to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also
relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in
patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was
a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an
angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease,
cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse
outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group
than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia,
hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the
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
Following oral administration of irbesartan/hydrochlorothiazide tablets, the absolute oral bioavailability is
60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect the
bioavailability of irbesartan/hydrochlorothiazide tablets. 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. Limited accumulation of irbesartan
(< 20%) is observed in plasma upon repeated once-daily dosing. Steady-state plasma concentrations are
attained within 3 days after initiation of a once-daily dosing regimen.
Hydrochlorothiazide is 68% protein-bound in the plasma, and its apparent volume of distribution is 0.83-
1.14 l/kg. Hydrochlorothiazide crosses the placental but not the blood-brain barrier, and is excreted in
Following oral or intravenous administration of
C 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
C 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.
The terminal elimination half-life of irbesartan is 11-15 hours.
Hydrochlorothiazide is not metabolised but is eliminated rapidly by the kidneys. At least 61% of the oral
dose is eliminated unchanged within 24 hours.
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 C
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. The mean plasma half-life of hydrochlorothiazide reportedly ranges
from 5-15 hours.
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.
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
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
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
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.
There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In non-
clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day in
macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). At
very high doses (≥ 500 mg/kg/day) degenerative changes in the kidneys (such as interstitial nephritis,
tubular distention, basophilic tubules, increased plasma concentrations of urea and creatinine) were
induced by irbesartan in the rat and the macaque and are considered secondary to the hypotensive effects
of the medicinal product which led to decreased renal perfusion. Furthermore, irbesartan induced
hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥ 90 mg/kg/day, in macaques at ≥ 10
mg/kg/day). All of these changes were considered to be caused by the pharmacological action of
irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/hypertrophy of the renal
juxtaglomerular cells does not appear to have any relevance.
There was no evidence of mutagenicity, clastogenicity or carcinogenicity.
Fertility and reproductive performance were not affected in studies of male and female rats even at oral
doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including mortality at the
highest dose. No significant effects on the number of corpora lutea, implants, or live fetuses were
observed. Irbesartan did not affect survival, development, or reproduction of offspring. Studies in animals
indicate that the radiolabeled irbesartan is detected in rat and rabbit fetuses. Irbesartan is excreted in the
milk of lactating rats.
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation,
hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, abortion
or early resorption was noted at doses causing significant maternal toxicity, including mortality. No
teratogenic effects were observed in the rat or rabbit.
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
Cellulose, microcrystalline (E460)
Silica, colloidal anhydrous
Starch pregelatinised (maize)
Magnesium stearate (E470b)
Quinoline yellow Al lake (E104)
Iron oxide red (E172)
6.3 Shelf life
The in-use shelf life of the product when stored in HDPE bottles is 90 days.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
HDPE Bottles with PP screw caps containing 500 tablets
Amber/Aclar/PVC – Aluminium blisters of 14, 28, 30, 56, 90, 98, 100 tablets
Amber/Aclar/PVC – Aluminium perforated unit-dose blisters of 56 tablets
Amber/Aclar/PVC – Aluminium blister calendar pack of 28 tablets
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local
7. Marketing authorisation holder
Generics [UK] Limited t/a Mylan,
Station Close, Potters Bar,
Hertfordshire, EN6 1TL,
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
10. Date of revision of the text
Company Contact Details
Generics UK T/A Mylan
Building 4, Trident Place, Mosquito Way, Hatfield, Hertfordshire, AL10 9UL
+44 (0)1707 853 000
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