RASILEZ HCT 150mg / 25mg tablets medication leaflet

Each film-coated tablet contains 150 mg aliskiren (as hemifumarate) and 12.5 mg hydrochlorothiazide.

Each tablet contains 25 mg lactose (as monohydrate) and 24.5 mg wheat starch.

Each film-coated tablet contains 150 mg aliskiren (as hemifumarate) and 25 mg hydrochlorothiazide.

Each tablet contains 50 mg lactose (as monohydrate) and 49 mg wheat starch.

Each film-coated tablet contains 300 mg aliskiren (as hemifumarate) and 12.5 mg hydrochlorothiazide.

Each tablet contains 25 mg lactose (as monohydrate) and 24.5 mg wheat starch.

Each film-coated tablet contains 300 mg aliskiren (as hemifumarate) and 25 mg hydrochlorothiazide.

Each tablet contains 50 mg lactose (as monohydrate) and 49 mg wheat starch.

For the full list of excipients, see section 6.1.

Film-coated tablet.

White, biconvex, ovaloid film-coated tablet imprinted with “LCI” on one side and “NVR” on theother.

Pale yellow, biconvex, ovaloid film-coated tablet imprinted with “CLL” on one side and “NVR” onthe other.

Violet white, biconvex, ovaloid film-coated tablet imprinted with “CVI” on one side and “NVR” onthe other.

Light yellow, biconvex, ovaloid film-coated tablet imprinted with “CVV” on one side and “NVR” onthe other.

Treatment of essential hypertension in adults.

Rasilez HCT is indicated in patients whose blood pressure is not adequately controlled on aliskiren orhydrochlorothiazide used alone.

Rasilez HCT is indicated as substitution therapy in patients adequately controlled with aliskiren andhydrochlorothiazide, given concurrently, at the same dose level as in the combination.

The recommended dose of Rasilez HCT is one tablet per day.

The antihypertensive effect is largely manifested within 1 week and the maximum effect is generallyseen within 4 weeks.

Individual dose titration with each of the two components may be recommended before changing tothe fixed combination. When clinically appropriate, direct change from monotherapy to the fixedcombination may be considered.

Rasilez HCT 150 mg/12.5 mg may be administered in patients whose blood pressure is not adequatelycontrolled with aliskiren 150 mg or hydrochlorothiazide 12.5 mg alone.

Rasilez HCT 150 mg/25 mg may be administered in patients whose blood pressure is not adequatelycontrolled with aliskiren 150 mg or hydrochlorothiazide 25 mg alone or by Rasilez HCT150 mg/12.5 mg.

Rasilez HCT 300 mg/12.5 mg may be administered in patients whose blood pressure is not adequatelycontrolled with aliskiren 300 mg or hydrochlorothiazide 12.5 mg alone or by Rasilez HCT150 mg/12.5 mg.

Rasilez HCT 300 mg/25 mg may be administered in patients whose blood pressure is not adequatelycontrolled with aliskiren 300 mg or hydrochlorothiazide 25 mg alone or by Rasilez HCT300 mg/12.5 mg or Rasilez HCT 150 mg/25 mg.

If blood pressure remains uncontrolled after 2-4 weeks of therapy, the dose may be titrated up to amaximum of Rasilez HCT 300 mg/25 mg daily. Dosing should be individualised and adjustedaccording to the patient’s clinical response.

For convenience, patients receiving aliskiren and hydrochlorothiazide from separate tablets may beswitched to a fixed combination tablet of Rasilez HCT containing the same component doses.

Due to the hydrochlorothiazide component, Rasilez HCT is contraindicated for use in patients withanuria and in patients with severe renal impairment (glomerular filtration rate (GFR)< 30 ml/min/1.73 m2). No adjustment of the initial dose is required for patients with mild to moderaterenal impairment (see sections 4.4 and 5.2).

Rasilez HCT is contraindicated in patients with severe hepatic impairment and should be used withcaution in patients with mild to moderate hepatic impairment or progressive liver disease. Noadjustment of the initial dose is required for patients with mild to moderate hepatic impairment (seesections pct. 4.3, pct. 4.4 and 5.2).

The recommended starting dose of aliskiren in elderly patients is 150 mg. No clinically meaningfuladditional blood pressure reduction is observed by increasing the dose to 300 mg in the majority ofelderly patients.

The safety and efficacy of Rasilez HCT in children below 18 years have not yet been established. Nodata are available.

Rasilez HCT is contraindicated in children from birth to less than 2 years. Rasilez HCT should not beused in children aged 2 to less than 6 years because of safety concerns due to potential aliskirenoverexposure (see sections pct. 4.3, pct. 4.4, pct. 5.2, and 5.3). The safety and efficacy of Rasilez HCT in childrenaged 6 to 17 years have not yet been established. Currently available data are described in sections 4.8,5.1, and 5.2. Use of Rasilez HCT is not recommended in this population.

Oral use. The tablets should be swallowed whole with some water. Rasilez HCT should be taken oncea day, always with or always without food, preferably at the same time each day. Patients shouldestablish a convenient daily schedule of medicinal product intake and maintain a steady temporalrelationship with food intake. Concomitant intake with fruit juice and/or drinks containing plantextracts (including herbal teas) should be avoided (see section 4.5).

− Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or toother sulfonamide-derived substances.

− History of angioedema with aliskiren.

− Hereditary or idiopathic angioedema.

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

− Anuria.

− Severe renal impairment (GFR < 30 ml/min/1.73 m2).

− Hyponatraemia, hypercalcaemia, symptomatic hyperuricaemia and refractory hypokalaemia.

− Severe hepatic impairment.

− The concomitant use of aliskiren with ciclosporin and itraconazole, two highly potent

P-glycoprotein (P-gp) inhibitors, and other potent P-gp inhibitors (e.g. quinidine), iscontraindicated (see section 4.5).

− The concomitant use of Rasilez HCT with an angiotensin converting enzyme inhibitors (ACEI)or an angiotensin II receptor blockers (ARB) is contraindicated in patients with diabetesmellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

− Children from birth to less than 2 years (see sections 4.2 and 5.3).

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).

In the event of severe and perisistent diarrhoea, Rasilez HCT therapy should be stopped(see section 4.8).

Hypotension, syncope, stroke, hyperkalaemia, and decreased renal function (including acute renalfailure) have been reported in susceptible individuals, especially if combining medicinal products thataffect this system (see section 5.1). Dual blockade of the RAAS by combining aliskiren with an ACEIor an ARB is therefore not recommended. If dual blockade therapy is considered absolutely necessary,this should only occur under specialist supervision and subject to frequent close monitoring of renalfunction, electrolytes and blood pressure.

Aliskiren should be used with caution in patients with serious congestive heart failure (New York

Heart Association (NYHA) functional class III-IV) (see section 5.1). Rasilez HCT should be used withcaution in patients with heart failure due to limited clinical efficacy and safety data.

Aliskiren should be used with caution in patients with heart failure treated with furosemide ortorasemide (see section 4.5).

Symptomatic hypotension could occur after initiation of treatment with Rasilez HCT in the followingcases:

* Patients with marked volume depletion or patients with salt depletion (e.g. those receiving highdoses of diuretics) or

* Combined use of aliskiren with other agents acting on the RAAS.

The volume or salt depletion should be corrected prior to administration of Rasilez HCT, or thetreatment should start under close medical supervision.

Treatment with Rasilez 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 Rasilez HCT should be discontinued until stable correction of the potassium balance.

Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy withaliskiren may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in patientswith cirrhosis of the liver, patients experiencing brisk diuresis, patients with inadequate oralelectrolyte intake and patients receiving concomitant therapy with corticosteroids oradrenocorticotropic hormone (ACTH) (see sections 4.5 and 4.8).

Conversely, increases in serum potassium have been observed with aliskiren in post-marketingexperience and these may be exacerbated by concomitant use of other agents acting on the RAAS orby non-steroidal anti-inflammatory drugs (NSAIDs). Consistent with standard medical practice,periodic determination of renal function including serum electrolytes is advised if co-administration isconsidered necessary (see sections 4.5 and 4.8).

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 Rasilez HCT therapy, the treatment should be discontinued untilnormalisation of natraemia.

There is no evidence that Rasilez HCT would reduce or prevent diuretic-induced hyponatraemia.

Chloride deficit is generally mild and usually does not require treatment.

