SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Irbesartan and Hydrochlorothiazide Bristol 300/12.5mg film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 300 mg of irbesartan and 12.5 mg of hydrochlorothiazide. Excipient with known effect:

Also contains 52 mg of lactose monohydrate.

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Film-coated tablet

300 mg/12.5: Light pink, oblong, biconvex film-coated tablets. The tablet dimensions are 17.5 mm x 9.4 mm.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of essential hypertension.

This fixed dose combination is indicated in adult patients whose blood pressure is not adequately controlled on irbesartan or hydrochlorothiazide alone (see section5.1).

4.2 Posology and method of administration

Posology

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 and Hydrochlorothiazide Bristol 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 and Hydrochlorothiazide Bristol 300 mg/12.5 mg may be administered in patients insufficiently controlled by irbesartan 300 mg or by Irbesartan and Hydrochlorothiazide Bristol 150 mg/12.5 mg.

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

Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended.

When necessary, this medicine 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, this medicine 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

This medicine is not indicated in patients with severe hepatic impairment. Thiazides should be used with caution in patients with impaired hepatic function. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment (see section 4.3).

ElderlyNo dosage adjustment of is necessary in older people.

Paediatric population

This medicine 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.

This medicine can be taken once daily, 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 and hydrochlorothiazide with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Hypotension - Volume-depleted patients: This medicine has been rarely associated with symptomatic hypotension in hypertensive patients without other risk factors for hypotension. Symptomatic hypotension may be expected to occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before initiating therapy with this medicine .

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 this medicine, a similar effect should be anticipated.

Renal impairment and kidney transplantation: When this medicine 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 and hydrochlorothiazide in patients with a recent kidney transplantation. This medicine 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 and hydrochlorothiazide in patients with hepatic impairment.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism: Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of this medicine 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 inthis medicine , minimal or no effects were reported. Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

Electrolyte imbalance: As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia, hyponatraemia, and hypochloremic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.

Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with irbesartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH. Conversely, due to the irbesartan component of this medicine 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 this medicine (see section 4.5).

There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatraemia. Chloride deficit is generally mild and usually does not require treatment.

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

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

Lithium: The combination of lithium and irbesartan and hydrochlorthiazide is not recommended (see section 4.5).

Anti-doping test: Hydrochlorothiazide contained in this medicinal product could produce a positive analytic result in an anti-doping test.

General: In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated with acute hypotension, azotemia, oliguria, or rarely acute renal failure (see section 4.5). As with any antihypertensive agent, excessive blood pressure decrease in patients with ischemic cardiopathy or ischemic cardiovascular disease could result in a myocardial infarction or stroke.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Acute Myopia and Secondary Acute Angle-Closure Glaucoma: Sulfonamide drugs or sulphonamide 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 this medicine 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 or ACE-inhibitors:

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 and hydrochlorothiazide Therefore, the combination of lithium and irbesartan and hydrochlorothiazide is not recommended (see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Medicinal products affecting potassium: The potassium-depleting effect of hydrochlorothiazide is attenuated by the potassium-sparing effect of irbesartan.

However, this effect of hydrochlorothiazide on serum potassium would be expected to be potentiated by other medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium). Conversely, based on the experience with the use of other medicinal products that blunt the renin-angiotensin system, concomitant use of potassium-sparing

diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin sodium) may lead to increases in serum potassium. Adequate monitoring of serum potassium in patients at risk is recommended (see section 4.4).

Medicinal products affected by serum potassium disturbances: Periodic monitoring of serum potassium is recommended when this medicine 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 preexisting renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

Additional information on irbesartan interactions: In clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan

have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of irbesartan.

