EXFORGE HCT 10mg / 320mg / 25mg tablets medication leaflet

Exforge HCT 5 mg/160 mg/12.5 mg film-coated tablets

Exforge HCT 10 mg/160 mg/12.5 mg film-coated tablets

Exforge HCT 5 mg/160 mg/25 mg film-coated tablets

Exforge HCT 10 mg/160 mg/25 mg film-coated tablets

Exforge HCT 10 mg/320 mg/25 mg film-coated tablets

Exforge HCT 5 mg/160 mg/12.5 mg film-coated tablets

Each film-coated tablet contains 5 mg of amlodipine (as amlodipine besylate), 160 mg of valsartan,and 12.5 mg of hydrochlorothiazide.

Exforge HCT 10 mg/160 mg/12.5 mg film-coated tablets

Each film-coated tablet contains 10 mg of amlodipine (as amlodipine besylate), 160 mg of valsartan,and 12.5 mg of hydrochlorothiazide.

Exforge HCT 5 mg/160 mg/25 mg film-coated tablets

Each film-coated tablet contains 5 mg of amlodipine (as amlodipine besylate), 160 mg of valsartan,and 25 mg of hydrochlorothiazide.

Exforge HCT 10 mg/160 mg/25 mg film-coated tablets

Each film-coated tablet contains 10 mg of amlodipine (as amlodipine besylate), 160 mg of valsartan,and 25 mg of hydrochlorothiazide.

Exforge HCT 10 mg/320 mg/25 mg film-coated tablets

Each film-coated tablet contains 10 mg of amlodipine (as amlodipine besylate), 320 mg of valsartanand 25 mg of hydrochlorothiazide.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Exforge HCT 5 mg/160 mg/12.5 mg film-coated tablets

White, ovaloid, biconvex tablets with bevelled edge, debossed “NVR” on one side and “VCL” on theother side. Approximate size: 15 mm (length) x 5.9 mm (width).

Exforge HCT 10 mg/160 mg/12.5 mg film-coated tablets

Pale yellow, ovaloid, biconvex tablets with bevelled edge, debossed “NVR” on one side and “VDL”on the other side. Approximate size: 15 mm (length) x 5.9 mm (width).

Exforge HCT 5 mg/160 mg/25 mg film-coated tablets

Yellow, ovaloid, biconvex tablets with bevelled edge, debossed “NVR” on one side and “VEL” on theother side. Approximate size: 15 mm (length) x 5.9 mm (width).

Exforge HCT 10 mg/160 mg/25 mg film-coated tablets

Brown-yellow, ovaloid, biconvex tablets with bevelled edge, debossed “NVR” on one side and “VHL”on the other side. Approximate size: 15 mm (length) x 5.9 mm (width).

Exforge HCT 10 mg/320 mg/25 mg film-coated tablets

Brown-yellow, ovaloid, biconvex tablets with bevelled edge, debossed “NVR” on one side and “VFL”on the other side. Approximate size: 19 mm (length) x 7.5 mm (width).

Treatment of essential hypertension as substitution therapy in adult patients whose blood pressure isadequately controlled on the combination of amlodipine, valsartan and hydrochlorothiazide (HCT),taken either as three single-component formulations or as a dual-component and a single-componentformulation.

The recommended dose of Exforge HCT is one tablet per day, to be taken preferably in the morning.

Before switching to Exforge HCT patients should be controlled on stable doses of themonocomponents taken at the same time. The dose of Exforge HCT should be based on the doses ofthe individual components of the combination at the time of switching.

The maximum recommended dose of Exforge HCT is 10 mg/320 mg/25 mg.

Due to the hydrochlorothiazide component, Exforge HCT is contraindicated for use in patients withanuria (see section 4.3) and in patients with severe renal impairment (glomerular filtration rate (GFR)<30 ml/min/1.73 m2) (see sections pct. 4.3, pct. 4.4 and 5.2).

No adjustment of the initial dose is required for patients with mild to moderate renal impairment (seesections 4.4 and 5.2).

Due to the valsartan component, Exforge HCT is contraindicated in patients with severe hepaticimpairment (see section 4.3). In patients with mild to moderate hepatic impairment withoutcholestasis, the maximum recommended dose is 80 mg valsartan and therefore Exforge HCT is notsuitable in this group of patients (see sections pct. 4.3, pct. 4.4 and 5.2). Amlodipine dose recommendationshave not been established in patients with mild to moderate hepatic impairment. When switchingeligible hypertensive patients (see section 4.1) with hepatic impairment to Exforge HCT, the lowestavailable dose of the amlodipine component should be used.

Heart failure and coronary artery disease

There is limited experience with the use of Exforge HCT, particulary at the maximum dose, in patientswith heart failure and coronary artery disease. Caution is advised in patients with heart failure andcoronary artery disease, particularly at the maximum dose of Exforge HCT, 10 mg/320 mg/25 mg.

Elderly (age 65 years or over)

Caution, including more frequent monitoring of blood pressure, is recommended in elderly patients,particularly at the maximum dose of Exforge HCT, 10 mg/320 mg/25 mg, since available data in thispatient population are limited. When switching eligible elderly hypertensive patients (see section 4.1)to Exforge HCT, the lowest available dose of the amlodipine component should be used.

There is no relevant use of Exforge HCT in the paediatric population (patients below age 18 years) forthe indication of essential hypertension.

Oral use.

Exforge HCT can be taken with or without food.

The tablets should be swallowed whole with some water, at the same time of the day and preferably inthe morning.

− Hypersensitivity to the active substances, to other sulphonamide derivatives, to dihydropyridinederivatives, or to any of the excipients listed in section 6.1.

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

− Hepatic impairment, biliary cirrhosis or cholestasis.

− Severe renal impairment (GFR <30 ml/min/1.73 m2), anuria and patients undergoing dialysis.

− Concomitant use of Exforge HCT with aliskiren-containing products in patients with diabetesmellitus or renal impairment (GFR <60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

− Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia.

− Severe hypotension.

− Shock (including cardiogenic shock).

− Obstruction of the outflow tract of the left ventricle (e.g. hypertrophic obstructivecardiomyopathy and high grade aortic stenosis).

− Haemodynamically unstable heart failure after acute myocardial infarction.

The safety and efficacy of amlodipine in hypertensive crisis have not been established.

Sodium- and/or volume-depleted patients

Excessive hypotension, including orthostatic hypotension, was seen in 1.7% of patients treated withthe maximum dose of Exforge HCT (10 mg/320 mg/25 mg) compared to 1.8% ofvalsartan/hydrochlorothiazide (320 mg/25 mg) patients, 0.4% of amlodipine/valsartan (10 mg/320 mg)patients, and 0.2% of hydrochlorothiazide/amlodipine (25 mg/10 mg) patients in a controlled trial inpatients with moderate to severe uncomplicated hypertension.

In sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics,symptomatic hypotension may occur after initiation of treatment with Exforge HCT. Exforge HCTshould be used only after correction of any pre-existing sodium and/or volume depletion.

If excessive hypotension occurs with Exforge HCT, the patient should be placed in the supine positionand, if necessary, given an intravenous infusion of normal saline. Treatment can be continued onceblood pressure has been stabilised.

Serum electrolyte changes

Amlodipine/valsartan/hydrochlorothiazide

In the controlled trial of Exforge HCT, the counteracting effects of valsartan 320 mg andhydrochlorothiazide 25 mg on serum potassium approximately balanced each other in many patients.

In other patients, one or the other effect may be dominant. Periodic determinations of serumelectrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Periodic determination of serum electrolytes and potassium in particular should be performed atappropriate intervals to detect possible electrolyte imbalance, especially in patients with other riskfactors such as impaired renal function, treatment with other medicinal products or history of priorelectrolyte imbalances.

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containingpotassium, or other medicinal products that may increase potassium levels (heparin, etc.) is notrecommended. Monitoring of potassium should be undertaken as appropriate.

Treatment with Exforge HCT should only start after correction of hypokalaemia and any coexistinghypomagnesaemia. Thiazide diuretics can precipitate new onset hypokalaemia or exacerbate pre-existing hypokalaemia. Thiazide diuretics should be administered with caution in patients withconditions involving enhanced potassium loss, for example salt-losing nephropathies and prerenal(cardiogenic) impairment of kidney function. If hypokalaemia develops during hydrochlorothiazidetherapy, Exforge HCT should be discontinued until stable correction of the potassium balance.

Thiazide diuretics can precipitate new onset hyponatraemia and hypochloroaemic alkalosis orexacerbate pre-existing hyponatraemia. Hyponatraemia, accompanied by neurological symptoms(nausea, progressive disorientation, apathy) has been observed. Treatment with hydrochlorothiazideshould only be started after correction of pre-existing hyponatraemia. In case severe or rapidhyponatraemia develops during Exforge HCT therapy, the treatment should be discontinued untilnormalisation of natraemia.

All patients receiving thiazide diuretics should be periodically monitored for imbalances inelectrolytes, particularly potassium, sodium and magnesium.

Thiazide diuretics may precipitate azotaemia in patients with chronic kidney disease. When Exforge

HCT is used in patients with renal impairment periodic monitoring of serum electrolytes (includingpotassium), creatinine and uric acid serum levels is recommended. Exforge HCT is contraindicated inpatients with severe renal impairment, anuria or undergoing dialysis (see section 4.3).

No dose adjustment of Exforge HCT is required for patients with mild to moderate renal impairment(GFR ≥30 ml/min/1.73 m2).

Renal artery stenosis

Exforge HCT should be used with caution to treat hypertension in patients with unilateral or bilateralrenal artery stenosis or stenosis to a solitary kidney since blood urea and serum creatinine mayincrease in such patients.

Kidney transplantation

To date there is no experience of the safe use of Exforge HCT in patients who have had a recentkidney transplantation.

Valsartan is mostly eliminated unchanged via the bile. The half-life of amlodipine is prolonged and

AUC values are higher in patients with impaired liver function; dose recommendations have not beenestablished. In patients with mild to moderate hepatic impairment without cholestasis, the maximumrecommended dose is 80 mg valsartan, and therefore, Exforge HCT is not suitable in this group ofpatients (see sections 4.2, pct. 4.3 and 5.2).

Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swellingof the face, lips, pharynx, and/or tongue, has been reported in patients treated with valsartan. Some ofthese patients previously experienced angioedema with other medicinal products including ACEinhibitors. Exforge HCT should be discontinued immediately in patients who develop angioedema andshould not be re-administered.

Intestinal angioedema

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists,including valsartan (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, valsartan should be discontinued and appropriate monitoringshould be initiated until complete resolution of symptoms has occurred.

Heart failure and coronary artery disease/post-myocardial infarction

As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renalfunction may be anticipated in susceptible individuals. In patients with severe heart failure whoserenal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with

ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria and/orprogressive azotaemia and (rarely) with acute renal failure and/or death. Similar outcomes have beenreported with valsartan. Evaluation of patients with heart failure or post-myocardial infarction shouldalways include assessment of renal function.

In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA (New

York Heart Association Classification) III and IV heart failure of non-ischaemic aetiology, amlodipinewas associated with increased reports of pulmonary oedema despite no significant difference in theincidence of worsening heart failure as compared to placebo.

Calcium channel blockers, including amlodipine, should be used with caution in patients withcongestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Caution is advised in patients with heart failure and coronary artery disease, particularly at themaximum dose of Exforge HCT, 10 mg/320 mg/25 mg, since available data in these patientpopulations is limited.

Aortic and mitral valve stenosis

As with all other vasodilators, special caution is indicated in patients with mitral stenosis or significantaortic stenosis that is not high grade.

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).

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonistvalsartan as their renin-angiotensin system is not activated. Therefore, Exforge HCT is notrecommended in this population.

Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activatesystemic lupus erythematosus.

Other metabolic disturbances

Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum levelsof cholesterol, triglycerides and uric acid. In diabetic patients dosage adjustments of insulin or oralhypoglycaemic agents may be required.

Due to the hydrochlorothiazide component, Exforge HCT is contraindicated in symptomatichyperuricaemia. Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance ofuric acid and may cause or exacerbate hyperuricaemia as well as precipitate gout in susceptiblepatients.

Thiazides reduce urinary calcium excretion and may cause intermittant and slight elevation of serumcalcium in the absence of known disorders of calcium metabolism. Exforge HCT is contraindicated inpatients with hypercalcaemia and should only be used after correction of any pre-existinghypercalcaemia. Exforge HCT should be discontinued if hypercalcaemia develops during treatment.

Serum levels of calcium should be periodically monitored during treatment with thiazides. Markedhypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinuedbefore carrying out tests for parathyroid function.

Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). Ifphotosensitivity reaction occurs during treatment with Exforge HCT, it is recommended to stop thetreatment. If a readministration of the diuretic is deemed necessary, it is recommended to protectexposed areas to the sun or to artificial UVA.

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

Hydrochlorothiazide, a sulphonamide, has been associated with an idiosyncratic reaction resulting inchoroidal effusion with visual field defect, acute transient myopia and acute angle-closure glaucoma.

Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur withinhours to a week of treatment initiation. Untreated acute-angle closure glaucoma can lead to permanentvision loss.

The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical orsurgical treatment may need to be considered if the intraocular pressure remains uncontrolled. Riskfactors for developing acute angle closure glaucoma may include a history of sulphonamide orpenicillin allergy.

Caution should be exercised in patients who have shown prior hypersensitivity to other angiotensin IIreceptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients withallergy and asthma.

Elderly (age 65 years or over)

Caution, including more frequent monitoring of blood pressure, is recommended in elderly patients,particularly at the maximum dose of Exforge HCT, 10 mg/320 mg/25 mg, since available data in thispatient population are limited.

There is evidence that the concomitant use of ACE inhibitors, ARBs or aliskiren increases the risk ofhypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dualblockade of RAAS through the combined use of ACE inhibitors, ARBs or aliskiren is therefore notrecommended (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 ARBs should not be used concomitantly in patients with diabetic nephropathy.

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamouscell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide exposure has beenobserved in two epidemiological studies based on the Danish National Cancer Registry.

Photosensitising actions of hydrochlorothiazide could act as a possible mechanism for NMSC.

Patients taking hydrochlorothiazide should be informed of the risk of NMSC and advised to regularlycheck their skin for any new lesions and promptly report any suspicious skin lesions. Possiblepreventive 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 minimise the risk of skin cancer.

Suspicious skin lesions should be promptly examined potentially including histological examinationsof biopsies. The use of hydrochlorothiazide may also need to be reconsidered in patients who haveexperienced 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, Exforge HCTshould be withdrawn, and appropriate treatment given. Hydrochlorothiazide should not beadministered to patients who previously experienced ARDS following hydrochlorothiazide intake.

No formal interaction studies with other medicinal products have been performed with Exforge HCT.

Thus, only information on interactions with other medicinal products that are known for the individualactive substances is provided in this section.

However, it is important to take into account that Exforge HCT may increase the hypotensive effect ofother antihypertensive agents.

Exforge Known interactions Effect of the interaction with other medicinal products

HCT with the followingindividual agentscomponent

Valsartan Lithium Reversible increases in serum lithium concentrations andand toxicity have been reported during concomitant

HCT administration of lithium with ACE inhibitors, angiotensin

II receptor antagonists including valsartan or thiazides.

Since renal clearance of lithium is reduced by thiazides,the risk of lithium toxicity may presumably be increasedfurther with Exforge HCT. Therefore careful monitoringof serum lithium concentrations is recommended duringconcomitant use.

Valsartan Potassium-sparing If a medicinal product that affects potassium levels isdiuretics, potassium considered necessary in combination with valsartan,supplements, salt frequent monitoring of potassium plasma levels is advised.

substitutes containingpotassium and othersubstances that mayincrease potassiumlevels

Amlodipine Grapefruit or grapefruit Administration of amlodipine with grapefruit or grapefruitjuice juice is not recommended as bioavailability may beincreased in some patients, resulting in increased bloodpressure lowering effects.

Exforge Known interactions Effect of the interaction with other medicinal products

HCT with the followingindividual agentscomponent

Amlodipine CYP3A4 inhibitors Concomitant use of amlodipine with strong or moderate(i.e. ketoconazole, CYP3A4 inhibitors (protease inhibitors, azole antifungals,itraconazole, ritonavir) macrolides like erythromycin or clarithromycin, verapamilor diltiazem) may give rise to significant increase inamlodipine exposure. The clinical translation of thesepharmacokinetic variations may be more pronounced inthe elderly. Clinical monitoring and dose adjustment maythus be required.

CYP3A4 inducers Upon co-administration of known inducers of the(anticonvulsant agents CYP3A4, the plasma concentration of amlodipine may[e.g. carbamazepine, vary. Therefore, blood pressure should be monitored andphenobarbital, dose regulation considered both during and afterphenytoin, concomitant medication particularly with strong CYP3A4fosphenytoin, inducers (e.g. rifampicin, hypericum perforatum).

primidone], rifampicin,

Hypericum perforatum[St. John’s wort])

Simvastatin Co-administration of multiple doses of 10 mg amlodipinewith 80 mg simvastatin resulted in a 77% increase inexposure to simvastatin compared to simvastatin alone. Itis recommended to limit the dose of simvastatin to 20 mgdaily in patients on amlodipine.

Dantrolene (infusion) In animals, lethal ventricular fibrillation andcardiovascular collapse are observed in association withhyperkalaemia after administration of verapamil andintravenous dantrolene. Due to risk of hyperkalaemia, it isrecommended that the co-administration of calciumchannel blockers such as amlodipine be avoided inpatients susceptible to malignant hyperthermia and in themanagement of malignant hyperthermia.

Tacrolimus There is a risk of increased tacrolimus blood levels whenco-administered with amlodipine. In order to avoidtoxicity of tacrolimus, administration of amlodipine in apatient treated with tacrolimus requires monitoring oftacrolimus blood levels and dose adjustment of tacrolimuswhen appropriate.

Valsartan Non-steroidal anti- NSAIDS can attenuate the antihypertensive effect of bothand HCT inflammatory drugs angiotensin II antagonists and hydrochlorothiazide when(NSAIDs), including administered simultaneously. Furthermore, concomitantselective use of Exforge HCT and NSAIDs may lead to worseningcyclooxygenase-2 of renal function and an increase in serum potassium.

inhibitors (COX-2 Therefore, monitoring of renal function at the beginning ofinhibitors), the treatment is recommended, as well as adequateacetylsalicylic acid hydration of the patient.

(>3 g/day), and non-selective NSAIDs

Valsartan Inhibitors of the uptake The results of an in vitro study with human liver tissuetransporter (rifampicin, indicate that valsartan is a substrate of the hepatic uptakeciclosporin) or efflux transporter OATP1B1 and of the hepatic efflux transportertransporter (ritonavir) MRP2. Co-administration of inhibitors of the uptaketransporter (rifampicin, ciclosporin) or efflux transporter(ritonavir) may increase the systemic exposure tovalsartan.

HCT Alcohol, barbiturates Concomitant administration of thiazide diuretics withor narcotics substances that also have a blood pressure lowering effect(e.g. by reducing sympathetic central nervous systemactivity or direct vasodilatation) may potentiate orthostatichypotension.

Amantadine Thiazides, including hydrochlorothiazide, may increasethe risk of adverse reactions caused by amantadine.

Anticholinergic agents The bioavailability of thiazide-type diuretics may beand other medicinal increased by anticholinergic agents (e.g. atropine,products affecting biperiden), apparently due to a decrease in gastrointestinalgastric motility motility and the stomach emptying rate. Conversely, it isanticipated that prokinetic substances such as cisapridemay decrease the bioavailability of thiazide-type diuretics.

Antidiabetic agents Thiazides may alter glucose tolerance. Dose adjustment of(e.g. insulin and oral the antidiabetic medicinal product may be necessary.

antidiabetic agents)− Metformin Metformin should be used with caution because of the riskof lactic acidosis induced by possible functional renalfailure linked to hydrochlorothiazide.

Beta blockers and Concomitant use of thiazide diuretics, includingdiazoxide hydrochlorothiazide, with beta blockers may increase therisk of hyperglycaemia. Thiazide diuretics, includinghydrochlorothiazide, may enhance the hyperglycaemiceffect of diazoxide.

Ciclosporin Concomitant treatment with ciclosporin may increase therisk of hyperuricaemia and gout-type complications.

Cytotoxic agents Thiazides, including hydrochlorothiazide, may reduce therenal excretion of cytotoxic agents (e.g.

cyclophosphamide, methotrexate) and potentiate theirmyelosuppressive effects.

Digitalis glycosides Thiazide-induced hypokalaemia or hypomagnesaemia mayoccur as undesirable effects, favouring the onset ofdigitalis-induced cardiac arrhythmias.

Iodine contrasting In case of diuretic-induced dehydration, there is anagents increased risk of acute renal failure, especially with highdoses of iodine products. Patients should be re-hydratedbefore the administration.

Ion exchange resins Absorption of thiazide diuretics, includinghydrochlorothiazide, is decreased by cholestyramine orcolestipol. This could result in sub-therapeutic effects ofthiazide diuretics. However, staggering the dosage ofhydrochlorothiazide and resin such thathydrochlorothiazide is administered at least 4 hours beforeor 4-6 hours after the administration of resins wouldpotentially minimise the interaction.

Medicinal products The hypokalaemic effect of hydrochlorothiazide may beaffecting serum increased by concomitant administration of kaliureticpotassium level diuretics, corticosteroids, laxatives, adrenocorticotropichormone (ACTH), amphotericin, carbenoxolone,penicillin G and salicylic acid derivatives orantiarrhythmics. If these medicinal products are to beprescribed with the amlodipine /valsartan/hydrochlorothiazide combination, monitoring ofpotassium plasma levels is advised.

Medicinal products The hyponatraemic effect of diuretics may be intensifiedaffecting serum sodium by concomitant administration of medicinal products suchlevel as antidepressants, antipsychotics, antiepileptics, etc.

Caution is indicated in long-term administration of thesemedicinal products.

Medicinal products that Due to the risk of hypokalaemia, hydrochlorothiazidecould induce torsades should be administered with caution when associated withde pointes medicinal products that could induce torsades de pointes,in particular Class Ia and Class III antiarrhythmics andsome antipsychotics.

Medicinal products Dose adjustment of uricosuric medicinal products may beused in the treatment of necessary as hydrochlorothiazide may raise the level ofgout (probenecid, serum uric acid. Increase of dose of probenecid orsulfinpyrazone and sulfinpyrazone may be necessary.

allopurinol) Co-administration of thiazide diuretics, includinghydrochlorothiazide, may increase the incidence ofhypersensitivity reactions to allopurinol.

Methyldopa There have been isolated reports of haemolytic anaemiaoccurring with concomitant use of hydrochlorothiazideand methyldopa.

Non-depolarising Thiazides, including hydrochlorothiazide, potentiate theskeletal muscle action of curare derivatives.

relaxants (e.g.

tubocurarine)

Other anti-hypertensive Thiazides potentiate the antihypertensive action of othermedicinal products antihypertensive drugs (e.g. guanethidine, methyldopa,beta-blockers, vasodilators, calcium channel blockers,

ACE inhibitors, ARBs and Direct Renin Inhibitors[DRIs]).

Pressor amines (e.g. Hydrochlorothiazide may reduce the response to pressornoradrenaline, amines such as noradrenaline. The clinical significance ofadrenaline) this effect is uncertain and not sufficient to preclude theiruse.

Vitamin D and calcium Administration of thiazide diuretics, includingsalts hydrochlorothiazide, with vitamin D or with calcium saltsmay potentiate the rise in serum calcium. Concomitant useof thiazide type diuretics may lead to hypercalcaemia inpatients pre-disposed for hypercalcaemia (e.g.

hyperparathyroidism, malignancy or vitamin-D-mediatedconditions) by increasing tubular calcium reabsorption.

Dual blockade of the RAAS with ARBs, ACE inhibitors or aliskiren

Clinical trial data have shown that dual blockade of the RAAS through the combined use of ACEinhibitors, ARBs or aliskiren is associated with a higher frequency of adverse events such ashypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared tothe use of a single RAAS-acting agent (see sections pct. 4.3, pct. 4.4 and 5.1).

Amlodipine

The safety of amlodipine in human pregnancy has not been established. In animal studies,reproductive toxicity was observed at high doses (see section 5.3). Use in pregnancy is onlyrecommended when there is no safer alternative and when the disease itself carries greater risk for themother and foetus.

The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the firsttrimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second andthird trimesters of pregnancy (see sections 4.3 and 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 AIIRAs 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 (seesections 4.3 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 the pharmacological mechanism of action ofhydrochlorothiazide, its use during the second and third trimester may compromise foeto-placentalperfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance andthrombocytopenia.

Amlodipine/valsartan/hydrochlorothiazide

There is no experience on the use of Exforge HCT in pregnant women. Based on the existing data withthe components, the use of Exforge HCT is not recommended during first trimester and contra-indicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant hasbeen estimated with an interquartile range of 3-7%, with a maximum of 15%. The effect of amlodipineon infants is unknown. No information is available regarding the use of valsartan during breast-feeding. Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high dosescausing intense diuresis can inhibit milk production. The use of Exforge HCT during breast-feeding isnot recommended. If Exforge HCT is used during breast-feeding, doses should be kept as low aspossible. Alternative treatments with better established safety profiles during breast-feeding arepreferable, especially while nursing a newborn or preterm infant.

There are no clinical studies on fertility with Exforge HCT.

Valsartan had no adverse effects on the reproductive performance of male or female rats at oral dosesup to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose on a mg/m2 basis(calculations assume an oral dose of 320 mg/day and a 60-kg patient).

Amlodipine

Reversible biochemical changes in the head of spermatozoa have been reported in some patientstreated by calcium channel blockers. Clinical data are insufficient regarding the potential effect ofamlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).

Patients taking Exforge HCT and driving vehicles or using machines should take into account thatdizziness or weariness may occasionally occur.

Amlodipine can have mild or moderate influence on the ability to drive and use machines. If patientstaking Exforge HCT suffer from dizziness, headache, fatigue or nausea the ability to react may beimpaired.

The safety profile of Exforge HCT presented below is based on clinical studies performed with

Exforge HCT and the known safety profile of the individual components amlodipine, valsartan andhydrochlorothiazide.

The safety of Exforge HCT has been evaluated at its maximum dose of 10 mg/320 mg/25 mg in onecontrolled short-term (8 weeks) clinical study with 2,271 patients, 582 of whom received valsartan incombination with amlodipine and hydrochlorothiazide. Adverse reactions were generally mild andtransient in nature and only infrequently required discontinuation of therapy. In this active controlledclinical trial, the most common reasons for discontinuation of therapy with Exforge HCT weredizziness and hypotension (0.7%).

In the 8-week controlled clinical study, no significant new or unexpected adverse reactions wereobserved with triple therapy treatment compared to the known effects of the monotherapy or dualtherapy components.

In the 8-week controlled clinical study, changes in laboratory parameters observed with thecombination of Exforge HCT were minor and consistent with the pharmacological mechanism ofaction of the monotherapy agents. The presence of valsartan in the triple combination attenuated thehypokalaemic effect of hydrochlorothiazide.

The following adverse reactions, listed by MedDRA System Organ Class and frequency, concern

Exforge HCT (amlodipine/valsartan/HCT) and amlodipine, valsartan and HCT individually.

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).

MedDRA Adverse reactions Frequency

System Organ Exforge Amlodipine Valsartan HCT

Class HCT

Neoplasms Non-melanoma skin cancer -- -- -- Notbenign, (Basal cell carcinoma and knownmalignant and Squamous cell carcinoma)unspecified (inclcysts and polyps)

Blood and Agranulocytosis, bone -- -- -- Very rarelymphatic system marrow failuredisorders Haemoglobin and -- -- Not known --haematocrit decreased

Haemolytic anaemia -- -- -- Very rare

Leukopenia -- Very rare -- Very rare

Neutropenia -- -- Not known --

Thrombocytopenia, -- Very rare Not known Raresometimes with purpura

Aplastic anaemia -- -- -- Notknown

Immune system Hypersensitivity -- Very rare Not known Very raredisorders

Metabolism and Anorexia Uncommon -- -- --nutrition Hypercalcaemia Uncommon -- -- Raredisorders Hyperglycaemia -- Very rare -- Rare

Hyperlipidaemia Uncommon -- -- --

Hyperuricaemia Uncommon -- -- Common

Hypochloraemic alkalosis -- -- -- Very rare

Hypokalaemia Common -- -- Verycommon

Hypomagnesaemia -- -- -- Common

Hyponatraemia Uncommon -- -- Common

Worsening of diabetic -- -- -- Raremetabolic state

Psychiatric Depression -- Uncommon -- Raredisorders Insomnia/sleep disorders Uncommon Uncommon -- Rare

Mood swings -- Uncommon --

Confusion -- Rare -- --

Nervous system Coordination abnormal Uncommon -- -- --disorders Dizziness Common Common -- Rare

Dizziness postural, dizziness Uncommon -- -- --exertional

Dysgeusia Uncommon Uncommon -- --

Extrapyramidal syndrome -- Not known -- --

Headache Common Common -- Rare

Hypertonia -- Very rare -- --

Lethargy Uncommon -- -- --

Paraesthesia Uncommon Uncommon -- Rare

Peripheral neuropathy, Uncommon Very rare -- --neuropathy

Somnolence Uncommon Common -- --

Syncope Uncommon Uncommon -- --

Tremor -- Uncommon -- --

Hypoesthesia -- Uncommon -- --

Eye disorders Acute angle-closure -- -- -- Notglaucoma known

Visual disturbance -- Uncommon -- --

Visual impairment Uncommon Uncommon -- Rare

Choroidal effusion -- -- -- Not

Known

Ear and labyrinth Tinnitus -- Uncommon -- --disorders Vertigo Uncommon -- Uncommon --

Cardiac disorders Palpitations -- Common -- --

Tachycardia Uncommon -- -- --

Arrhythmias (including -- Very rare -- Rarebradycardia, ventriculartachycardia, and atrialfibrillation)

Myocardial infarction -- Very rare -- --

Vascular Flushing -- Common -- --disorders Hypotension Common Uncommon -- --

Orthostatic hypotension Uncommon -- -- Common

Phlebitis, thrombophlebitis Uncommon -- -- --

Vasculitis -- Very rare Not known --

Respiratory, Cough Uncommon Very rare Uncommon --thoracic and Dyspnoea Uncommon Uncommon -- --mediastinal Acute respiratory distress -- -- -- Very raredisorders syndrome (ARDS) (seesection 4.4)

Respiratory distress, -- -- -- Very rarepulmonary oedema,pneumonitis

Rhinitis -- Uncommon -- --

Throat irritation Uncommon -- -- --

Gastrointestinal Abdominal discomfort, Uncommon Common Uncommon Raredisorders abdominal pain upper

Breath odour Uncommon -- -- --

Change of bowel habit -- Uncommon -- --

Constipation -- -- -- Rare

Decreased appetite -- -- -- Common

Diarrhoea Uncommon Uncommon -- Rare

Dry mouth Uncommon Uncommon -- --

Dyspepsia Common Uncommon -- --

Gastritis -- Very rare -- --

Gingival hyperplasia -- Very rare -- --

Nausea Uncommon Common -- Common

Pancreatitis -- Very rare -- Very rare

Vomiting Uncommon Uncommon -- Common

Intestinal angioedema -- -- Very rare --

Hepatobiliary Liver function test abnormal, -- Very rare** Not known --disorders including blood bilirubinincrease

Hepatitis -- Very rare -- --

Intrahepatic cholestasis, -- Very rare -- Rarejaundice

Skin and Alopecia -- Uncommon --subcutaneous Angioedema -- Very rare Not known --tissue disorders Dermatitis bullous -- -- Not known --

Cutaneous lupus -- -- -- Very rareerythematosus-likereactions, reactivation ofcutaneous lupuserythematosus

Erythema multiforme -- Very rare -- Notknown

Exanthema -- Uncommon -- --

Hyperhidrosis Uncommon Uncommon -- --

Photosensitivity reaction* -- Very rare -- Rare

Pruritus Uncommon Uncommon Not known --

Purpura -- Uncommon -- Rare

Rash -- Uncommon Not known Common

Skin discoloration -- Uncommon -- --

Urticaria and other forms of -- Very rare -- Commonrash

Vasculitis necrotising and -- Not known -- Very raretoxic epidermal necrolysis

Exfoliative dermatitis -- Very rare -- --

Stevens-Johnson syndrome -- Very rare -- --

Quincke oedema -- Very rare -- --

Musculoskeletal Arthralgia -- Uncommon -- --and connective Back pain Uncommon Uncommon -- --tissue disorders Joint swelling Uncommon -- -- --

Muscle spasm Uncommon Uncommon -- Notknown

Muscular weakness Uncommon -- -- --

Myalgia Uncommon Uncommon Not known --

Pain in extremity Uncommon -- -- --

Ankle swelling -- Common -- --

Renal and Blood creatinine increased Uncommon -- Not known --urinary disorders Micturition disorder Uncommon

Nocturia -- Uncommon -- --

Pollakiuria Common Uncommon

Renal dysfunction -- -- -- Notknown

Acute renal failure Uncommon -- -- Notknown

Renal failure and -- -- Not known Rareimpairment

Reproductive Impotence Uncommon Uncommon -- Commonsystem and Gynaecomastia Uncommon -- --breast disorders

General disorders Abasia, gait disturbance Uncommon -- -- --and Asthenia Uncommon Uncommon -- Notadministration knownsite conditions Discomfort, malaise Uncommon Uncommon -- --

Fatigue Common Common Uncommon --

Non cardiac chest pain Uncommon Uncommon -- --

Oedema Common Common -- --

Pain -- Uncommon -- --

Pyrexia -- -- -- Notknown

Investigations Lipids increased -- Verycommon

Blood urea nitrogen Uncommon -- -- --increased

Blood uric acid increased Uncommon -- --

Glycosuria Rare

Blood potassium decreased Uncommon -- -- --

Blood potassium increased -- -- Not known --

Weight increase Uncommon Uncommon -- --

Weight decrease -- Uncommon -- --

* See section 4.4 Photosensitivity

** Mostly consistent with cholestasis

Non-melanoma skin cancer: based on available data from epidemiological studies, cumulativedose-dependent association between hydrochlorothiazide and NMSC has been observed (see alsosections 4.4 and 5.1).

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.

There is no experience of overdose with Exforge HCT. The major symptom of overdose with valsartanis possibly pronounced hypotension with dizziness. Overdose with amlodipine may result in excessiveperipheral vasodilation and, possibly, reflex tachycardia. Marked and potentially prolonged systemichypotension, including shock with fatal outcome, have been reported with amlodipine.

Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipineoverdose that may manifest with a delayed onset (24-48 hours post-ingestion) and require ventilatorysupport. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiacoutput may be precipitating factors.

Amlodipine/Valsartan/Hydrochlorothiazide

Clinically significant hypotension due to Exforge HCT overdose calls for active cardiovascularsupport, including frequent monitoring of cardiac and respiratory function, elevation of extremities,and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful inrestoring vascular tone and blood pressure, provided that there is no contraindication to its use.

Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

Amlodipine

If ingestion is recent, induction of vomiting or gastric lavage may be considered. Administration ofactivated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipinehas been shown to significantly decrease amlodipine absorption.

Amlodipine is unlikely to be removed by haemodialysis.

Valsartan is unlikely to be removed by haemodialysis.

Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia,hypochloraemia) and hypovolaemia resulting from excessive diuresis. The most common signs andsymptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasms and oraccentuate arrhythmia associated with the concomitant use of digitalis glycosides or certainanti-arrhythmic medicinal products.

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

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, angiotensin II antagonists,other combinations, ATC code: C09DX01.

Exforge HCT combines three antihypertensive compounds with complementary mechanisms tocontrol blood pressure in patients with essential hypertension: amlodipine belongs to the calciumantagonist class and valsartan to the angiotensin II antagonist class of medicines andhydrochlorothiazide belongs to the thiazide diuretics class of medicines. The combination of thesesubstances has an additive antihypertensive effect.

Amlodipine/Valsartan/Hydrochlorothiazide

Exforge HCT was studied in a double-blind, active controlled study in hypertensive patients. A total of2,271 patients with moderate to severe hypertension (mean baseline systolic/diastolic blood pressurewas 170/107 mmHg) received treatments of amlodipine/valsartan/hydrochlorothiazide10 mg/320 mg/25 mg, valsartan/hydrochlorothiazide 320 mg/25 mg, amlodipine/valsartan10 mg/320 mg, or hydrochlorothiazide/amlodipine 25 mg/10 mg. At study initiation patients wereassigned lower doses of their treatment combination and were titrated to their full treatment dose byweek 2.

At week 8, the mean reductions in systolic/diastolic blood pressure were 39.7/24.7 mmHg with

Exforge HCT, 32.0/19.7 mmHg with valsartan/hydrochlorothiazide, 33.5/21.5 mmHg withamlodipine/valsartan, and 31.5/19.5 mmHg with amlodipine/hydrochlorothiazide. The triplecombination therapy was statistically superior to each of the three dual combination treatments inreduction of diastolic and systolic blood pressures. The reductions in systolic/diastolic blood pressurewith Exforge HCT were 7.6/5.0 mmHg greater than with valsartan/hydrochlorothiazide,6.2/3.3 mmHg greater than with amlodipine/valsartan, and 8.2/5.3 mmHg greater than withamlodipine/hydrochlorothiazide. The full blood pressure lowering effect was achieved 2 weeks afterbeing on their maximal dose of Exforge HCT. Statistically greater proportions of patients achievedblood pressure control (<140/90 mmHg) with Exforge HCT (71%) compared to each of the three dualcombination therapies (45-54%) (p<0.0001).

In a subgroup of 283 patients focusing on ambulatory blood pressure monitoring, clinically andstatistically superior reductions in 24-hour systolic and diastolic blood pressures were observed withthe triple combination compared to valsartan/hydrochlorothiazide, valsartan/amlodipine, andhydrochlorothiazide/amlodipine.

Amlodipine

The amlodipine component of Exforge HCT inhibits the transmembrane entry of calcium ions intocardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine isdue to a direct relaxant effect on vascular smooth muscle, causing reductions in peripheral vascularresistance and in blood pressure.

Experimental data suggest that amlodipine binds to both dihydropyridine and non-dihydropyridinebinding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependentupon the movement of extracellular calcium ions into these cells through specific ion channels.

Following administration of therapeutic doses to patients with hypertension, amlodipine producesvasodilation, resulting in a reduction of supine and standing blood pressures. These decreases in bloodpressure are not accompanied by a significant change in heart rate or plasma catecholamine levels withchronic dosing.

Plasma concentrations correlate with effect in both young and elderly patients.

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in adecrease in renal vascular resistance and increases in glomerular filtration rate and effective renalplasma flow, without change in filtration fraction or proteinuria.

As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest andduring exercise (or pacing) in patients with normal ventricular function treated with amlodipine havegenerally demonstrated a small increase in cardiac index without significant influence on dP/dt or onleft ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not beenassociated with a negative inotropic effect when administered in the therapeutic dose range to intactanimals and humans, even when co-administered with beta blockers to humans.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animalsor humans. In clinical studies in which amlodipine was administered in combination with betablockers to patients with either hypertension or angina, no adverse effects on electrocardiographicparameters were observed.

Amlodipine has been studied in patients with chronic stable angina, vasospastic angina andangiographically documented coronary artery disease.

Use in patients with hypertension

A randomised double-blind morbidity-mortality study called the Antihypertensive and Lipid-Loweringtreatment to prevent Heart Attack Trial (ALLHAT) was performed to compare newer therapies:

amlodipine 2.5-10 mg/day (calcium channel blocker) or lisinopril 10-40 mg/day (ACE-inhibitor) asfirst-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/day in mild to moderatehypertension.

A total of 33,357 hypertensive patients aged 55 or older were randomised and followed for a mean of4.9 years. The patients had at least one additional coronary heart disease risk factor, including:

previous myocardial infarction or stroke (>6 months prior to enrollment) or documentation of otheratherosclerotic cardiovascular disease (overall 51.5%), type 2 diabetes (36.1%), high densitylipoprotein - cholesterol <35 mg/dl or <0.906 mmol/l (11.6%), left ventricular hypertrophy diagnosedby electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%).

The primary endpoint was a composite of fatal coronary heart disease or non-fatal myocardialinfarction. There was no significant difference in the primary endpoint between amlodipine-basedtherapy and chlorthalidone-based therapy: risk ratio (RR) 0.98 95% CI (0.90-1.07) p=0.65. Amongsecondary endpoints, the incidence of heart failure (component of a composite combinedcardiovascular endpoint) was significantly higher in the amlodipine group as compared to thechlorthalidone group (10.2% versus 7.7%, RR 1.38, 95% CI [1.25-1.52] p<0.001). However, there wasno significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-based therapy RR 0.96 95% CI [0.89-1.02] p=0.20.

Valsartan is an orally active, potent and specific angiotensin II receptor antagonist. It acts selectivelyon the receptor subtype AT1, which is responsible for the known actions of angiotensin II.

Administration of valsartan to patients with hypertension results in a drop in blood pressure withoutaffecting pulse rate.

In most patients, after administration of a single oral dose, onset of antihypertensive activity occurswithin 2 hours, and the peak drop in blood pressure is achieved within 4-6 hours. The antihypertensiveeffect persists over 24 hours after administration. During repeated administration, the maximumreduction in blood pressure with any dose is generally attained within 2-4 weeks.

The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has beenshown that there is a high-affinity receptor in the renal cortex as the primary binding site for thethiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule. The mode ofaction of thiazides is through inhibition of the Na+Cl- symporter perhaps by competing for the Cl- site,thereby affecting electrolyte reabsorption mechanisms: directly increasing sodium and chlorideexcretion to an approximately equal extent, and indirectly, by this diuretic action, reducing plasmavolume, with consequent increases in plasma renin activity, aldosterone secretion and urinarypotassium loss, and a decrease in serum potassium.

Based on available data from epidemiological studies, cumulative dose-dependent association betweenhydrochlorothiazide and NMSC has been observed. One study included a population comprised of71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 populationcontrols, respectively. High hydrochlorothiazide use (≥50000 mg cumulative) was associated with anadjusted odds ratio (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 relationship was observed for both BCC and SCC. Another studyshowed a possible association between lip cancer (SCC) and exposure to hydrochlorothiazide:

633 cases of lip cancer were matched with 63,067 population controls, using a risk-set samplingstrategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95%

CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25000 mg) and OR 7.7 (5.7-10.5) for thehighest cumulative dose (~100000 mg) (see also section 4.4).

The European Medicines Agency has waived the obligation to submit the results of studies with

Exforge HCT in all subsets of the paediatric population in essential hypertension (see section 4.2 forinformation on paediatric use).

Other: dual blockade of the renin-angiotensin-aldosterone system (RAAS)

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 an

ARB.

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 ARBs.

ACE inhibitors and ARBs should therefore not be used concomitantly in patients with diabeticnephropathy (see section 4.4).

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 ARB in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovasculardisease, 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 inthe 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 theplacebo group.

Amlodipine, valsartan and hydrochlorothiazide exhibit linear pharmacokinetics.

Amlodipine/valsartan/hydrochlorothiazide

Following oral administration of Exforge HCT in normal healthy adults, peak plasma concentrationsof amlodipine, valsartan and hydrochlorothiazide are reached in 6-8 hours, 3 hours, and 2 hours,respectively. The rate and extent of absorption of amlodipine, valsartan and hydrochlorothiazide from

Exforge HCT are the same as when administered as individual dosage forms.

Amlodipine

After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations ofamlodipine are reached in 6-12 hours. Absolute bioavailability has been calculated as between 64% and80%. Amlodipine bioavailability is unaffected by food ingestion.

Volume of distribution is approximately 21 l/kg. In vitro studies with amlodipine have shown thatapproximately 97.5% of circulating drug is bound to plasma proteins.

Amlodipine is extensively (approximately 90%) metabolised in the liver to inactive metabolites.

Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of approximately30 to 50 hours. Steady-state plasma levels are reached after continuous administration for 7-8 days. Tenper cent of original amlodipine and 60% of amlodipine metabolites are excreted in urine.

Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reachedin 2-4 hours. Mean absolute bioavailability is 23%. Food decreases exposure (as measured by AUC) tovalsartan by about 40% and peak plasma concentration (Cmax) by about 50%, although from about 8 hpost dosing plasma valsartan concentrations are similar for the fed and fasted groups. This reduction in

AUC is not, however, accompanied by a clinically significant reduction in the therapeutic effect, andvalsartan can therefore be given either with or without food.

The steady-state volume of distribution of valsartan after intravenous administration is about 17 litres,indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound toserum proteins (94-97%), mainly serum albumin.

Valsartan is not transformed to a high extent as only about 20% of dose is recovered as metabolites. Ahydroxy metabolite has been identified in plasma at low concentrations (less than 10% of the valsartan

AUC). This metabolite is pharmacologically inactive.

Valsartan shows multiexponential decay kinetics (t½α <1 h and t½ß about 9 h). Valsartan is primarilyeliminated in faeces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug.

Following intravenous administration, plasma clearance of valsartan is about 2 l/h and its renalclearance is 0.62 l/h (about 30% of total clearance). The half-life of valsartan is 6 hours.

The absorption of hydrochlorothiazide, after an oral dose, is rapid (Tmax about 2 hours). The increase inmean AUC is linear and dose proportional in the therapeutic range.

The effect of food on hydrochlorothiazide absorption, if any, has little clinical significance. Absolutebioavailability of hydrochlorothiazide is 70% after oral administration.

The apparent volume of distribution is 4-8 l/kg. Circulating hydrochlorothiazide is bound to serumproteins (40-70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes atapproximately 3 times the level in plasma.

Hydrochlorothiazide is eliminated predominantly as unchanged compound.

Hydrochlorothiazide is eliminated from plasma with a half-life averaging 6 to 15 hours in the terminalelimination phase. There is no change in the kinetics of hydrochlorothiazide on repeated dosing, andaccumulation is minimal when dosed once daily. More than 95% of the absorbed dose is beingexcreted as unchanged compound in the urine. The renal clearance is composed of passive filtrationand active secretion into the renal tubule.

Paediatric patients (age below 18 years)

No pharmacokinetic data are available in the paediatric population.

Elderly (age 65 years or over)

Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In elderlypatients, amlodipine clearance tends to decline, causing increases in the area under the curve (AUC)and elimination half-life. Mean systemic AUC of valsartan is higher by 70% in the elderly than in theyoung, therefore caution is required when increasing the dosage.

Systemic exposure to valsartan is slightly elevated in the elderly as compared to the young, but thishas not been shown to have any clinical significance.

Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy andhypertensive elderly subjects compared to young healthy volunteers.

Since the three components are equally well tolerated in younger and elderly patients, normal doseregimens are recommended (see section 4.2).

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. As expectedfor a compound where renal clearance accounts for only 30% of total plasma clearance, no correlationwas seen between renal function and systemic exposure to valsartan.

Patients with mild to moderate renal impairment may therefore receive the usual initial dose (seesections 4.2 and 4.4).

In the presence of renal impairment, mean peak plasma levels and AUC values of hydrochlorothiazideare increased and the urinary excretion rate is reduced. In patients with mild to moderate renalimpairment, a 3-fold increase in hydrochlorothiazide AUC has been observed. In patients with severerenal impairment an 8-fold increase in AUC has been observed. Exforge HCT is contraindicated inpatients with severe renal impairment, anuria or undergoing dialysis (see section 4.3).

Very limited clinical data are available regarding amlodipine administration in patients with hepaticimpairment. Patients with hepatic impairment have decreased clearance of amlodipine with resultingincrease of approximately 40-60% in AUC. On average, in patients with mild to moderate chronicliver disease, exposure (measured by AUC values) to valsartan is twice that found in healthyvolunteers (matched by age, sex and weight). Due to the valsartan component, Exforge HCT iscontraindicated in patients with hepatic impairment (see sections 4.2 and 4.3).

Amlodipine/Valsartan/Hydrochlorothiazide

In a variety of preclinical safety studies conducted in several animal species with amlodipine,valsartan, hydrochlorothiazide, valsartan/hydrochlorothiazide, amlodipine/valsartan andamlodipine/valsartan/hydrochlorothiazide (Exforge HCT), there was no evidence of systemic or targetorgan toxicity that would adversely affect the development of Exforge HCT for clinical use in humans.

Preclinical safety studies of up to 13 weeks in duration were conducted withamlodipine/valsartan/hydrochlorothiazide in rats. The combination resulted in expected reduction ofred blood cell mass (erythrocytes, haemoglobin, haematocrit, and reticulocytes), increase in serumurea, increase in serum creatinine, increase in serum potassium, juxtaglomerular (JG) hyperplasia inthe kidney and focal erosions in the glandular stomach in rats. All these changes were reversible aftera 4-week recovery period and were considered to be exaggerated pharmacological effects.

The amlodipine/valsartan/hydrochlorothiazide combination was not tested for genotoxicity orcarcinogenicity as there was no evidence of any interaction between these substances, which havebeen on the market for a long time. However, amlodipine, valsartan and hydrochlorothiazide havebeen tested individually for genotoxicity and carcinogenicity with negative results.

Amlodipine

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration oflabour and decreased pup survival at dosages approximately 50 times greater than the maximumrecommended dosage for humans based on mg/kg.

There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended humandose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipinebesilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasmafollicle-stimulating hormone and testosterone were found as well as decreases in sperm density and inthe number of mature spermatids and Sertoli cells.

Carcinogenesis, mutagenesis

Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to providedaily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. Thehighest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of10 mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats.

Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.

* Based on patient weight of 50 kg

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand development.

In rats, maternally toxic doses (600 mg/kg/day) during the last days of gestation and lactation led tolower survival, lower weight gain and delayed development (pinna detachment and ear-canal opening)in the offspring (see section 4.6). These doses in rats (600 mg/kg/day) are approximately 18 times themaximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of320 mg/day and a 60-kg patient).

In non-clinical safety studies, high doses of valsartan (200 to 600 mg/kg body weight) caused in rats areduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit) and evidence ofchanges in renal haemodynamics (slightly raised blood urea nitrogen, and renal tubular hyperplasiaand basophilia in males). These doses in rats (200 and 600 mg/kg/day) are approximately 6 and18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral doseof 320 mg/day and a 60-kg patient).

In marmosets at comparable doses, the changes were similar though more severe, particularly in thekidney where the changes developed to a nephropathy including raised blood urea nitrogen andcreatinine.

Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes wereconsidered to be caused by the pharmacological action of valsartan which produces prolongedhypotension, particularly in marmosets. For therapeutic doses of valsartan in humans, the hypertrophyof the renal juxtaglomerular cells does not seem to have any relevance.

Exforge HCT 5 mg/160 mg/12.5 mg film-coated tablets

Cellulose microcrystalline

Crospovidone (type A)

Silica, colloidal anhydrous

Magnesium stearate

Hypromellose, substitution type 2910 (3 mPa.s)

Titanium dioxide (E171)

Macrogol 4000

Talc

Exforge HCT 10 mg/160 mg/12.5 mg film-coated tablets

Cellulose microcrystalline

Crospovidone (type A)

Silica, colloidal anhydrous

Magnesium stearate

Hypromellose, substitution type 2910 (3 mPa.s)

Macrogol 4000

Talc

Titanium dioxide (E171)

Iron oxide, yellow (E172)

Iron oxide, red (E172)

Exforge HCT 5 mg/160 mg/25 mg film-coated tablets

Cellulose microcrystalline

Crospovidone (type A)

Silica, colloidal anhydrous

Magnesium stearate

Hypromellose, substitution type 2910 (3 mPa.s)

Macrogol 4000

Talc

Titanium dioxide (E171)

Iron oxide, yellow (E172)

Exforge HCT 10 mg/160 mg/25 mg film-coated tablets

Cellulose microcrystalline

Crospovidone (type A)

Silica, colloidal anhydrous

Magnesium stearate

Hypromellose, substitution type 2910 (3 mPa.s)

Macrogol 4000

Talc

Iron oxide, yellow (E172)

Exforge HCT 10 mg/320 mg/25 mg film-coated tablets

Cellulose microcrystalline

Crospovidone (type A)

Silica, colloidal anhydrous

Magnesium stearate

Hypromellose, substitution type 2910 (3 mPa.s)

Macrogol 4000

Talc

Iron oxide, yellow (E172)

Not applicable.

2 years

Do not store above 30°C.

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

PVC/PVDC blisters. One blister contains 7, 10 or 14 film-coated tablets.

Pack sizes: 14, 28, 30, 56, 90, 98 or 280 film-coated tablets.

Multipacks of 280 tablets, comprising 20 cartons, each containing 14 tablets.

PVC/PVDC perforated unit dose blisters for hospital use:

Pack sizes: 56, 98 or 280 film-coated tablets

Multipacks of 280 tablets, comprising 4 cartons, each containing 70 tablets.

Not all pack sizes may be marketed.

No special requirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

Exforge HCT 5 mg/160 mg/12.5 mg film-coated tablets

EU/1/09/569/001-012

Exforge HCT 10 mg/160 mg/12.5 mg film-coated tablets

EU/1/09/569/013-024

Exforge HCT 5 mg/160 mg/25 mg film-coated tablets

EU/1/09/569/025-036

Exforge HCT 10 mg/160 mg/25 mg film-coated tablets

EU/1/09/569/037-048

Exforge HCT 10 mg/320 mg/25 mg film-coated tablets

EU/1/09/569/049-060

Date of first authorisation: 16 October 2009

Date of latest renewal: 30 June 2014

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

Medicines Agency http://www.ema.europa.eu