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 m2) (see sections 4.5 and 5.1).

4.4. Special warnings and precautions for use

Acute Respiratory Toxicity

Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS) have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, Irbesartan/Hydrochlorothiazide Mylan should be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.

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 azotaemia 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 is not recommended.

Metabolic and endocrine effects:

Thiazide therapy may impair glucose tolerance Latent diabetes mellitus may become manifest during thiazide therapy. Irbesartan may induce hypoglycaemia, particularly in diabetic patients. In patients treated with insulin or antidiabetics an appropriate blood glucose monitoring should be considered; a dose adjustment of insulin or antidiabetics may be required when indicated (see section 4.5).

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 hypomagnesaemia.

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.

Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).

Lithium:

The combination of lithium and Irbesartan/Hydrochlorothiazide Mylan is not recommended (see section 4.5).

Intestinal angioedema:

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists, [including irbesartan] (see section 4.8). These patients presented with abdominal pain, nausea, vomiting and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, irbesartan should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

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).

Choroidal effusion, Acute Myopia and Secondary Acute Angle-Closure Glaucoma:

Sulfonamide or sulfonamide derivative drugs can cause an idiosyncratic reaction, resulting in choroidal effusion with visual field defect, 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).

Excipients:

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

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 m2) 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.

Repaglinide:

Irbesartan has the potential to inhibit OATP1B1. In a clinical study, it was reported that irbesartan increased the Cmax and AUC of repaglinide (substrate of OATP1B1) by 1.8-fold and 1.3-fold, respectively, when administered 1 hour before repaglinide. In another study, no relevant pharmacokinetic interaction was reported, when the two drugs were co-administered. Therefore, dose adjustment of antidiabetic treatment such as repaglinide may be required (see section 4.4).

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 foetotoxicity (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 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 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 the ability to drive and use machines. 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:

Very rare:

Cough

acute respiratory distress syndrome (ARDS) (see section 4.4)

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:

anaemia, thrombocytopenia

General disorders and administration site conditions:

Uncommon:

chest pain

Immune system disorders:

Not known:

Anaphylactic reaction including anaphylactic shock

Metabolism and nutrition disorders:

Not known:

Hypoglycaemia

Gastrointestinal disorders

Rare

Intestinal angioedema

Table 3: Adverse reactions (regardless of relationship to medicinal product) reported with the use of hydrochlorothiazide alone

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Not known

Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma)

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, choroidal effusion, 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 angiitis (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.

Description of selected adverse reactions

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).

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.