Additional information on hydrochlorothiazide interactions: When administered concurrently, the following medicinal products may interact with thiazide diuretics:

Alcohol: Potentiation of orthostatic hypotension may occur;

Antidiabetic medicinal products (oral agents and insulins): Dosage adjustment of the antidiabetic medicinal product may be required (see section 4.4);

Colestyramine and Colestipol resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. This medicine should be taken at least one hour before or four hours after these medications;

Corticosteroids, ACTH: Electrolyte depletion, particularly hypokalaemia, may be increased;

Digitalis glycosides: Thiazide induced hypokalaemia or hypomagnaesemia favour the onset of digitalis-induced cardiac arrhythmias (see section 4.4);

Non-steroidal anti-inflammatory drugs: The administration of a non-steroidal antiinflammatory drug may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients;

Pressor amines (e.g. noradrenaline): The effect of pressor amines may be decreased, but not sufficiently to preclude their use;

Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): The effect of nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide;

Antigout medicinal products: Dosage adjustments of antigout medicinal products may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence

of hypersensitivity reactions to allopurinol;

Calcium salts: Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly;

Carbamazepine: Concomitant use of carbamazepine and hydrochlorothiazide has been associated with the risk of symptomatic hyponatraemia. Electrolytes should be monitored during concomitant use. If possible, another class of diuretics should be used;

Other interactions: The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides. Anticholinergic agents (e.g. atropine, beperiden) may increase the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides

may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

4.6 Fertility, pregnancy and lactation

Pregnancy:

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.

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 this medicine 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 and hydrochlorothiazide during breast-feeding, this medicine is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.

It is unknown whether irbesartan or its metabolites are excreted in human milk. Available pharmacodynamic/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 this medicine during breast feeding is not recommended. If this medicine 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, this medicine is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or weariness may occur during treatment of hypertension.

Undesirable effects

Irbesartan/hydrochlorothiazide combination:

Among 898 hypertensive patients who received various doses of irbesartan/hydrochlorothiazide (range: 37.5 mg/6.25 mg to 300 mg/25 mg) in placebo-controlled trials, 29.5% of the patients experienced adverse reactions. The most commonly reported ADRs were dizziness (5.6%), fatigue (4.9%), nausea/vomiting (1.8%), and abnormal urination (1.4%). In addition, increases in blood urea nitrogen (BUN) (2.3%), creatine kinase (1.7%) and creatinine (1.1%) were also commonly observed in the trials.

Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled trials.

The frequency of adverse reactions listed below is defined using the following convention: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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

System Organ Class	Frequency	Adverse reaction
Investigations	Common	increases in blood urea nitrogen (BUN), creatinine and creatine kinase
	Uncommon	decreases in serum potassium and sodium
Cardiac disorders	Uncommon	syncope, hypotension, tachycardia, oedema
Nervous system disorders	Common	dizziness
	Uncommon	orthostatic dizziness
	Not known	headache
Ear and labyrinth disorders	Not known	tinnitus
Respiratory, thoracic and mediastinal disorders	Not known	cough
Gastrointestinal disorders	Common	nausea/vomiting
	Uncommon	diarrhoea
	Not known	dyspepsia, dysgeusia
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)
Musculoskeletal and connective tissue disorders	Uncommon	swelling extremity
	Not known	arthralgia, myalgia
Metabolism and nutrition disorders	Not known	hyperkalaemia
Vascular disorders	Uncommon	flushing
General disorders and administration site conditions	Common	fatigue
Immune system	Not known	cases of hypersensitivity

disorders		reactions such as angioedema, rash, urticaria
Hepatobiliary disorders	Uncommon	jaundice
	Not known	hepatitis, abnormal liver function
Reproductive system and breast disorders	Uncommon	sexual dysfunction, libido changes

Additional information on individual components: In addition to the adverse reactions listed above for the combination product, other adverse reactions previously reported with one of the individual components may be potential adverse reactions with irbesartan and hydrochlorothiazide. Tables 2 and 3 below detail the adverse reactions reported with the individual components of irbesartan and hydrochlorothiazide.

Table 2: Adverse reactions reported with the use of irbesartan alone
System Organ Class	Frequency	Adverse reaction
General disorders and administration site conditions	Uncommon	chest pain

