IFIRMACOMBI 300mg / 25mg tablets medication leaflet

Ifirmacombi 150 mg/12.5 mg film-coated tablets

Ifirmacombi 300 mg/12.5 mg film-coated tablets

Ifirmacombi 300 mg/25 mg film-coated tablets

Ifirmacombi 150 mg/12.5 mg film-coated tablets

Each film-coated tablet contains 150 mg irbesartan (as irbesartan hydrochloride) and 12.5 mghydrochlorothiazide.

Ifirmacombi 300 mg/12.5 mg film-coated tablets

Each film-coated tablet contains 300 mg irbesartan (as irbesartan hydrochloride) and 12.5 mghydrochlorothiazide.

Ifirmacombi 300 mg/25 mg film-coated tablets

Each film-coated tablet contains 300 mg irbesartan (as irbesartan hydrochloride) and 25 mghydrochlorothiazide.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Ifirmacombi 150 mg/12.5 mg film-coated tablets

Pale pink, biconvex, oval, film-coated tablets.

Ifirmacombi 300 mg/12.5 mg film-coated tablets

White, biconvex, capsule shaped, film-coated tablets.

Ifirmacombi 300 mg/25 mg film-coated tablets

Pale pink, biconvex, capsule shaped, film-coated tablets.

Treatment of essential hypertension.

This fixed dose combination is indicated in adult patients whose blood pressure is not adequatelycontrolled on irbesartan or hydrochlorothiazide alone (see section 5.1).

Ifirmacombi can be taken once daily, with or without food.

Dose titration with the individual components (i.e. irbesartan and hydrochlorothiazide) may berecommended.

When clinically appropriate direct change from monotherapy to the fixed combinations may beconsidered:

- Ifirmacombi 150 mg/12.5 mg may be administered in patients whose blood pressure is notadequately controlled with hydrochlorothiazide or irbesartan 150 mg alone;

- Ifirmacombi 300 mg/12.5 mg may be administered in patients insufficiently controlled byirbesartan 300 mg or by Ifirmacombi 150 mg/12.5 mg.

- Ifirmacombi 300 mg/25 mg may be administered in patients insufficiently controlled by

Ifirmacombi 300 mg/12.5 mg.

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

When necessary, Ifirmacombi may be administered with another antihypertensive medicinal product(see section pct. 4.3, pct. 4.4, 4.5 and 5.1).

Due to the hydrochlorothiazide component, Ifirmacombi is not recommended for patients with severerenal dysfunction (creatinine clearance < 30 ml/min). Loop diuretics are preferred to thiazides in thispopulation. No dosage adjustment is necessary in patients with renal impairment whose renalcreatinine clearance is ≥ 30 ml/min (see sections 4.3 and 4.4).

Ifirmacombi is not indicated in patients with severe hepatic impairment. Thiazides should be used withcaution in patients with impaired hepatic function. No dosage adjustment of Ifirmacombi is necessaryin patients with mild to moderate hepatic impairment (see section 4.3).

No dosage adjustment of Ifirmacombi is necessary in older people.

Ifirmacombi is not recommended for use in children and adolescents because the safety and efficacyhave not been established. No data are available.

For oral use.

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or toother 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 Ifirmacombi with aliskiren-containing products is contraindicated inpatients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5and 5.1)

Hypotension - Volume-depleted patients:

Ifirmacombi has been rarely associated with symptomatic hypotension in hypertensive patientswithout other risk factors for hypotension. Symptomatic hypotension may be expected to occur inpatients 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 Ifirmacombi.

Renal artery stenosis - Renovascular hypertension:

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateralrenal artery stenosis or stenosis of the artery to a single functioning kidney are treated with angiotensinconverting enzyme inhibitors or angiotensin II receptor antagonists. While this is not documented with

Ifirmacombi, a similar effect should be anticipated.

When Ifirmacombi is used in patients with impaired renal function, a periodic monitoring ofpotassium, creatinine and uric acid serum levels is recommended.

There is no experience regarding the administration of Ifirmacombi in patients with recent kidneytransplantation.

Ifirmacombi 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 withimpaired renal function. No dosage adjustment is necessary in patients with renal impairment whosecreatinine 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 beadministered with caution.

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers oraliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (includingacute 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 specialistsupervision 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 withdiabetic nephropathy.