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

Thiazides reduce urinary calcium excretion and may cause an intermittent and slight elevation ofserum calcium in the absence of known disorders of calcium metabolism. Rasilez HCT iscontraindicated in patients with hypercalcaemia and should only be used after correction of any pre-existing hypercalcaemia. Rasilez HCT should be discontinued if hypercalcaemia develops duringtreatment. Serum levels of calcium should be periodically monitored during treatment with thiazides.

Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should bediscontinued before carrying out tests for parathyroid function.

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

HCT is used in patients with renal impairment, periodic monitoring of serum electrolytes includingpotassium, creatinine and uric acid serum levels is recommended. Rasilez HCT is contraindicated inpatients with severe renal impairment or anuria (see section 4.2 and 4.3)

There is no experience regarding the administration of Rasilez HCT in patients who have recentlyundergone kidney transplantation. Rasilez HCT should be used with caution in patients who haverecently undergone kidney transplantation due to limited clinical efficacy and safety data.

Caution should be exercised when aliskiren is given in the presence of conditions pre-disposing tokidney dysfunction such as hypovolaemia (e.g. due to blood loss, severe or prolonged diarrhoea,prolonged vomiting, etc.), heart disease, liver disease, diabetes mellitus or kidney disease. Acute renalfailure, reversible upon discontinuation of treatment, has been reported in at-risk patients receivingaliskiren in post-marketing experience. In the event that any signs of renal failure occur, aliskirenshould be promptly discontinued.

There are no data with Rasilez HCT in patients with hepatic impairment. Rasilez HCT iscontraindicated in patients with severe hepatic impairment and should be used with caution in patientswith mild to moderate hepatic impairment or progressive liver disease. No adjustment of the initialdose is required for patients with mild to moderate hepatic impairment (see sections 4.2, pct. 4.3 and 5.2).

Special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructivehypertrophic cardiomyopathy.

No controlled clinical data are available on the use of Rasilez HCT in patients with unilateral orbilateral renal artery stenosis, or stenosis to a solitary kidney. However, there is an increased risk ofrenal insufficiency, including acute renal failure, when patients with renal artery stenosis are treatedwith aliskiren. Therefore, caution should be exercised in these patients. If renal failure occurs,treatment should be discontinued.

Anaphylactic reactions have been observed during treatment with aliskiren from post-marketingexperience (see section 4.8). Angioedema or symptoms suggestive of angioedema (swelling of theface, lips, throat and/or tongue) have been reported in patients treated with aliskiren.

A number of these patients had a history of angioedema or symptoms suggestive of angioedema,which in some cases followed use of other medicinal product that can cause angioedema, including

RAAS blockers (angiotensin converting enzyme inhibitors or angiotensin receptor blockers) (seesection 4.8).

In post-marketing experience, angioedema or angioedema-like reactions have been reported whenaliskiren was co-administered with ACEIs and/or ARBs (see section 4.8).

In a post-authorisation observational study, the co-administration of aliskiren with ACEIs or ARBs hasbeen associated with an increased risk of angioedema. The mechanism of this effect has not beenestablished. In general, dual blockade of the RAAS by combining aliskiren with an ACEI or an ARBis not recommended (see section “Dual blockade of the renin-angiotensin-aldosterone system(RAAS)” above and also sections 4.5 and 4.8).

Special caution is necessary in patients with a hypersensitivity predisposition.

Patients with a history of angioedema may be at increased risk of experiencing angioedema duringtreatment with aliskiren (see sections 4.3 and 4.8). Caution should therefore be exercised whenprescribing aliskiren to patients with a history of angioedema, and such patients should be closelymonitored during treatment (see section 4.8) especially at the beginning of the treatment.

If anaphylactic reactions or angioedema occur, Rasilez HCT should be promptly discontinued andappropriate therapy and monitoring provided until complete and sustained resolution of signs andsymptoms has occurred. Patients should be informed to report to the physician any signs suggestive ofallergic reactions, in particular difficulties in breathing or swallowing, swelling of face, extremities,eyes, lips or tongue. Where there is involvement of the tongue, glottis or larynx, adrenaline should beadministered. In addition, measures necessary to maintain patent airways should be provided.

Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activatesystemic lupus erythematosus. In the event that any signs or clinical suspicion of systematic lupuserythematosus (SLE), Rasilez HCT should be promptly discontinued and appropriate therapy andmonitoring provided until complete and sustained resolution of signs and symptoms has occurred.

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

Due to the hydrochlorothiazide component, Rasilez HCT is contraindicated in symptomatichyperuricaemia (see section 4.3). Hydrochlorothiazide may raise the serum uric acid level due toreduced clearance of uric acid and may cause or exacerbate hyperuricaemia as well as precipitate goutin susceptible patients.

Thiazides reduce urinary calcium excretion and may cause an intermittent and slight elevation ofserum calcium in the absence of known disorders of calcium metabolism. Rasilez HCT iscontraindicated in patients with hypercalcaemia and should only be used after correction of any pre-existing hypercalcaemia. Rasilez HCT should be discontinued if hypercalcaemia develops duringtreatment. Serum levels of calcium should be periodically monitored during treatment with thiazides.

Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should bediscontinued before 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 Rasilez HCT, it is recommended to stop thetreatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protectexposed areas to the sun or to artificial UVA.

Sulfonamide or sulfonamide derivative drugs can cause an idiosyncratic reaction resulting in choroidaleffusion with visual field defect, transient myopia and acute angle-closure glaucoma. Symptomsinclude acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeksof drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. Theprimary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgicaltreatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors fordeveloping acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Excessive reduction of blood pressure in patients with ischaemic cardiopathy or ischaemiccardiovascular disease could result in a myocardial infarction or stroke.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients, but are more likely in patientswith allergy and asthma.

Rasilez HCT contains lactose. Patients with rare hereditary problems of galactose intolerance, totallactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Rasilez HCT contains wheat starch. Wheat starch in this medicine contains only very low levels ofgluten (less than 100ppm) and is very unlikely to cause problems if you have coeliac disease. Onedosage unit contains no more than 100 micrograms of gluten. If you have wheat allergy (differentfrom coeliac disease) you should not take this medicine. You should consult your doctor prior totaking this medicine.

Aliskiren is a P-glycoprotein (P-gp) substrate, and there is a potential for aliskiren overexposure inchildren with an immature P-gp drug transporter system. The age at which the transporter system ismature cannot be determined (see sections 5.2 and 5.3). Therefore, Rasilez HCT is contraindicated inchildren from birth to less than 2 years and should not be used in children aged 2 to less than 6 years(see section 4.2 and 4.3). The safety and efficacy of aliskiren in children aged 6 to 17 years have notyet been established. Currently available data are described in sections 4.8, 5.1, and 5.2.

The potassium-depleting effect of hydrochlorothiazide is attenuated by the potassium-sparing effect ofaliskiren. 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, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin,carbenoxolone, penicillin G, salicylic acid derivatives). Conversely, concomitant use of other agentsaffecting the RAAS, of NSAIDs or of agents that increase serum potassium levels (e.g. potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, heparin) may lead toincreases in serum potassium. If co-administration with an agent affecting the level of serumpotassium is considered necessary, caution is advisable (see sections 4.4 and 5.1).

Periodic monitoring of serum potassium is recommended when Rasilez HCT is administered withmedicinal products affected by serum potassium disturbances (e.g. digitalis glycosides,antiarrhythmics).

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors(COX-2 inhibitors), acetylsalicylic acid and non-selective NSAIDs

NSAIDs may reduce the anti-hypertensive effect of aliskiren. NSAIDs may also weaken the diureticand antihypertensive activity of hydrochlorothiazide.

In some patients with compromised renal function (dehydrated patients or elderly patients) aliskirenand hydrochlorothiazide given concomitantly with NSAIDs may result in further deterioration of renalfunction, including possible acute renal failure, which is usually reversible. Therefore, the use of

Rasilez HCT with an NSAID requires caution, especially in elderly patients.

The antihypertensive effect of Rasilez HCT may be increased with the concomitant use of otherantihypertensive agents. Therefore, caution should be used if coadmnistering with any otherhypertensive agents

Contraindicated (see section 4.3)

A single dose interaction study in healthy subjects has shown that ciclosporin (200 and 600 mg)increases Cmax of aliskiren 75 mg approximately 2.5-fold and AUC approximately 5-fold. The increasemay be higher with higher aliskiren doses. In healthy subjects, itraconazole (100 mg) increases AUCand Cmax of aliskiren (150 mg) by 6.5-fold and 5.8-fold, respectively. Therefore, concomitant use ofaliskiren and P-gp potent inhibitors is contraindicated (see section 4.3).