Table 3: Adverse reactions reported with the use of hydrochlorothiazide alone
System Organ Class	Frequency	Adverse reaction
Investigations	Not known	electrolyte imbalance (including hypokalaemia and hyponatraemia, see section 4.4), hyperuricaemia, glycosuria, hyperglycaemia, increases in cholesterol and triglycerides
Cardiac disorders	Not known	cardiac arrhythmias
Blood and lymphatic system disorders	Not known	aplastic anaemia, bone marrow depression, neutropenia/agranulocytosis, haemolytic anaemia, leucopenia, thrombocytopenia
Nervous system disorders		vertigo, paraesthesia, lightheadedness, restlessness
Eye disorders		transient blurred vision, xanthopsia, acute myopia and secondary acute angle-

		closure glaucoma
Respiratory, thoracic and mediastinal disorders		respiratory distress (including pneumonitis and pulmonary oedema)
Gastrointestinal disorders		pancreatitis, anorexia, diarrhoea, constipation, gastric irritation, sialadenitis, loss of appetite
Renal and urinary disorders		interstitial nephritis, renal dysfunction
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 disorders		weakness, muscle spasm
Vascular disorders		postural hypotension
General disorders and administration site conditions		fever
Hepatobiliary disorders		jaundice (intrahepatic cholestatic jaundice)
Psychiatric disorders		depression, sleep disturbances

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

No specific information is available on the treatment of overdose withthis medicine. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Management depends on the time since ingestion and the severity of the symptoms. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should

be placed in a supine position, with salt and volume replacements given quickly.

The most likely manifestations of irbesartan overdose are expected to be hypotension and tachycardia; bradycardia might also occur.

Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloremia, hyponatraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasms and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicinal products.

Irbesartan is not removed by haemodialysis. The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin-II antagonists, combinations ATC code: C09DA04.

This medicine is a combination of an angiotensin-II receptor antagonist, irbesartan, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.

Irbesartan is a potent, orally active, selective angiotensin-II receptor (AT1 subtype) antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors

results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at the recommended doses in patients without risk of electrolyte imbalance (see sections 4.4 and 4.5). Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its activity.

Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. Presumably through blockade of the renin-angiotensin-aldosterone system, 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 150 mg/12.5 mg were 100%. The trough to peak effects measured by cuff during office visits were 68% and 76% for irbesartan and hydrochlorothiazide 150 mg/12.5 mg and irbesartan and hydrochlorothiazide 300 mg/12.5 mg, respectively. These 24-hour effects were observed without excessive blood pressure lowering at peak and are consistent with safe and effective blood-pressure lowering over the once-daily dosing interval.

In patients not adequately controlled on 25 mg hydrochlorothiazide alone, the addition of irbesartan gave an added placebo-subtracted systolic/diastolic mean reduction of 11.1/7.2 mm Hg.

The blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide is apparent after the first dose and substantially present within 12 weeks, with the maximal effect occurring by 6- 8 weeks. In long-term follow-up studies, the effect of irbesartan/hydrochlorothiazide was maintained for over one year.

Although not specifically studied with the irbesartan and hydrochlorothiazide, rebound hypertension has not been seen with either irbesartan or hydrochlorothiazide.

The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality has not been studied. Epidemiological studies have shown that long term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.

There is no difference in response to irbesartan and hydrochlorothiazide, regardless of age or gender. As is the case with other medicinal products that affect the renin-angiotensin system, black hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches that of non-black patients.

Efficacy and safety of irbesartan and hydrochlorothiazide as initial therapy for severe hypertension (defined as SeDBP > 110 mmHg) was evaluated in a multicenter, randomized, double-blind, active-controlled, 8-week, parallel-arm study. A total of 697 patients were randomized in a 2:1 ratio to either

irbesartan/hydrochlorothiazide 150 mg/12.5 mg or to irbesartan 150 mg and systematically 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 pectoris in 3.5% of the participants.

The primary objective of this study was to compare the proportion of patients whose SeDBP was controlled (SeDBP < 90 mmHg) at Week 5 of treatment. Forty-seven percent (47.2%) of patients on the combination achieved 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. Following oral administration of irbesartan and hydrochlorothiazide, the absolute oral bioavailability is 60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect the bioavailability of irbesartan and hydrochlorothiazide. Peak plasma concentration occurs at 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for hydrochlorothiazide.

Plasma protein binding of irbesartan is approximately 96%, with negligible binding to cellular blood components. The volume of distribution for irbesartan is 53-93 litres. Hydrochlorothiazide is 68% protein-bound in the plasma, and its apparent volume of distribution is 0.83-1.14 l/kg.

Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. A less than proportional increase in oral absorption at doses beyond 600 mg was observed; themechanism for this is unknown. The total body and renal clearance are 157-176 and 3.0-3.5 ml/min,

respectively. The terminal elimination half-life of irbesartan is 11-15 hours. Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values were also somewhat greater in older 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 older people. The mean plasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hours.

Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or intravenous administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidneys. At least 61% of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier, and is excreted in breast milk.

Renal impairment: In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. In patients with creatinine clearance < 20 ml/min, the elimination half-life of hydrochlorothiazide was reported to increase to 21 hours.

Hepatic impairment: In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic impairment.

5.3 Preclinical safety data

Irbesartan/hydrochlorothiazide: The potential toxicity of the

irbesartan/hydrochlorothiazide combination after oral administration was evaluated in rats and macaques in studies lasting up to 6 months. There were no toxicological findings observed of relevance to human therapeutic use. The following changes, observed in rats and macaques receiving the irbesartan/hydrochlorothiazide combination at 10/10 and 90/90 mg/kg/day, were also seen with one of the two medicinal products alone and/or were secondary to decreases in blood pressure (no significant toxicologic interactions were observed):

•    kidney changes, characterized by slight increases in serum urea and creatinine, and hyperplasia/hypertrophy of the juxtaglomerular apparatus, which are a direct consequence of the interaction of irbesartan with the renin-angiotensin system;

•    slight decreases in erythrocyte parameters (erythrocytes, haemoglobin, haematocrit);

•    stomach discoloration, ulcers and focal necrosis of gastric mucosa were observed in few rats in a 6 months toxicity study at irbesartan 90 mg/kg/day, hydrochlorothiazide 90 mg/kg/day, and irbesartan/hydrochlorothiazide 10/10 mg/kg/day. These lesions were not observed in macaques;

• decreases in serum potassium due to hydrochlorothiazide and partly prevented when hydrochlorothiazide was given in combination with irbesartan.

Most of the above mentioned effects appear to be due to the pharmacological activity of irbesartan (blockade of angiotensin-II-induced inhibition of renin release, with stimulation of the renin-producing cells) and occur also with angiotensin converting enzyme inhibitors. These findings appear to have no relevance to the use of therapeutic doses of irbesartan/hydrochlorothiazide in humans.

No teratogenic effects were seen in rats given irbesartan and hydrochlorothiazide in combination at doses that produced maternal toxicity. The effects of the irbesartan/hydrochlorothiazide combination on fertility have not been evaluated in animal studies, as there is no evidence of adverse effect on fertility in animals or humans with either irbesartan or hydrochlorothiazide when administered alone. However, another angiotensin-II antagonist affected fertility parameters in animal studies when given alone. These findings were also observed with lower doses of this other angiotensin-II antagonist when given in combination with hydrochlorothiazide.

There was no evidence of mutagenicity or clastogenicity with the irbesartan/hydrochlorothiazide combination. The carcinogenic potential of irbesartan and hydrochlorothiazide in combination has not been evaluated in animal studies.

Irbesartan: There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In non-clinical safety studies, high doses of irbesartan (>

250 mg/kg/day in rats and > 100 mg/kg/day in macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). At very high doses (> 500 mg/kg/day) degenerative changes in the kidneys (such as interstitial nephritis, tubular distention, basophilic tubules, increased plasma concentrations of urea and creatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to the hypotensive effects of the medicinal product which led to decreased renal perfusion. Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at > 90 mg/kg/day, in macaques at > 10 mg/kg/day). All of these changes were considered to be caused by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. There was no evidence of mutagenicity, clastogenicity or carcinogenicity. 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

Tablet-core

Microcrystalline cellulose Pregelatinised maize starch Lactose monohydrate Poloxamer

Croscarmellose sodium Magnesium Stearate

Film-coating (300mg/12.5 mg)

Hypromellose Titanium dioxide (E171)

Microcrystalline cellulose Purified stearic acid Iron oxide red (E172)

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

24 months

6.4 Special precautions for storage

Do not store above 30°C.

Store in the original package in order to protect from light and moisture.

6.5 Nature and contents of container

White PVC/PCTFE / Aluminium and/or white PVC/PE/PVDC/ Aluminium blister packs of 14, 28, 56 or 98 tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Bristol Laboratories Ltd,

Unit 3, Canalside,

Northbridge Road, Berkhamsted,

Herts, HP4 1EG, UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 17907/0518

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

06/10/2015

10    DATE OF REVISION OF THE TEXT

06/10/2015