Thiazides should be used with caution in patients with impaired hepatic function or progressive liverdisease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. There isno clinical experience with Ifirmacombi in patients with hepatic impairment.

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitralstenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism:

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal productsacting through inhibition of the renin-angiotensin system. Therefore, the use of Ifirmacombi is notrecommended.

Thiazide therapy may impair glucose tolerance. Latent diabetes mellitus may become manifest duringthiazide therapy. Irbesartan may induce hypoglycaemia, particularly in diabetic patients. In patientstreated with insulin or antidiabetics an appropriate blood glucose monitoring should be considered; adose adjustment of inslulin 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 Ifirmacombi, minimal or no effects were reported.

Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazidetherapy.

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should beperformed at appropriate intervals.

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

Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy withirbesartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patientswith cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receivinginadequate oral intake of electrolytes and in patients receiving concomitant therapy withcorticosteroids or ACTH. Conversely, due to the irbesartan component of Ifirmacombi hyperkalaemiamight 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-sparingdiuretics, potassium supplements or potassium-containing salts substitutes should be co-administeredcautiously with Ifirmacombi (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 ofserum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemiamay be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying outtests for parathyroid function.

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

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, vomitingand diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. Ifintestinal angioedema is diagnosed, irbesartan/hydrochlorothiazide should be discontinued andappropriate monitoring should be initiated until complete resolution of symptoms has occurred.

The combination of lithium and Ifirmacombi is not recommended (see section 4.5).

Anti-doping test:

Hydrochlorothiazide contained in this medicinal product could produce a positive analytic result in ananti-doping test.

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 renaldisease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors orangiotensin-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 ischemic cardiopathy or ischemic cardiovasculardisease could result in a myocardial infarction or stroke.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history ofallergy 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 thiazidediuretics.

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

Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unlesscontinued AIIRA therapy is considered essential, patients planning pregnancy should be changed toalternative antihypertensive treatments which have an established safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, ifappropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Choroidal effusion, acute myopia and secondary acute angle-closure glaucoma:

Sulfonamide drugs or sulfonamide derivative drugs can cause an idiosyncratic reaction, resulting inchoroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma. Whilehydrochlorothiazide is a sulfonamide, only isolated cases of acute angle-closure glaucoma have beenreported so far with hydrochlorothiazide. Symptoms include acute onset of decreased visual acuity orocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closureglaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake asrapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocularpressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may includea history of sulfonamide or penicillin allergy (see section 4.8).

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamouscell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure hasbeen 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 theirskin for any new lesions and promptly report any suspicious skin lesions. Possible preventivemeasures such as limited exposure to sunlight and UV rays and, in case of exposure, adequateprotection should be advised to the patients in order to minimize the risk of skin cancer. Suspiciousskin 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).

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 developswithin minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea,fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, Ifirmacombishould be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administeredto patients who previously experienced ARDS following hydrochlorothiazide intake.

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

Other antihypertensive agents:

The antihypertensive effect of Ifirmacombi may be increased with the concomitant use of otherantihypertensive agents. Irbesartan and hydrochlorothiazide (at doses up to 300 mg irbesartan/25 mghydrochlorothiazide) have been safely administered with other antihypertensive agents includingcalcium channel blockers and beta-adrenergic blockers. Prior treatment with high dose diuretics mayresult in volume depletion and a risk of hypotension when initiating therapy with irbesartan with orwithout 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 associatedwith a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renalfunction (including acute renal failure) compared to the use of a single RAAS-acting agent (seesections pct. 4.3, pct. 4.4 and 5.1).

Reversible increases in serum lithium concentrations and toxicity have been reported duringconcomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effectshave been very rarely reported with irbesartan so far. Furthermore, renal clearance of lithium isreduced by thiazides so the risk of lithium toxicity could be increased with Ifirmacombi. Therefore,the combination of lithium and Ifirmacombi is not recommended (see section 4.4). If the combinationproves 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 ofirbesartan. However, this effect of hydrochlorothiazide on serum potassium would be expected to bepotentiated by other medicinal products associated with potassium loss and hypokalaemia (e.g. otherkaliuretic diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium). Conversely, basedon 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 containingpotassium 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 riskis recommended (see section 4.4).