Not recommended (see section 4.2)

Administration of fruit juice with aliskiren resulted in a decrease in AUC and Cmax of aliskiren. Co-administration of grapefruit juice with aliskiren 150 mg resulted in a 61% decrease in aliskiren AUCand co-administration with aliskiren 300 mg resulted in a 38% decrease in aliskiren AUC. Co-administration of orange or apple juice with aliskiren 150 mg resulted in a 62% decrease in aliskiren

AUC or in a 63% decrease in aliskiren AUC, respectively. This decrease is likely due to an inhibitionof organic anion transporting polypeptide-mediated uptake of aliskiren by components of fruit juice inthe gastrointestinal tract. Therefore, because of the risk of therapeutic failure, fruit juice should not betaken together with Rasilez HCT. The effect of drinks containing plant extracts (including herbal teas)on the absorption of aliskiren has not been investigated. However, compounds potentially inhibitingorganic anion transporting polypeptide-mediated uptake of aliskiren are widely present in fruits,vegetables, and many other plant products. Therefore, drinks containing plant extracts, includingherbal teas, should not be taken together with Rasilez HCT.

Clinical study data has shown that dual blockade of the RAAS through the combined use of ACEIs,

ARBs or aliskiren is associated with a higher frequency of adverse events such as hypotension, stroke,hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of asingle RAAS-acting agent (see sections pct. 4.3, pct. 4.4 and 5.1).

MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption andbiliary excretion of aliskiren in preclinical studies (see section 5.2). Rifampicin, which is an inducer of

P-gp, reduced aliskiren bioavailability by approximately 50% in a clinical study. Other inducers of P-gp (St. John’s wort) might decrease the bioavailability of aliskiren. Although this has not beeninvestigated for aliskiren, it is known that P-gp also controls tissue uptake of a variety of substratesand P-gp inhibitors can increase the tissue-to-plasma concentration ratios. Therefore, P-gp inhibitorsmay increase tissue levels more than plasma levels. The potential for drug interactions at the P-gp sitewill likely depend on the degree of inhibition of this transporter.

Co-administration of ketoconazole (200 mg) or verapamil (240 mg) with aliskiren (300 mg) resulted ina 76% or 97% increase in aliskiren AUC, respectively. The change in plasma levels of aliskiren in thepresence of ketoconazole or verapamil is expected to be within the range that would be achieved if thedose of aliskiren were doubled; aliskiren doses of up to 600 mg, or twice the highest recommendedtherapeutic dose, have been found to be well tolerated in controlled clinical studies. Preclinical studiesindicate that aliskiren and ketoconazole co-administration enhances aliskiren gastrointestinalabsorption and decreases biliary excretion. Therefore, caution should be exercised when aliskiren isadministered with ketoconazole, verapamil or other moderate P-gp inhibitors (clarithromycin,telithromycin, erythromycin, amiodarone).

Concomitant use of other agents affecting the RAAS, of NSAIDs or of agents that increase serumpotassium levels (e.g. potassium-sparing diuretics, potassium supplements, salt substitutes containingpotassium, heparin) may lead to increases in serum potassium. If co-medication with an agentaffecting the level of serum potassium is considered necessary, routine monitoring of potassium levelswould be advisable.

NSAIDs may reduce the anti-hypertensive effect of aliskiren. In some patients with compromisedrenal function (dehydrated patients or elderly patients) aliskiren given concomitantly with NSAIDsmay result in further deterioration of renal function, including possible acute renal failure, which isusually reversible. Therefore, the combination of aliskiren with an NSAID requires caution, especiallyin elderly patients.

Oral co-administration of aliskiren and furosemide had no effect on the pharmacokinetics of aliskirenbut reduced exposure to furosemide by 20-30% (the effect of aliskiren on furosemide administeredintramuscularly or intravenously has not been investigated). After multiple doses of furosemide(60 mg/day) co-administered with aliskiren (300 mg/day) to patients with heart failure the urinarysodium excretion and the urine volume were reduced during the first 4 hours by 31% and 24%,respectively, as compared to furosemide alone. The mean weight of patients concomitantly treatedwith furosemide and 300 mg aliskiren (84.6 kg) was higher than the weight of patients treated withfurosemide alone (83.4 kg). Smaller changes in furosemide pharmacokinetics and efficacy wereobserved with aliskiren 150 mg/day.

The available clinical data did not indicate that higher doses of torasemide were used after co-administration with aliskiren. Torasemide renal excretion is known to be mediated by organic aniontransporters (OATs). Aliskiren is minimally excreted via the renal route, and only 0.6% of thealiskiren dose is recovered in urine following oral administration (see section 5.2). However, sincealiskiren has been shown to be a substrate for the organic anion-transporting polypeptide 1A2(OATP1A2) (see section ‘Organic anion transporting polypeptide (OATP’ below) inhibitors), there isa potential for aliskiren to reduce plasma torasemide exposure by an interference with the absorptionprocess.

In patients treated with both aliskiren and oral furosemide or torasemide, it is therefore recommendedthat the effects of furosemide or torasemide be monitored when initiating and adjusting furosemide,torasemide or aliskiren therapy to avoid changes in extracellular fluid volume and possible situationsof volume overload (see section 4.4).

The effects of aliskiren on warfarin pharmacokinetics have not been evaluated.

Although meals (low or high fat content) have been shown to reduce the absorption of aliskirensubstantially, the efficacy of aliskiren was shown to be similar when taken either with a light meal orwithout a meal (see section 4.2). The available clinical data do not suggest an additive effect ofdifferent types of foods and/or drinks, however the potential for decreased aliskiren bioavailability dueto this additive effect has not been studied and therefore cannot be excluded. Concomitantadministration of aliskiren with fruit juice or drinks containing plant extracts, including herbal teas,should be avoided.

Compounds that have been investigated in clinical pharmacokinetic studies include acenocoumarol,atenolol, celecoxib, pioglitazone, allopurinol, isosorbide-5-mononitrate and hydrochlorothiazide. Nointeractions have been identified.

Co-administration of aliskiren with either metformin (↓28%), amlodipine (↑29%) or cimetidine(↑19%) resulted in between 20% and 30% change in Cmax or AUC of aliskiren. When administeredwith atorvastatin, steady-state aliskiren AUC and Cmax increased by 50%. Co-administration ofaliskiren had no significant impact on atorvastatin, metformin or amlodipine pharmacokinetics. As aresult no dose adjustment for aliskiren or these co-administered medicinal products is necessary.

Digoxin and verapamil bioavailability may be slightly decreased by aliskiren.

Aliskiren does not inhibit the CYP450 isoenzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A).

Aliskiren does not induce CYP3A4. Therefore, aliskiren is not expected to affect the systemicexposure of substances that inhibit, induce or are metabolised by these enzymes. Aliskiren ismetabolised minimally by the cytochrome P450 enzymes. Hence, interactions due to inhibition orinduction of CYP450 isoenzymes are not expected. However, CYP3A4 inhibitors often also affect P-gp. Increased aliskiren exposure during co-administration of CYP3A4 inhibitors that also inhibit P-gpcan therefore be expected (see other P-gp references in section 4.5).

No relevant interactions with atenolol, digoxin, amlodipine or cimetidine have been observed. Whenadministered with atorvastatin (80 mg), steady-state aliskiren (300 mg) AUC and Cmax increased by50%. In experimental animals, it has been shown that P-gp is a major determinant of aliskirenbioavailability. Inducers of P-gp (St. John’s wort, rifampicin) might therefore decrease thebioavailability of aliskiren.

Preclinical studies indicate that aliskiren might be a substrate of organic anion transportingpolypeptides. Therefore, the potential exists for interactions between OATP inhibitors and aliskirenwhen administered concomitantly (see section “Fruit juice and drinks containing plant extracts”above).).

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

Renal clearance of lithium is reduced by thiazides, therefore the risk of lithium toxicity may beincreased with hydrochlorothiazide. Co-administration of lithium and hydrochlorothiazide is notrecommended. If this combination proves essential, careful monitoring of serum lithium level isrecommended during concomitant use.

