Irbesartan 300mg Hydrochlorothiazide 12.5mg tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Irbesartan; Hydrochlorothiazide
Available from:
Mylan
ATC code:
C09DA04
INN (International Name):
Irbesartan; Hydrochlorothiazide
Dosage:
300mg ; 12.5mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 02050502; GTIN: 5016695005263
Authorization number:
PL 04569/1293

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Object 1

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

Tablet.

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

Posology

Irbesartan/Hydrochlorothiazide Mylan can be taken once daily.

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 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).

Special Populations

Renal impairment:

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).

Hepatic impairment:

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).

Elderly:

No dosage adjustment of Irbesartan/Hydrochlorothiazide Mylan is necessary in elderly.

Paediatric population:

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.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or to other

sulfonamide-derived substances (hydrochlorothiazide is a sulfonamide-derived substance)

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

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

Refractory hypokalaemia, hypercalcaemia

Severe hepatic impairment, biliary cirrhosis and cholestasis

The concomitant use of Irbesartan/Hydrochlorothiazide Mylan with aliskiren-containing products is

contraindicated in patients with diabetes mellitus or renal impairment (GFR) < 60 ml/min/1.73 m

) (see

sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Hypotension-Volume-depleted patients:

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

diabetic nephropathy.

Hepatic impairment:

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver

disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. There is no

clinical experience with Irbesartan/Hydrochlorothiazide 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.

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 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

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 tablets, 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 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

parathyroid function.

Thiazides have been shown to increase the urinary excretion of magnesium, which may result in

hypomagnaesaemia.

Lithium:

The combination of lithium and Irbesartan/Hydrochlorothiazide Mylan is not recommended (see section

4.5).

Anti-doping test:

Hydrochlorothiazide contained in this medicinal product could produce a positive analytic result in an

anti-doping test.

General:

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-

angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal

disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or

angiotensin II receptor antagonists that affect this system has been associated with acute hypotension,

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

diuretics.

Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If

photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-

administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun

or to artificial UVA.

Pregnancy:

Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless

continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to

alternative antihypertensive treatments which have an established safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if

appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Acute Myopia and Secondary Acute Angle-Closure Glaucoma:

Sulfonamide drugs or sulfonamide derivative drugs can cause an idiosyncratic reaction, resulting in

transient myopia and acute angle-closure glaucoma. While hydrochlorothiazide is a sulfonamide, only

isolated cases of acute angle-closure glaucoma have been reported so far with hydrochlorothiazide.

Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours

to weeks of drug initiation.

Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to

discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be

considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-

closure glaucoma may include a history of sulfonamide or penicillin allergy (see section 4.8).

Lactose:

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).

Aliskiren-containing products:

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

ml/min/1.73 m

) 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).

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 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,

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 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

Pregnancy

Angiotensin II Receptor Antagonists (AIIRAs):

The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The use

of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and

4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors

during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be

excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor

Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is

considered essential, patients planning pregnancy should be changed to alternative antihypertensive

treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed,

treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be

started.

Exposure to AIIRA therapy during the second and third trimesters is known to induce human 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.

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.

Breast-feeding

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:

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.

Fertility

Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducing the

first signs of parental toxicity (see section 5.3).

4.7 Effects on ability to drive and use machines

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

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%), 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:

Not known:

cases of hypersensitivity reactions

such as angioedema, rash, urticaria

Metabolism and nutrition disorders

Not known:

hyperkalaemia

Nervous system disorders:

Common:

dizziness

Uncommon:

orthostatic dizziness

Not known:

headache

Ear and labyrinth disorders:

Not known:

tinnitus

Cardiac disorders:

Uncommon:

syncope, hypotension, tachycardia,

oedema

Vascular disorders:

Uncommon:

flushing

Respiratory, thoracic and mediastinal

disorders:

Not known:

cough

Gastrointestinal disorders:

Common:

nausea/vomiting

Uncommon:

diarrhoea

Not known:

dyspepsia, dysgeusia

Hepatobiliary disorders:

Uncommon:

jaundice

Not known:

hepatitis, abnormal liver function

Musculoskeletal and connective tissue

disorders:

Uncommon:

swelling extremity

Not known:

arthralgia, myalgia

Renal and urinary disorders:

Common:

abnormal urination

Not known:

impaired renal function including

isolated cases of renal failure in

patients at risk (see section 4.4)

Reproductive system and breast

disorders

Uncommon:

sexual dysfunction, libido changes

General disorders and administration

site conditions:

Common:

fatigue

Investigations:

Common:

increases in blood urea nitrogen

(BUN), creatinine and creatinine

kinase

Uncommon:

decreases in serum potassium and

sodium

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:

Not known:

thrombocytopenia

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

Blood and lymphatic system disorders:

Not known

aplastic anaemia, bone marrow

depression,

neutropenia/agranulocytosis,

haemolytic anaemia, leucopenia,

thrombocytopenia

Psychiatric disorders:

Not known:

depression, sleep disturbances

Nervous system disorders:

Not known:

vertigo, paraesthesia, light-headedness,

restlessness

Eye disorders:

Not known:

transient blurred vision, xanthopsia,

acute myopia and secondary acute

angle-closure glaucoma

Cardiac disorders:

Not known:

cardiac arrhythmias

Vascular disorders:

Not known:

postural hypotension

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

Hepatobiliary disorders:

Not known:

jaundice (intrahepatic cholestatic

jaundice)

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

Renal and urinary disorders:

Not known:

interstitial nephritis, renal dysfunction,

General disorders and administration site

conditions:

Not known:

fever

Investigations:

Not known:

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.

4.9 Overdose

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

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,

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:

C09DA04.

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

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 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

blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular

disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D

was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and

mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared

to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also

relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in

patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was

a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an

angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease,

cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse

outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group

than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia,

hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the

placebo group.

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.

Absorption

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.

Distribution

Plasma protein binding of irbesartan is approximately 96%, with negligible binding to cellular blood

components. The volume of distribution for irbesartan is 53-93 litres. 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

breast milk.

Biotransformation

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.

Elimination

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.

Gender

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.

Elderly

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.

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.

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.

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

Cellulose, microcrystalline (E460)

Silica, colloidal anhydrous

Sodium laurilsulfate

Starch pregelatinised (maize)

Magnesium stearate (E470b)

Povidone (K-90)

Lactose monohydrate

Croscarmellose sodium

Quinoline yellow Al lake (E104)

Iron oxide red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

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

requirements.

7. Marketing authorisation holder

Generics [UK] Limited t/a Mylan,

Station Close, Potters Bar,

Hertfordshire, EN6 1TL,

United Kingdom.

8. Marketing authorisation number(s)

PL 04569/1293

9. Date of first authorisation/renewal of the authorisation

21/01/2013

10. Date of revision of the text

September 2016

Company Contact Details

Generics UK T/A Mylan

Address

Building 4, Trident Place, Mosquito Way, Hatfield, Hertfordshire, AL10 9UL

Telephone

+44 (0)1707 853 000

Medical Information Direct Line

+44 (0)1707 853 000

Customer Care direct line

+44 (0)1707 853 000 select option 2

Stock Availability

+44 (0)1707 853 000 select option 2

http://www.mylan.com

+44 (0)1707 261 803

Medical Information e-mail

[email

protected]

Medical Information Fax

+44 (0)1707 261 803

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