Periodic monitoring of serum potassium is recommended when Ifirmacombi is administered withmedicinal 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 anincreased risk of worsening of renal function, including possible acute renal failure, and an increase inserum potassium, especially in patients with poor pre-existing renal function. The combination shouldbe administered with caution, especially in the elderly. Patients should be adequately hydrated andconsideration should be given to monitoring renal function after initiation of concomitant therapy, andperiodically thereafter.

Repaglinide:

Irbesartan has the potential to inhibit OATP1B1. In a clinical study, it was reported that irbesartanincreased 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 relevantpharmacokinetic interaction was reported, when the two drugs were co-administered. Therefore, doseadjustment of antidiabetic treatment such as repaglinide may be required (see section 4.4).

Additional information on irbesartan interactions:

In clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartanis mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significantpharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministeredwith warfarin, a medicinal product metabolised by CYP2C9. The effects of CYP2C9 inducers such asrifampicin on the pharmacokinetic of irbesartan have not been evaluated. The pharmacokinetic ofdigoxin was not altered by co-administration of irbesartan.

When administered concurrently, the following medicinal products may interact with thiazidediuretics:

Alcohol: potentiation of orthostatic hypotension may occur;

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

Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is impaired in the presence ofanionic exchange resins. Ifirmacombi should be taken at least one hour before or four hours after thesemedications;

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

Digitalis glycosides: thiazide induced hypokalaemia or hypomagnaesemia favour the onset ofdigitalis-induced cardiac arrhythmias (see section 4.4);

Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory drugmay 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 notsufficiently to preclude their use;

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

Antigout medicinal products: dosage adjustments of antigout medicinal products may be necessary ashydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid orsulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidenceof hypersensitivity reactions to allopurinol;

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

Carbamazepine: concomitant use of carbamazepine and hydrochlorothiazide has been associated withthe risk of symptomatic hyponatraemia. Electrolytes should be monitored during concomitant use. Ifpossible, another class of diuretics should be used;

Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced bythiazides.

Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide-typediuretics 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.

Angiotensin II Receptor Antagonists (AIIRAs):

The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). Theuse of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitorsduring the first trimester of pregnancy has not been conclusive; however a small increase in riskcannot 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 alternativeantihypertensive treatments which have an established safety profile for use in pregnancy. Whenpregnancy 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 humanfoetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonataltoxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound checkof renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections4.3 and 4.4).

There is limited experience with hydrochlorothiazide during pregnancy, especially during the firsttrimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on thepharmacological mechanism of action of hydrochlorothiazide its use during the second and thirdtrimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects likeicterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension orpreeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without abeneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in raresituations where no other treatment could be used.

Since Ifirmacombi contains hydrochlorothiazide, it is not recommended during the first trimester ofpregnancy. A switch to a suitable alternative treatment should be carried out in advance of a plannedpregnancy.

Angiotensin II Receptor Antagonists (AIIRAs):

Because no information is available regarding the use of Ifirmacombi during breast-feeding,

Ifirmacombi is not recommended and alternative treatments with better established safety profilesduring 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 itsmetabolites in milk (for details see 5.3).

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causingintense diuresis can inhibit the milk production. The use of Ifirmacombi during breast feeding is notrecommended. If Ifirmacombi is used during breast feeding, doses should be kept as low as possible.

Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducingthe first signs of parental toxicity (see section 5.3).

Based on its pharmacodynamic properties, Ifirmacombi is unlikely to affect the ability to drive and usemachines. When driving vehicles or operating machines, it should be taken into account thatoccasionally dizziness or weariness may occur during treatment of hypertension.

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 patientsexperienced 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 ureanitrogen (BUN) (2.3%), creatine kinase (1.7%) and creatinine (1.1%) were also commonly observed inthe trials.

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

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

Investigations Common: increases in blood urea nitrogen (BUN), creatinineand 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 Not known: coughmediastinal disorders

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 ofrenal failure in patients at risk (see section 4.4)

Musculoskeletal and Uncommon: swelling extremityconnective tissue disorders Not known: arthralgia, myalgia

Metabolism and nutrition Not known: hyperkalaemiadisorders

Vascular disorders Uncommon: flushing

General disorders and Common: fatigueadministration site conditions

Immune system disorders Not known: cases of hypersensitivity reactions such asangioedema, rash, urticaria

Hepatobiliary disorders Uncommon: jaundice

Not known: hepatitis, abnormal liver function

Reproductive system and Uncommon: sexual dysfunction, libido changesbreast disorders

Additional information on individual components: in addition to the adverse reactions listed above forthe combination product, other adverse reactions previously reported with one of the individualcomponents may be potential adverse reactions with Ifirmacombi. Tables 2 and 3 below detail theadverse reactions reported with the individual components of Ifirmacombi.