Due to the risk of hypokalaemia, hydrochlorothiazide should be administered with caution whenassociated with medicinal products that could induce torsades de pointes, in particular Class Ia and

Class III antiarrhythmics and some antipsychotics.

The hyponatraemic effect of diuretics may be intensified by concomitant administration of medicinalproducts such as antidepressants, antipsychotics, antiepileptics, etc. Caution is indicated in long-termadministration of these medicinal products.

Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline. The clinicalsignificance of this effect is uncertain and not sufficient to preclude their use.

Thiazide-induced hypokalaemia or hypomagnesaemia may occur as undesirable effects, favouring theonset of digitalis-induced cardiac arrhythmias.

Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calciumsalts may potentiate the rise in serum calcium. Concomitant use of thiazide type diuretics may lead tohypercalcaemia in patients pre-disposed for hypercalcaemia (e.g. hyperparathyroidism, malignancy, orvitamin-D-mediated conditions) by increasing tubular calcium reabsorption.

Thiazides may alter glucose tolerance. Dose adjustment of the antidiabetic medicinal product may benecessary (see section 4.4). Metformin should be used with caution because of the risk of lacticacidosis induced by possible functional renal failure linked to hydrochlorothiazide.

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta blockers may increasethe risk of hyperglycaemia. Thiazide diuretics, including hydrochlorothiazide, may enhance thehyperglycaemic effect of diazoxide.

Dose adjustment of uricosuric medicinal products may be necessary as hydrochlorothiazide may raisethe level of serum uric acid. Increase of dose of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide diuretics, including hydrochlorothiazide, may increase the incidence ofhypersensitivity reactions to allopurinol.

The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine,biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate.

Conversely, it is anticipated that prokinetic substances such as cisapride may decrease thebioavailability of thiazide-type diuretics.

Thiazides, including hydrochlorothiazide, may increase the risk of adverse reactions caused byamantadine.

Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine orcolestipol. This could result in sub-therapeutic effects of thiazide diuretics. However, staggering thedose of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 hoursbefore or 4-6 hours after the administration of resins would potentially minimise the interaction.

Thiazides, including hydrochlorothiazide, may reduce the renal excretion of cytotoxic agents (e.g.

cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

Thiazides, including hydrochlorothiazide, potentiate the action of skeletal muscle relaxants such ascurare derivatives.

Concomitant administration of thiazide diuretics with subtances that also have a blood pressurelowering effect (e.g. by reducing sympathetic central nervous system activity or direct vasodilatation)may potentiate orthostatic hypotension.

There have been isolated reports of haemolytic anaemia occurring with concomitant use ofhydrochlorothiazide and methyldopa.

In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially withhigh doses of iodine products. Patients should be rehydrated before administration.

There are no data on the use of aliskiren in pregnant women. Aliskiren was not teratogenic in rats orrabbits (see section 5.3). Other substances that act directly on the RAAS have been associated withserious foetal malformations and neonatal death when used during second and third trimesters. Thereis limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester.

Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action 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.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension orpre-eclampsia 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.

No specific clinical studies have been performed with this combination, therefore Rasilez HCT shouldnot be used during the first trimester of pregnancy or in women planning to become pregnant and iscontraindicated during the second and third trimesters (see section 4.3). A switch to a suitablealternative treatment should be carried out in advance of a planned pregnancy. If pregnancy is detectedduring therapy, Rasilez HCT should be discontinued as soon as possible.

It is not known whether aliskiren is excreted in human milk. Aliskiren was secreted in the milk oflactating rats.

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causingintense diuresis can inhibit milk production.

The use of Rasilez HCT during breast-feeding is not recommended. If Rasilez HCT is used duringbreast-feeding, doses should be kept as low as possible.

There are no clinical data on fertility.

Rasilez HCT has minor influence on the ability to drive and use machines. When driving vehicles orusing machines, it must be borne in mind that dizziness or drowsiness may occasionally occur whentaking Rasilez HCT.

The safety of Rasilez HCT has been evaluated in more than 3,900 patients, including over 700 treatedfor over 6 months, and 190 for over 1 year. The incidence of adverse reactions showed no associationwith gender, age, body mass index, race or ethnicity. Treatment with Rasilez HCT had an overallincidence of adverse experiences at doses up to 300 mg/25 mg similar to placebo. The most commonadverse reaction observed with Rasilez HCT is diarrhoea. The adverse reactions previously reportedwith one of the individual components of Rasilez HCT (aliskiren and hydrochlorothiazide) andincluded in the tabulated list of adverse reactions may occur with Rasilez HCT.

The frequency of adverse reactions listed below is defined using the following convention: verycommon (≥ 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) and not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

The adverse reactions observed with Rasilez HCT or with monotherapy with one or both of the twocomponents are included in the table below. For adverse reactions observed with more than onecomponent of a fixed-dose combination, the highest frequency is listed in the table below.

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

Not known Non-melanoma skin cancer (Basal cell carcinoma and

Squamous cell carcinoma)

Rare Thrombocytopenia sometimes with purpurah

Very rare Agranulocytosish, bone marrow depressionh, haemolyticanaemiah, leucopeniah

Not known Aplastic anaemiah

Rare Anaphylactic reactionsa, hypersensitivity reactionsa,h

Very common Hypokalaemiah

Common Hyperuricaemiah, hypomagnesaemiah

Rare Hypercalcaemiah, hyperglycaemiah, worsening of diabeticmetabolic stateh

Very rare Hypochloraemic alkalosish

Rare Depressionh, sleep disturbancesh

Rare Headacheh, paraesthesiah

Rare Visual impairmenth

Not known Acute angle-closure glaucomah, choroidal effusionh

Ear and labyrinth disorders

Not known Vertigoa

Common Dizzinessa,h

Uncommon Palpitationsa, oedema peripherala

Rare Cardiac arrhythmiash

Common Orthostatic hypotensionh

Uncommon Hypotensionc,a

Uncommon Cougha

Very rare Respiratory distress (including pneumonitis and pulmonaryoedema) h

Not known Dyspnoeaa

Common Diarrhoeac,a,h, decreased appetiteh, nausea and vomitinga,h

Rare Abdominal discomforth, constipationh

Very rare Pancreatitish

Rare Intrahepatic cholestasish, jaundicea,h

Not known Liver disordera,*, hepatitisa, liver failurea,**

Common Urticaria and other forms of rasha,h

Uncommon Severe cutaneous adverse reactions (SCARs) including

Stevens Johnson syndromea, toxic epidermal necrolysis(TEN)a, oral mucosal reactionsa, pruritusa

Rare Angioedemaa, erythemaa, photosensitivity reactionsh

Very rare Cutaneous lupus erythematosus-like reactionsh, reactivationof cutaneous lupus erythematosush, vasculitis necrotising andtoxic epidermal necrolysish

Not known Erythema multiformeh

Common Arthralgiaa

Not known Muscle spasmh

Uncommon Acute renal failurea,h, renal impairmenta

Not known Renal dysfunctionh

Common Impotenceh

Not known Astheniah, pyrexiah

Very common Increases in cholesterol and triglyceridesh

Common Hyperkalaemiaa, hyponatraemia c, a, h

Uncommon Liver enzyme increaseda

Rare Haemoglobin decreaseda, haematocrit decreaseda, bloodcreatinine increaseda, glycosuriahc Adverse reaction observed with Rasilez HCTa Adverse reaction observed with monotherapy with aliskirenh Adverse reaction observed with monotherapy with hydrochlorothiazide

* Isolated cases of liver disorder with clinical symptoms and laboratory evidence of more markedhepatic dysfunction.

** Including one case of “liver failure fulminant” reported in the post-marketing experience, for whicha causal relationship with aliskiren cannot be excluded.

Diarrhoea is a dose-related adverse reaction for aliskiren. In controlled clinical study, the incidence ofdiarrhoea in Rasilez HCT-treated patients was 1.3% compared to 1.4% for aliskiren- or 1.9% forhydrochlorothiazide-treated patients.

In a large placebo-controlled clinical study, the opposite effects of aliskiren (150 mg or 300 mg) andhydrochlorothiazide (12.5 mg or 25 mg) on serum potassium approximately balanced each other inmany patients. In other patients, one or the other effect may be dominant. Periodic determinations ofserum potassium to detect possible electrolyte imbalance should be performed in patients at risk atappropriate intervals (see sections 4.4 and 4.5).

Additional information on individual components

Adverse reactions previously reported with one of the individual components may occur with Rasilez

HCT even if not observed in clinical study.

Hypersensitivity reactions including anaphylactic reactions and angioedema have occurred duringtreatment with aliskiren.

In controlled clinical study, angioedema and hypersensitivity reactions occurred rarely duringtreatment with aliskiren with rates comparable to treatment with placebo or comparators.

Cases of angioedema or symptoms suggestive of angioedema (swelling of the face, lips, throat and/ortongue) have also been reported in post-marketing experience. A number of these patients had ahistory of angioedema or symptoms suggestive of angioedema which in some cases was associatedwith the administration of other medicinal products known to cause angioedema, including RAASblockers (ACEIs or ARBs).

In post-marketing experience, cases of angioedema or angioedema-like reactions have been reportedwhen aliskiren was co-administered with ACEIs and/or ARBs.

Hypersensitivity reactions including anaphylactic reactions have also been reported in post-marketingexperience (see section 4.4).

In the event of any signs suggesting a hypersensitivity reaction/angioedema (in particular difficultiesin breathing or swallowing, rash, itching, hives or swelling of the face, extremities, eyes, lips and/ortongue, dizziness) patients should discontinue treatment and contact the physician (see section 4.4).

Arthralgia has been reported in post-marketing experience. In some cases this occurred as part of ahypersensitivity reaction.

In post-marketing experience, renal dysfunction, and cases of acute renal failure have been reported inpatients at risk (see section 4.4).

Small decreases in haemoglobin and haematocrit (mean decreases of approximately 0.05 mmol/l and0.16 volume percent, respectively) were observed. No patients discontinued therapy due to anaemia.

This effect is also seen with other agents acting on the renin-angiotensin system, such as ACEIs and

ARBs.

Increases in serum potassium have been observed with aliskiren and these may be exacerbated byconcomitant use of other agents acting on the RAAS or by NSAIDs. Consistent with standard medicalpractice, periodic determination of renal function including serum electrolytes is advised if co-administration is considered necessary.

Aliskiren has been evaluated for safety in a randomised, double-blind, 8-week study in267 hypertensive patients aged 6 to 17 years, mostly overweight/obese, followed by an extensionstudy including 208 patients treated for 52 weeks. An additional 52 to 104 weeks non-interventionalobservational extension study in 106 patients (no study treatment administered) was conducted withthe objective to evaluate the long-term safety in terms of growth and development of children 6-17years of age with hypertension (primary or secondary) at baseline in the core study, previously treatedwith aliskiren.

The frequency, type and severity of adverse reactions in children were generally similar to those seenin hypertensive adults. No overall clinically relevant adverse impact in paediatric patients aged 6 to17 years was observed after treatment with aliskiren for up to one year based on physicaldevelopment, assessed in patients with primary or secondary hypertension, and neurocognitivedevelopment assessed only in patients with secondary hypertension (19 patients: 9 previously treatedwith aliskiren and 10 previously treated with enalapril). See section 4.2, pct. 4.8, 5.1 and 5.2 forinformation on paediatric use.

Hydrochlorothiazide has been extensively prescribed for many years, frequently in higher doses thanthose contained in Rasilez HCT. The adverse reactions listed in the table above, which are markedwith the reference “h”, have been reported in patients treated with thiazide diuretics alone, includinghydrochlorothiazide.

Based on available data from epidemiological studies, cumulative dose-dependent association between

HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).

Reporting 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.

The most likely manifestation of overdose would be hypotension, related to the antihypertensive effectof aliskiren.

Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia,hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. The mostcommon signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result inmuscle spasms and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalisglycosides or certain antiarrhythmic medicinal products.

If symptomatic hypotension should occur, supportive treatment should be initiated.

In a study conducted in patients with end stage renal disease (ESRD) receiving haemodialysis, dialysisclearance of aliskiren was low (< 2% of oral clearance). Therefore, dialysis is not adequate to treataliskiren over-exposure.

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system; renin inhibitor, ATCcode: C09XA52

Rasilez HCT combines two antihypertensive active substances to control blood pressure in patientswith essential hypertension: Aliskiren belongs to the class of direct renin inhibitors andhydrochlorothiazide to the class of thiazide diuretics. The combination of these substances withcomplementary mechanisms of action provides an additive antihypertensive effect, reducing bloodpressure to a greater degree than either component alone.

Aliskiren is an orally active, non-peptide, potent and selective direct inhibitor of human renin.

By inhibiting the enzyme renin, aliskiren inhibits the RAAS at the point of activation, blocking theconversion of angiotensinogen to angiotensin I and decreasing levels of angiotensin I andangiotensin II. Whereas other agents that inhibit the RAAS (angiotensin converting enzyme inhibitors(ACEI) and angiotension II receptor blockers (ARB)) cause a compensatory rise in plasma reninactivity (PRA), treatment with aliskiren decreases PRA in hypertensive patients by approximately 50to 80%. Similar reductions were found when aliskiren was combined with other antihypertensiveagents. The clinical implications of the effects on PRA are not known at the present time.

In hypertensive patients, once-daily administration of aliskiren at doses of 150 mg and 300 mgprovided dose-dependent reductions in both systolic and diastolic blood pressure that were maintainedover the entire 24-hour dose interval (maintaining benefit in the early morning) with a mean peak totrough ratio for diastolic response of up to 98% for the 300 mg dose. 85 to 90% of the maximal blood-pressure-lowering effect was observed after 2 weeks. The blood-pressure-lowering effect wassustained during long-term treatment (12 months), and was independent of age, gender, body massindex and ethnicity.

Combination therapy studies are available for aliskiren added to the diuretic hydrochlorothiazide, thecalcium channel blocker amlodipine and the beta blocker atenolol. These combinations wereefficacious and well tolerated.

The efficacy and safety of aliskiren-based therapy were compared to ramipril-based therapy in a 9-month non-inferiority study in 901 elderly patients (≥ 65 years) with essential systolic hypertension.

Aliskiren 150 mg or 300 mg per day or ramipril 5 mg or 10 mg per day were administered for36 weeks with optional add-on therapy of hydrochlorothiazide (12.5 mg or 25 mg) at week 12, andamlodipine (5 mg or 10 mg) at week 22. Over the 12 week period, aliskiren monotherapy loweredsystolic/diastolic blood pressure by 14.0/5.1 mmHg, compared to 11.6/3.6 mmHg for ramipril,consistent with aliskiren being non-inferior to ramipril at the doses chosen and the differences insystolic and diastolic blood pressure were statistically significant. Tolerability was comparable in bothtreatment arms, however cough was more often reported with the ramipril regimen than the aliskirenregimen (14.2% vs. 4.4%), whilst diarrhoea was more common with the aliskiren regimen than for theramipril regimen (6.6% vs. 5.0%).

In a 8-week study in 754 hypertensive elderly (≥ 65 years) and very elderly patients (30% ≥ 75 years)aliskiren at doses of 75 mg, 150 mg and 300 mg provided statistically significant superior reduction inblood pressure (both systolic and diastolic) when compared to placebo. No additional blood pressurelowering effect was detected with 300 mg aliskiren compared to 150 mg aliskiren. All three doseswere well tolerated in both elderly and very elderly patients. In a pooled analysis of efficacy and safetydata from clinical study up to 12 months duration, there was no statistically significant difference inblood pressure reduction between aliskiren 300 mg and aliskiren 150 mg in elderly patients(≥ 65 years).

There has been no evidence of first-dose hypotension and no effect on pulse rate in patients treated incontrolled clinical studies. With cessation of treatment, blood pressure gradually returned towardsbaseline levels over a period of several weeks, with no evidence of a rebound effect for blood pressureor PRA.

In a 36-week study involving 820 patients with ischaemic left ventricular dysfunction, no changes inventricular remodelling as assessed by left ventricular end systolic volume were detected withaliskiren compared to placebo on top of background therapy.

The combined rates of cardiovascular death, hospitalisation for heart failure, recurrent heart attack,stroke and resuscitated sudden death were similar in the aliskiren group and the placebo group.

However, in patients receiving aliskiren there was a significantly higher rate of hyperkalaemia,hypotension and kidney dysfunction when compared to the placebo group.

Aliskiren was evaluated for cardiovascular and/or renal benefit in a double-blind placebo controlledrandomised trial in 8,606 patients with type 2 diabetes and chronic kidney disease (evidenced byproteinuria and/or GFR < 60 ml/min/1.73 m2) with or without cardiovascular disease. In most patientsarterial blood pressure was well controlled at baseline. The primary endpoint was a composite ofcardiovascular and renal complications.

In this study, aliskiren 300 mg was compared to placebo when added to standard of care whichincluded either an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. Thestudy was discontinued prematurely because the participants were unlikely to benefit from aliskiren.

The final study results indicated a hazard ratio for the primary endpoint of 1.097 in favour of placebo(95.4% Confidence Interval: 0.987, 1.218, 2-sided p=0.0787). In addition, an increased incidence ofadverse events was observed with aliskiren compared to placebo (38.2% versus 30.3%). In particularthere was an increased incidence of renal dysfunction (14.5% versus 12.4%), hyperkalaemia (39.1%versus 29.0%), hypotension-related events (19.9% versus 16.3%) and adjudicated stroke endpoints(3.4% versus 2.7%). The increased incidence of stroke was greater in patients with renal insufficiency.

Aliskiren 150 mg (increased to 300 mg if tolerated) added to conventional therapy was evaluated in adouble-blind placebo-controlled randomised trial in 1,639 patients with reduced ejection fractionhospitalised for an episode of acute heart failure (NYHA Class III-IV) who were haemodynamicallystable at baseline. The primary endpoint was cardiovascular death or heart failure rehospitalisationwithin 6 months; secondary endpoints were assessed within 12 months.

The study showed no benefit of aliskiren when administered on top of standard therapy for acute heartfailure and an increased risk of cardiovascular events in patients with diabetes mellitus. Study resultsindicated a non-significant effect of aliskiren with a hazard ratio of 0.92 (95% Confidence Interval:

0.76-1.12; p=0.41, aliskiren vs. placebo). Different treatment effects of aliskiren were reported foroverall mortality within 12 months dependent on diabetes mellitus status. In the subgroup of patientswith diabetes mellitus the hazard ratio was 1.64 in favour of placebo (95% Confidence Interval:

1.15-2.33), whereas the hazard ratio in the subgroup of patients without diabetes was 0.69 in favour ofaliskiren (95% Confidence Interval: 0.50-0.94); p-value for interaction = 0.0003. An increasedincidence of hyperkalaemia (20.9% versus 17.5%), renal impairment/renal failure (16.6% versus12.1%) and hypotension (17.1% versus 12.6%) was observed in the aliskiren group compared withplacebo and was greater in patients with diabetes.

Aliskiren was evaluated for cardiovascular mortality and morbidity benefit in a double-blind activecontrolled randomised study in 7,064 patients with chronic heart failure and reduced left ventricularejection fraction, of which 62% had a history of hypertension. The primary endpoint was a compositeof cardiovascular death and first hospitalisation for heart failure.

In this study, aliskiren at a target dose of 300 mg was compared to enalapril at a target dose of 20 mgwhen added to standard of care which included a beta blocker (and a mineralocorticoid receptorantagonist in 37% of patients) and a diuretic as needed. The study also evaluated the combination ofaliskiren and enalapril. Mean duration of follow-up was 3.5 years. The final results of the study did notdemonstrate statistically that aliskiren was non-inferior to enalapril on the primary endpoint, howeverthere was essentially no difference in the observed incidence rates between aliskiren and enalapril(hazard ratio of 0.99 with 95% Confidence Interval: 0.90-1.10). There was no significant benefit ofadding aliskiren to enalapril (primary endpoint: hazard ratio of 0.93 with 95% Confidence Interval:

0.85-1.03; p=0.1724, combination versus enalapril). Treatment effects were similar in patients withdiabetes and with renal insufficiency. The incidence of adjudicated stroke was not significantlydifferent between the aliskiren and enalapril groups (4.4% versus 4.0%; HR 1.12, 95% CI 0.848,1.485) or between the combination and enalapril groups (3.7% versus 4.0%; HR 0.93, 95% CI 0.697,1.251). The incidence of adverse events tended to be higher in patients with diabetes, or with GFR<60 ml/min/1.73 m², or with age ≥ 65 years; however, there was no difference between patients treatedwith aliskiren and those treated with enalapril.

The incidence of certain adverse events was similar between aliskiren and enalapril groups while therewas an increased incidence of adverse events with the combination of aliskiren and enalapril:

hyperkalaemia (21.4%, 13.2%, and 15.9% for combination, aliskiren and enalapril respectively); renalimpairment/renal failure (23.2%, 17.4% and 18.7%) and hypotension related events (27.0%, 22.3%and 22.4%).

There was a statistically significant increased incidence of syncope with the combination of aliskirenand enalapril compared to enalapril in the overall population (4.2% versus 2.8%; RR 1.51, 95% CI1.11-2.05) and in the subgroups NYHA I/II overall (4.8% versus 3.0%; RR 1.62, 95% CI 1.14-2.29).

The incidence of atrial fibrillation was 11.1%, 13.3%, and 11.0% in the combination, aliskiren, andenalapril groups, respectively.

Statistically significantly higher incidences in the occurrence of cardiac failure and ischaemic strokewere also found for aliskiren compared to enalapril in patients with NYHA I/II with hypertension, andin the occurrence of chronic cardiac failure and ventricular extrasystole in patients with NYHA III/IVwith hypertension. For the combination of aliskiren and enalapril there were statistically significantdifferences in the rate of angina unstable compared to enalapril.

No clinically relevant differences in efficacy or safety results were observed in the subpopulation ofelderly patients with a history of hypertension and chronic heart failure Class I-II compared to theoverall study population.

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 by competing for the Cl- site, therebyaffecting electrolyte reabsorption mechanisms: directly increasing sodium and chloride excretion to anapproximately equal extent, and indirectly by this diuretic action reducing plasma volume, withconsequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and adecrease in serum potassium.

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed. One study included a populationcomprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462population controls, respectively. High HCTZ use (≥50,000 mg cumulative) was associated with anadjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clearcumulative dose response relationship was observed for both BCC and SCC. Another study showed apossible association between lip cancer (SCC) and exposure to HCTZ: 633 cases of lip-cancer werematched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose(~100,000 mg) (see also section 4.4).

Over 3,900 hypertensive patients received Rasilez HCT once daily in clinical study.

In hypertensive patients, once-daily administration of Rasilez HCT provided dose-dependentreductions in both systolic and diastolic blood pressure that were maintained over the entire 24-hourdose interval. The antihypertensive effect is largely manifested within 1 week and the maximum effectis generally seen within 4 weeks. The blood-pressure-lowering effect was sustained during long-termtreatment, and was independent of age, gender, body mass index and ethnicity. The antihypertensiveeffect of a single dose of the combination persisted for 24 hours. Upon withdrawal of the aliskirentreatment (aliskiren with or without hydrochlorothiazide add-on), the return of blood pressure towardsbaseline was gradual (3-4 weeks) with no evidence of the rebound effect.

Rasilez HCT was studied in a placebo-controlled trial including 2,762 hypertensive patients withdiastolic blood pressure ≥ 95 mmHg and < 110 mmHg (mean baseline blood pressure of153.6/99.2 mmHg). In this study, Rasilez HCT in doses from 150 mg/12.5 mg to 300 mg/25 mgproduced dose-dependent blood pressure reductions (systolic/diastolic) from 17.6/11.9 mmHg to21.2/14.3 mmHg, respectively, compared to 7.5/6.9 mmHg with placebo. The greater blood pressurereductions with these combination doses were also significantly greater than the respective doses ofaliskiren and hydrochlorothiazide when used alone. The combination of aliskiren andhydrochlorothiazide neutralised the reactive increase of PRA caused by hydrochlorothiazide.

When administered in hypertensive patients with markedly elevated blood pressure (systolic bloodpressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg), Rasilez HCT in doses from150 mg/12.5 mg to 300 mg/25 mg administered without up-titration from monotherapy demonstratedsignificantly greater systolic/diastolic blood pressure control rates (< 140/90 mmHg) as compared tothe respective monotherapies. In this population, Rasilez HCT 150 mg/12.5 mg to 300 mg/25 mgprovided dose-dependent systolic/diastolic blood pressure reduction from 20.6/12.4 mmHg to24.8/14.5 mmHg, which were significantly superior to the respective monotherapies. The safety of thecombination therapy was similar to the respective monotherapies regardless of severity ofhypertension or of the presence or absence of additional cardiovascular risk. Hypotension and relatedadverse events were uncommon with the combination treatment, with no increased incidence inelderly patients.

In a study in 880 randomised patients not adequately responsive to aliskiren 300 mg treatment, thecombination of aliskiren/hydrochlorothiazide 300 mg/25 mg produced systolic/diastolic bloodpressure reductions of 15.8/11.0 mmHg, which were significantly greater than aliskiren 300 mgmonotherapy. In a study in 722 randomised patients not adequately responsive to hydrochlorothiazide25 mg treatment, the combination of aliskiren/hydrochlorothiazide 300 mg/25 mg producedsystolic/diastolic blood pressure reductions of 16.78/10.7 mmHg, which were significantly greaterthan hydrochlorothiazide 25 mg monotherapy.

In another clinical studies, the efficacy and safety of Rasilez HCT were also assessed in 489 obesehypertensive patients who did not respond to hydrochlorothiazide 25 mg (baseline systolic/diastolicblood pressure 149.4/96.8 mmHg). In this difficult-to-treat population, Rasilez HCT provided a bloodpressure reduction (systolic/diastolic) of 15.8/11.9 mmHg compared to 15.4/11.3 mmHg forirbesartan/hydrochlorothiazide, 13.6/10.3 mmHg for amlodipine/hydrochlorothiazide and8.6/7.9 mmHg for hydrochlorothiazide monotherapy, with similar safety to hydrochlorothiazidemonotherapy.

In a study in 183 randomised patients with severe hypertension (mean sitting diastolic blood pressure≥ 105 and < 120 mmHg), aliskiren treatment regimen with optional addition of hydrochlorothiazide25 mg was shown to be safe and efficacious in reducing blood pressure.

In a multicentre, randomised, double-blind, 8-week study with aliskiren monotherapy (3 dose groupsby weight category [≥20 kg to <50 kg; ≥50 kg to <80 kg; ≥80 kg to ≤150 kg]: low 6.25/12.5/25 mg[0.13-0.31 mg/kg]; mid 37.5/75/150 mg [0.75-1.88 mg/kg]; and high dose 150/300/600 mg[3.0-7.5 mg/kg], with a wide dose ratio between the low, mid and high dose groups [1:6:24]) in 267paediatric hypertensive patients aged 6 to 17 years, mostly overweight/obese, aliskiren lowered officeand ambulatory blood pressure in a dose-dependent manner during the initial 4 week dose-findingphase of the study (Phase 1). However, in the subsequent 4 week randomised withdrawal phase of thestudy (Phase 2), the effect of aliskiren overlapped with the effects observed in patients switched toplacebo in all dose groups (low, p=0.8894; mid, p=0.9511; high, p=0.0563). The average differencesbetween aliskiren and placebo for the low and mid dose groups were <0.2 mmHg. The treatment withaliskiren was well tolerated in this study.

This study was extended with a 52-week double-blind, randomised study to evaluate the safety,tolerability and efficacy of aliskiren compared to enalapril in 208 paediatric hypertensive patients aged6 to 17 years (at baseline in the previous study). The starting dose in each group was assigneddepending on weight with three groups: ≥20 to <50 kg, ≥50 to <80 kg, and ≥80 to ≤150 kg. Thestarting doses for aliskiren were 37.5/75/150 mg in the low, mid and high weight groups, respectively.

The starting doses for enalapril were 2.5/5/10 mg in the low, mid and high weight groups,respectively. Optional titration of the respective study drug doses to the next highest weight-baseddose level was available by doubling the dose with each of the two allowed dose titrations, up to600 mg (highest studied dose in adults) for aliskiren and 40 mg for enalapril in the ≥80 to ≤150 kgweight group, if medically necessary to control the mean sitting systolic blood pressure (i.e. msSBPshould be less than the 90th percentile for age, gender and height). Overall, the mean age of thepatients was 11.8 years with 48.6% of patients being in the 6-11 years age group and 51.4% in the12-17 years age group. Mean weight was 68.0 kg with 57.7% of patients having BMI greater than orequal to the 95th percentile for age and gender. At the end of this extension study, changes in msSBPfrom baseline were similar with aliskiren compared to enalapril (-7.63 mmHg vs. -7.94 mmHg) in thefull analysis set. However, the significance of the non-inferiority testing was not maintained when theanalysis was performed on the per-protocol set in which the least square mean change in msSBP frombaseline was -7.84 mmHg with aliskiren and -9.04 mmHg with enalapril. In addition, due to thepossibility of up-titration if medically necessary to control the msSBP, no conclusion can be drawn onthe appropriate posology of aliskiren in patients aged 6 to 17 years.

After the first 52 week extension study, eligible male and female paediatric patients aged 6 to 17 yearswith primary or secondary hypertension, were enrolled in a 52 to 104 week off-therapy non-interventional observational extension study designed to evaluate the LT growth and development,through height and weight measurement, with added neurocognitive and renal function evaluations asfollow-up measures performed only in patients with secondary hypertension (19 patients: 9 previouslytreated with aliskiren and 10 previously treated with enalapril).

There were no statistically significant differences in the mean changes in weight, height, or BMIbetween the treatment groups from Baseline to LT Visit 18 (Week 104) (primary analysis).

In patients after 104 weeks (at LT Visit 19 [Week 156]), there were LS mean decreases from Baselinein weight and BMI in both treatment groups, with a slightly larger decrease in the aliskiren comparedto the enalapril treatment group.

There was a greater LS mean increase from Baseline in height after 104 weeks (at LT Visit 19 [Week156], secondary hypertension patients) compared to the increase observed after 52 weeks (at LT Visit18 [Week 104], primary hypertension patients), which is expected in these growing paediatric patients.

Results of the neurocognitive assessments showed some improvements in most of the test scores, withno meaningful difference between the treatment groups.

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

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

Following oral absorption, peak plasma concentrations of aliskiren are reached after 1-3 hours. Theabsolute bioavailability of aliskiren is approximately 2-3%. Meals with a high fat content reduce Cmaxby 85% and AUC by 70%. At steady state meals with low fat content reduce Cmax by 76% and AUC0-tau by 67% in hypertensive patients. However the efficacy of aliskiren was similar when taken with alight meal or under fasted state. Steady-state-plasma concentrations are reached within 5-7 daysfollowing once-daily administration and steady-state levels are approximately 2-fold greater than withthe initial dose.

MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption andbiliary excretion of aliskiren in pre-clinical studies.

Following intravenous administration, the mean volume of distribution at steady state is approximately135 litres, indicating that aliskiren distributes extensively into the extravascular space. Aliskirenplasma protein binding is moderate (47-51%) and independent of the concentration.

The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as unchangedcompound in the faeces (oral radioactive dose recovery = 91%). Approximately 1.4% of the total oraldose is metabolised. The enzyme responsible for this metabolism is CYP3A4. Approximately 0.6% ofthe dose is recovered in urine following oral administration. Following intravenous administration, themean plasma clearance is approximately 9 l/h.

Exposure to aliskiren increased slightly more than in proportion to the increase in dose. After singledose administration in the dose range of 75 to 600 mg, a 2-fold increase in dose results in a ~2.3 and2.6-fold increase in AUC and Cmax, respectively. Mechanisms responsible for the deviation from doseproportionality have not been identified. A possible mechanism is saturation of transporters at theabsorption site or at the hepatobiliary clearance route.

In a pharmacokinetic study of aliskiren treatment in 39 paediatric hypertensive patients aged 6 to17 years given daily doses of 2 mg/kg or 6 mg/kg aliskiren administered as granules (3.125 mg/tablet),pharmacokinetic parameters were similar to those in adults. The results of this study did not suggestthat age, body weight or gender have any significant effect on aliskiren systemic exposure (seesection 4.2).

In an 8-week randomised, double-blind study with aliskiren monotherapy in 267 paediatrichypertensive patients aged 6 to 17 years, mostly overweight/obese, fasting trough aliskirenconcentrations at day 28 were comparable to those observed in other studies in both adults andchildren using similar aliskiren doses.

Results from an in vitro MDR1 human tissue study suggested an age and tissue dependent pattern of

MDR1 (P-gp) transporter maturation. A high inter-individual variability of mRNA expression levelswas observed (up to 600-fold). Hepatic MDR1 mRNA expression was statistically significantly lowerin samples from foetuses, neonates and infants up to 23 months.

The age at which the transporter system is mature cannot be determined. There is a potential foraliskiren overexposure in children with an immature MDR1 (P-gp) system (see section “Transporters”above and sections 4.2, pct. 4.4 and 5.3).

The absorption of hydrochlorothiazide, after an oral dose, is rapid (Tmax about 2 h). 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 iseliminated from plasma with a half-life averaging 6 to 15 hours in the terminal elimination phase.

There is no change in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation isminimal when dosed once daily. There is more than 95% of the absorbed dose being excreted asunchanged compound in the urine. The renal clearance is composed of passive filtration and activesecretion into the renal tubule.

Following oral administration of Rasilez HCT tablets, the median peak plasma concentration time iswithin 1 hour for aliskiren and 2.5 hours for hydrochlorothiazide.

The rate and extent of absorption of Rasilez HCT are equivalent to the bioavailability of aliskiren andhydrochlorothiazide when administered as individual monotherapies. Similar food effect was observedfor Rasilez HCT as for the individual monotherapies.

Rasilez HCT has been shown to be effective as a once-a-day antihypertensive treatment in adultpatients, regardless of gender, age, body mass index and ethnicity.

The pharmacokinetics of aliskiren are not significantly affected in patients with mild to moderate liverdisease. Consequently, no initial dose adjustment of Rasilez HCT is required in patients with mild tomoderate hepatic impairment. No data are available on patients with severe hepatic impairment treatedby Rasilez HCT. Rasilez HCT is contraindicated in patients with severe hepatic impairment (seesection 4.3).

No adjustment of the initial dose is required for patients with mild to moderate renal impairment (seesections 4.2 and 4.4). In the presence of renal impairment, mean peak plasma levels and AUC valuesof hydrochlorothiazide are increased and the urinary excretion rate is reduced. In patients with mild tomoderate renal impairment, a 3-fold increase in hydrochlorothiazide AUC has been observed. Inpatients with severe renal impairment an 8-fold increase in AUC has been observed.

The pharmacokinetics of aliskiren were evaluated in patients with end stage renal disease receivinghaemodialysis. Administration of a single oral dose of 300 mg aliskiren was associated with veryminor changes in the pharmacokinetics of aliskiren (change in Cmax of less than 1.2 fold; increase in

AUC of up to 1.6 fold) compared to matched healthy subjects. Timing of haemodialysis did notsignificantly alter the pharmacokinetics of aliskiren in ESRD patients. Therefore, if administration ofaliskiren in ESRD patients receiving haemodialysis is considered necessary, no dose adjustment iswarranted in these patients. However, the use of aliskiren is not recommended in patients with severerenal impairment (see section 4.4).

No initial dose adjustment of Rasilez HCT is required in elderly patients. Limited data suggest that thesystemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjectscompared to young healthy volunteers.

No pharmacokinetic data on Rasilez HCT are available in the paediatric population.

Safety pharmacology studies with aliskiren did not reveal any adverse effects on central nervous,respiratory or cardiovascular function. Findings during repeat-dose toxicity studies in animals wereconsistent with the known local (gastrointestinal tract) irritation potential or the expectedpharmacological effects of aliskiren.

No carcinogenic potential for aliskiren was detected in a 2-year rat study and a 6-month transgenicmouse study. One colonic adenoma and one caecal adenocarcinoma recorded in rats at the dose of1500 mg/kg/day were not statistically significant.

Although aliskiren has known local (gastrointestinal tract) irritation potential, safety margins obtainedin humans at the dose of 300 mg during a study in healthy volunteers were considered to be appropriateat 9-11-fold based on faecal concentrations or 6-fold based on mucosa concentrations in comparisonwith 250 mg/kg/day in the rat carcinogenicity study.

Aliskiren was devoid of any mutagenic potential in the in vitro and in vivo mutagenicity studies.

Reproductive toxicity studies with aliskiren did not reveal any evidence of embryofoetal toxicity orteratogenicity at doses up to 600 mg/kg/day in rats or 100 mg/kg/day in rabbits. Fertility, pre-nataldevelopment and post-natal development were unaffected in rats at doses up to 250 mg/kg/day. Thedoses in rats and rabbits provided systemic exposures of 1 to 4 and 5 times higher, respectively, than themaximum recommended human dose (300 mg).

Preclinical evaluations to support the administration of hydrochlorothiazide in humans included invitro genotoxicity assays and reproductive toxicity and carcinogenicity studies in rodents. Extensiveclinical data are available for hydrochlorothiazide and these are reflected in the relevant sections.

The findings observed in the 2-week and 13-week toxicity studies were consistent with those observedpreviously with aliskiren or hydrochlorothiazide monotherapies. There were no new or unexpectedfindings observed of relevance to human use. Increased cellular vacuolation of the adrenal gland zonaglomerulosa was observed during the 13-week toxicity study in rats. The finding was observed inanimals treated with hydrochlorothiazide but not in those animals receiving aliskiren alone or vehicle.

There was no evidence that this finding was enhanced in the aliskiren/hydrochlorothiazidecombination as it was only apparent at a minimal severity in all animals.

In a juvenile toxicity study in 8-day-old rats, aliskiren administration at 100 mg/kg/day and300 mg/kg/day (2.3- and 6.8-fold the maximum recommended human dose) was associated with highmortality and severe morbidity. In another juvenile toxicity study in 14-day old rats, aliskirenadministration at 300 mg/kg/day (8.5-fold the maximum recommended human dose) was associatedwith delayed mortality. The systemic exposure to aliskiren in 8-day old rats was >400-fold higher thanin adult rats. Results from a mechanistic study showed that the MDR1 (P-gp) gene expression injuvenile rats was significantly lower when compared to adult rats. The increased aliskiren exposure injuvenile rats appears to be attributed mainly to lack of maturation of P-gp in the gastrointestinal tract.

There is therefore a potential for aliskiren overexposure in paediatric patients with immature MDR1efflux system (see sections 4.2, pct. 4.3 and 5.2).

Microcrystalline cellulose

Crospovidone, type A

Lactose monohydrate

Wheat starch

Povidone, K-30

Magnesium stearate

Colloidal anhydrous silica

Talc

Talc

Hypromellose substitution type 2910 (3 mPa·s)

Macrogol 4000

Titanium dioxide (E171)

Microcrystalline cellulose

Crospovidone, type A

Lactose monohydrate

Wheat starch

Povidone, K-30

Magnesium stearate

Silica colloidal anhydrous

Talc

Talc

Hypromellose substitution type 2910 (3 mPa·s)

Macrogol 4000

Titanium dioxide (E171)

Red iron oxide (E172)

Yellow iron oxide (E172)

Microcrystalline cellulose

Crospovidone, type A

Lactose monohydrate

Wheat starch

Povidone, K-30

Magnesium stearate

Silica colloidal anhydrous

Talc

Talc

Hypromellose substitution type 2910 (3 mPa·s)

Macrogol 4000

Titanium dioxide (E171)

Red iron oxide (E172)

Black iron oxide (E172)

Microcrystalline cellulose

Crospovidone, type A

Lactose monohydrate

Wheat starch

Povidone, K-30

Magnesium stearate

Silica colloidal anhydrous

Talc

Talc

Hypromellose substitution type 2910 (3 mPa·s)

Macrogol 4000

Titanium dioxide (E171)

Red iron oxide (E172)

Yellow iron oxide (E172)

Not applicable.

3 years

Do not store above 25°C.

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

PA/Alu/PVC - Alu blisters:

Single-packs containing 7, 14, 28, 30, 50 or 56 tablets.

Multi-packs containing 90 (3 packs of 30), 98 (2 packs of 49) or 280 (20 packs of 14) tablets.

PVC/polychlorotrifluoroethylene (PCTFE) - Alu blisters:

Single-packs containing 7, 14, 28, 30, 50, 56, 90 or 98 tablets.

Single-packs (perforated unit dose blister) containing 56 x 1 tablets.

Multi-packs containing 280 (20 packs of 14) tablets.

Multi-packs (perforated unit dose blister) containing 98 (2 packs of 49 x 1) tablets.

Not all pack sizes or strengths may be marketed.

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

Noden Pharma DAC

D'Olier Chambers16A D'Olier Street

Dublin 2

Ireland

EU/1/08/491/001-020

EU/1/08/491/021-040

EU/1/08/491/041-060

EU/1/08/491/061-080

Date of first authorisation: 16 January 2009

Date of latest renewal: 27 August 2018

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

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