Table 2: Adverse reactions reported with the use of irbesartan alone

Blood and lymphatic system Not known: anaemia, thrombocytopeniadisorders

General disorders and Uncommon: chest painadministration site conditions:

Immune system disorders: Not known: anaphylactic reaction including anaphylacticshock

Metabolism and nutrition Not known: hypoglycaemiadisorders:

Gastrointestinal disorders: Rare: intestinal angioedema

Table 3: Adverse reactions reported with the use of hydrochlorothiazide alone

Investigations Not known: electrolyte imbalance (including hypokalaemiaand hyponatraemia, see section 4.4),hyperuricaemia, glycosuria, hyperglycaemia,increases in cholesterol and triglycerides

Neoplasms benign, malignant Not known Non-melanoma skin cancer (Basal cell carcinomaand unspecified (incl cysts and and Squamous cell carcinoma)1polyps)

Cardiac disorders Not known: cardiac arrhythmias

Blood and lymphatic system Not known: aplastic anaemia, bone marrow depression,disorders: neutropenia/agranulocytosis, haemolytic anaemia,leucopenia, thrombocytopenia

Nervous system disorders Not known: vertigo, paraesthesia, light-headedness,restlessness

Eye disorders Not known: transient blurred vision, xanthopsia, choroidaleffusion, acute myopia and secondary acute angle-closure glaucoma

Respiratory, thoracic and Very rare: acute respiratory distress syndrome (ARDS) (seemediastinal disorders section 4.4)

Not known: respiratory distress (including pneumonitis andpulmonary oedema)

Gastrointestinal disorders Not known: pancreatitis, anorexia, diarrhoea, constipation,gastric irritation, sialadenitis, loss of appetite

Renal and urinary disorders Not known: interstitial nephritis, renal dysfunction

Skin and subcutaneous tissue Not known: anaphylactic reactions, toxic epidermal necrolysis,disorders necrotizing angitis (vasculitis, cutaneousvasculitis), cutaneous lupus erythematosus-likereactions, reactivation of cutaneous lupuserythematosus, photosensitivity reactions, rash,urticaria

Musculoskeletal and Not known: weakness, muscle spasmconnective tissue disorders

Vascular disorders Not known: postural hypotension

General disorders and Not known: feveradministration site conditions

Hepatobiliary disorders: Not known: jaundice (intrahepatic cholestatic jaundice)

Psychiatric disorders: Not known: depression, sleep disturbances1 Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulativedosedependent association between HCTZ and NMSC has been observed (see also sections 4.4 and5.1).

The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) mayincrease when titrating the hydrochlorothiazide.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No specific information is available on the treatment of overdose with Ifirmacombi. The patientshould be closely monitored, and the treatment should be symptomatic and supportive. Managementdepends on the time since ingestion and the severity of the symptoms. Suggested measures includeinduction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment ofoverdose. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, thepatient 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 commonsigns and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in musclespasms and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalisglycosides or certain anti-arrhythmic medicinal products.

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

Pharmacotherapeutic group: angiotensin II antagonists and diuretics, ATC code: C09DA04.

Ifirmacombi is a combination of an angiotensin-II receptor antagonist, irbesartan, and a thiazidediuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensiveeffect, 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 isexpected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the sourceor route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptorsresults in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasmaaldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone atthe 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 alsodegrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for itsactivity.

Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive effect of thiazidediuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption,directly increasing excretion of sodium and chloride in approximately equivalent amounts. Thediuretic 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-aldosteronesystem, co-administration of irbesartan tends to reverse the potassium loss associated with thesediuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs atabout 4 hours, while the action persists for approximately 6-12 hours.

The combination of hydrochlorothiazide and irbesartan produces dose-related additive reductions inblood pressure across their therapeutic dose ranges. The addition of 12.5 mg hydrochlorothiazide to300 mg irbesartan once daily in patients not adequately controlled on 300 mg irbesartan alone resultedin further placebo-corrected diastolic blood pressure reductions at trough (24 hours post-dosing) of6.1 mmHg. The combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide resulted in anoverall placebo-subtracted systolic/diastolic reductions of up to 13.6/11.5 mmHg.

Limited clinical data (7 out of 22 patients) suggest that patients not controlled with the300 mg/12.5 mg combination may respond when uptitrated to 300 mg/25 mg. In these patients, anincremental blood pressure lowering effect was observed for both systolic blood pressure (SBP) anddiastolic blood pressure (DBP) (13.3 and 8.3 mmHg, respectively).

Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide gave systolic/diastolicmean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of 12.9/6.9 mmHgin patients with mild-to-moderate hypertension. Peak effects occurred at 3-6 hours. When assessed byambulatory blood pressure monitoring, the combination 150 mg irbesartan and 12.5 mghydrochlorothiazide once daily produced consistent reduction in blood pressure over the 24 hoursperiod with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mmHg. Whenmeasured by ambulatory blood pressure monitoring, the trough to peak effects of Ifirmacombi150 mg/12.5 mg were 100%. The trough to peak effects measured by cuff during office visits were68% and 76% for Ifirmacombi 150 mg/12.5 mg and Ifirmacombi 300 mg/12.5 mg, respectively. These24-hour effects were observed without excessive blood pressure lowering at peak and are consistentwith 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 irbesartangave an added placebo-subtracted systolic/diastolic mean reduction of 11.1/7.2 mmHg.

The blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide is apparentafter 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 maintainedfor over one year. Although not specifically studied with the Ifirmacombi, rebound hypertension hasnot been seen with either irbesartan or hydrochlorothiazide.

The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality hasnot been studied. Epidemiological studies have shown that long term treatment withhydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.

There is no difference in response to Ifirmacombi, regardless of age or gender. As is the case withother medicinal products that affect the renin-angiotensin system, black hypertensive patients havenotably less response to irbesartan monotherapy. When irbesartan is administered concomitantly witha low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patientsapproaches that of non-black patients.

Efficacy and safety of the combination of irbesartan and hydrochlorothiazide as initial therapy forsevere hypertension (defined as SeDBP ≥ 110 mmHg) was evaluated in a multicentre, randomized,double-blind, active-controlled, 8-week, parallel-arm study. A total of 697 patients were randomizedin a 2:1 ratio to either irbesartan/hydrochlorothiazide 150 mg/12.5 mg or to irbesartan 150 mg andsystematically force titrated (before assessing the response to the lower dose) after one week toirbesartan/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% werehyperlipidemic and the most frequent cardiovascular condition was stable angina pectoris in 3.5% ofthe participants.

The primary objective of this study was to compare the proportion of patients whose SeDBP wascontrolled (SeDBP < 90 mmHg) at Week 5 of treatment. Forty-seven percent (47.2%) of patients onthe combination achieved trough SeDBP < 90 mmHg compared to 33.2% of patients on irbesartan(p = 0.0005). The mean baseline blood pressure was approximately 172/113 mmHg in each treatmentgroup and decreases of SeSBP/SeDBP at five weeks were 30.8/24.0 mmHg and 21.1/19.3 mmHg forirbesartan/hydrochlorothiazide and irbesartan, respectively (p < 0.0001).

The types and incidences of adverse events reported for patients treated with the combination weresimilar 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% ofpatients with hypotension and 2.8% and 3.1% of patients with dizziness as adverse reactions reportedin the combination and monotherapy groups, respectively.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and incombination 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 anangiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovasculardisease, 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 andmortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension ascompared to monotherapy was observed. Given their similar pharmacodynamic properties, theseresults 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 inpatients 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-inhibitoror an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidneydisease, cardiovascular disease, or both. The study was terminated early because of an increased riskof adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in thealiskiren 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 aliskirengroup than in the placebo group.

Based on available data from epidemiological studies, cumulative dosedependent association between

HCTZ and NMSC has been observed. One study included a population comprised of 71,533 cases of

BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively.

High HCTZ use (≥50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationshipwas observed for both BCC and SCC. Another study showed a possible association between lip cancer(SCC) and exposure to HCTZ: 633 cases of lip-cancer were matched with 63,067 population controls,using a risk-set sampling strategy. A cumulative doseresponse relationship was demonstrated with anadjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg) (see also section 4.4).

Concomitant administration of hydrochlorothiazide and irbesartan has no effect on thepharmacokinetics of either medicinal product.

Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation fortheir activity. Following oral administration of Ifirmacombi, the absolute oral bioavailability is 60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect thebioavailability of Ifirmacombi. Peak plasma concentration occurs at 1.5-2 hours after oraladministration for irbesartan and 1-2.5 hours for hydrochlorothiazide.

Plasma protein binding of irbesartan is approximately 96%, with negligible binding to cellular bloodcomponents. 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 plasmaconcentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limitedaccumulation 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 dosageadjustment is necessary in female patients. Irbesartan AUC and Cmax values were also somewhatgreater in older subjects (≥ 65 years) than those of young subjects (18-40 years). However the terminalhalf-life was not significantly altered. No dosage adjustment is necessary in older people. The meanplasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hours.

Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasmaradioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver viaglucuronide 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 orintravenous 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 unchangedirbesartan. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidneys. At least61% of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses theplacental but not the blood-brain barrier, and is excreted in breast milk.

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

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

Irbesartan/hydrochlorothiazide

The potential toxicity of the irbesartan/hydrochlorothiazide combination after oral administration wasevaluated in rats and macaques in studies lasting up to 6 months. There were no toxicological findingsobserved of relevance to human therapeutic use. The following changes, observed in rats andmacaques 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 inblood pressure (no significant toxicologic interactions were observed):

- kidney changes, characterized by slight increases in serum urea and creatinine, andhyperplasia/hypertrophy of the juxtaglomerular apparatus, which are a direct consequence of theinteraction 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 ina 6 months toxicity study at irbesartan 90 mg/kg/day, hydrochlorothiazide 90 mg/kg/day, andirbesartan/hydrochlorothiazide 10/10 mg/kg/day. These lesions were not observed in macaques;

- decreases in serum potassium due to hydrochlorothiazide and partly prevented whenhydrochlorothiazide 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-producingcells) and occur also with angiotensin converting enzyme inhibitors. These findings appear to have norelevance to the use of therapeutic doses of irbesartan/hydrochlorothiazide in humans.

No teratogenic effects were seen in rats given irbesartan and hydrochlorothiazide in combination atdoses that produced maternal toxicity. The effects of the irbesartan/hydrochlorothiazide combinationon fertility have not been evaluated in animal studies, as there is no evidence of adverse effect onfertility in animals or humans with either irbesartan or hydrochlorothiazide when administered alone.

However, another angiotensin-II antagonist affected fertility parameters in animal studies when givenalone. These findings were also observed with lower doses of this other angiotensin-II antagonistwhen given in combination with hydrochlorothiazide.

There was no evidence of mutagenicity or clastogenicity with the irbesartan/hydrochlorothiazidecombination. The carcinogenic potential of irbesartan and hydrochlorothiazide in combination has notbeen evaluated in animal studies.

Irbesartan

There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. Innon-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day inmacaques) 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 interstitialnephritis, tubular distention, basophilic tubules, increased plasma concentrations of urea andcreatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to thehypotensive 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 bythe pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, thehyperplasia/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 atoral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), includingmortality at the highest dose. No significant effects on the number of corpora lutea, implants, or livefoetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring.

Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses.

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, includingmortality. No teratogenic effects were observed in the rat or rabbit.

Equivocal evidence for a genotoxic or carcinogenic effect was found in some experimental models.

Mannitol

Hydroxypropylcellulose

Hydroxypropylcellulose, low-substituted

Sodium starch glycolate

Talc

Macrogol 6000

Castor oil, hydrogenated

Ifirmacombi 150 mg/12.5 mg and 300 mg/25 mg film-coated tablets

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol

Talc

Iron oxide, yellow (E172)

Iron oxide, red (E172)

Ifirmacombi 300 mg/12.5 mg film-coated tablets

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol

Talc

Not applicable.

5 years

This medicinal product does not require any special storage conditions.

Blister (OPA/Aluminium/PVC//Aluminium): 14, 28, 30, 56, 56 x 1, 84, 90 and 98 film-coated tablets,in a box.

Not all pack sizes may be marketed.

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

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

Ifirmacombi 150 mg/12.5 mg film-coated tablets

EU/1/11/673/001-008

Ifirmacombi 300 mg/12.5 mg film-coated tablets

EU/1/11/673/009-016

Ifirmacombi 300 mg/25 mg film-coated tablets

EU/1/11/673/017-024

Date of first authorisation: 04 March 2011

Date of latest renewal: 19 November 2015

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu