RASILEZ 300mg tablets medication leaflet

Rasilez 150 mg film-coated tablets

Rasilez 300 mg film-coated tablets

Rasilez 150 mg film-coated tablets

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

Rasilez 300 mg film-coated tablets

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

For the full list of excipients, see section 6.1.

Film-coated tablet.

Rasilez 150 mg film-coated tablets

Light-pink, biconvex, round tablet, imprinted “IL” on one side and “NVR” on the other side.

Rasilez 300 mg film-coated tablets

Light-red, biconvex, ovaloid tablet, imprinted “IU” on one side and “NVR” on the other side.

Treatment of essential hypertension in adults.

The recommended dose of Rasilez is 150 mg once daily. In patients whose blood pressure is notadequately controlled, the dose may be increased to 300 mg once daily.

The antihypertensive effect is substantially present within two weeks (85-90%) after initiating therapywith 150 mg once daily.

Rasilez may be used alone or in combination with other antihypertensive agents with the exception ofuse in combination with angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptorblockers (ARB) in patients with diabetes mellitus or renal impairment (glomerular filtration rate(GFR) < 60 ml/min/1.73 m2) (see sections pct. 4.3, pct. 4.4 and 5.1).

No adjustment of the initial dose is required for patients with mild to moderate renal impairment (seesections 4.4 and 5.2). Aliskiren is not recommended in patients with severe renal impairment (GFR< 30 ml/min/1.73 m2).

No adjustment of the initial dose is required for patients with mild to severe hepatic impairment (seesection 5.2).

Elderly patients aged 65 years and over

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.

Rasilez is contraindicated in children from birth to less than 2 years. Rasilez should not be used inchildren aged 2 to less than 6 years because of safety concerns due to potential aliskiren overexposure(see sections pct. 4.3, pct. 4.4, pct. 5.2, and 5.3). The safety and efficacy of Rasilez in children aged 6 to 17 yearshave not yet been established. Currently available data are described in sections 4.8, 5.1, and 5.2. Useof Rasilez is not recommended in this population.

Oral use. The tablets should be swallowed whole with some water. Rasilez should be taken once a day,always with or always without food, preferably at the same time each day. Patients should establish aconvenient daily schedule of medicinal product intake and maintain a steady temporal relationshipwith food intake. Concomitant intake with fruit juice and/or drinks containing plant extracts (includingherbal teas) should be avoided (see section 4.5).

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- History of angioedema with aliskiren.

- Hereditary or idiopathic angioedema.

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

- 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 with an angiotensin converting enzyme inhibitor(ACEI) or anangiotensin II receptor blocker (ARB) is contraindicated in patients with diabetes mellitus orrenal 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).

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

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).

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

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.

Symptomatic hypotension could occur after initiation of treatment with aliskiren 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, or the treatmentshould start under close medical supervision.

In clinical studies aliskiren has not been investigated in hypertensive patients with severe renalimpairment (serum creatinine ≥ 150 μmol/l or 1.70 mg/dl in women and ≥ 177 μmol/l or 2.00 mg/dl inmen and/or estimated GFR < 30 ml/min/1.73 m2), history of dialysis, nephrotic syndrome orrenovascular hypertension. It is not recommended in patients with severe renal impairment (GFR< 30 ml/min/1.73 m2).

As for other medicinal products acting on the renin-angiotensin system, caution should be exercisedwhen aliskiren is given in the presence of conditions pre-disposing to kidney dysfunction such ashypovolaemia (e.g. due to blood loss, severe prolonged diarrhoea, prolonged vomiting, etc.), heartdisease, liver disease, diabetes mellitus or kidney disease. Acute renal failure, reversible upondiscontinuation of treatment, has been reported in at-risk patients receiving aliskiren in post-marketingexperience. In the event that any signs of renal failure occur, aliskiren should be promptlydiscontinued.

Increases in serum potassium have been observed with aliskiren in post-marketing experience andthese may be exacerbated by concomitant use of other agents acting on the RAAS or by non-steroidalanti-inflammatory drugs (NSAIDs). Consistent with standard medical practice, periodic determinationof renal function including serum electrolytes is advised if co-administration is considered necessary.

Renal artery stenosis

No controlled clinical data are available on the use of aliskiren in patients with unilateral or bilateralrenal artery stenosis, or stenosis to a solitary kidney. However, there is an increased risk of renalinsufficiency, including acute renal failure, when patients with renal artery stenosis are treated withaliskiren. Therefore, caution should be exercised in these patients. If renal failure occurs, treatmentshould 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, treatment 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.

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 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 sections 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.

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

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

AUC and 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 inaliskiren AUC or in a 63% decrease in aliskiren AUC, respectively. This decrease is likely due to aninhibition of organic anion transporting polypeptide-mediated uptake of aliskiren by components offruit juice in the gastrointestinal tract. Therefore, because of the risk of therapeutic failure, fruit juiceshould not be taken together with aliskiren. The effect of drinks containing plant extracts (includingherbal teas) on the absorption of aliskiren has not been investigated. However, compounds potentiallyinhibiting organic anion transporting polypeptide-mediated uptake of aliskiren are widely present infruits, vegetables, and many other plant products. Therefore, drinks containing plant extracts,including herbal teas, should not be taken together with aliskiren (see section 4.2)

Clinical trial 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-administration 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 afterco-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.

Pharmacokinetic interaction with other medicinal products

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 Rasilez. When administered withatorvastatin, steady-state Rasilez AUC and Cmax increased by 50%. Co-administration of Rasilez hadno significant impact on atorvastatin, metformin or amlodipine pharmacokinetics. As a result no doseadjustment for Rasilez or these co-administered medicinal products is necessary.

Digoxin and verapamil bioavailability may be slightly decreased by Rasilez.

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-gp can 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 Rasilezbioavailability. Inducers of P-gp (St. John’s wort, rifampicin) might therefore decrease thebioavailability of Rasilez.

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).

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. As for any medicine that acts directly on the RAAS,alsikiren should not be used during the first trimester of pregnancy or in women planning to becomepregnant and is contraindicated during the second and third trimesters (see section 4.3). Healthcareprofessionals prescribing any agents acting on the RAAS should counsel women of childbearingpotential about the potential risk of these agents during pregnancy. If pregnancy is detected duringtherapy, treatment should be discontinued accordingly.

It is unknown whether aliskiren/metabolites are excreted in human milk. Aliskiren was secreted in themilk of lactating rats. A risk to the newborns/infants cannot be excluded. Aliskiren should not be usedduring breast-feeding.

There are no clinical data on fertility.

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

Rasilez.

Serious adverse reactions include anaphylactic reaction and angioedema which have been reported inpost-marketing experience and may occur rarely (less than 1 case per 1,000 patients). The mostcommon adverse reaction is diarrhoea.

Aliskiren has been evaluated for safety in more than 7,800 patients, including over 2,300 treated forover 6 months, and more than 1,200 for over 1 year. The adverse reactions are ranked under headingof frequency, the most frequent first, using the following convention: very common (≥1/10); common(≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare(<1/10,000) and not known (cannot be estimated from the available data).

Table 1

Rare: Anaphylactic reactions, hypersensitivity reactions

Common: Dizziness

Ear and labyrinth disorders

Not known: Vertigo

Uncommon: Palpitations, oedema peripheral

Uncommon: Hypotension

Uncommon: Cough

Not known: Dyspnoea

Common: Diarrhoea

Not known: Nausea, vomiting

Not known: Liver disorder*, jaundice, hepatitis, liver failure**

Uncommon: Severe cutaneous adverse reactions (SCARs) including Stevens

Johnson syndrome, toxic epidermal necrolysis (TEN) and oral mucosalreactions, rash, pruritus, urticaria

Rare: Angioedema, erythema

Common: Arthralgia

Uncommon: Acute renal failure, renal impairment

Common: Hyperkalaemia

Uncommon: Liver enzyme increased

Rare: Haemoglobin decreased, haematocrit decreased, blood creatinineincreased

Not known: Hyponatraemia

*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.

Hypersensitivity reactions including anaphylactic reactions and angioedema

In controlled clinical studies, 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 medicines known to cause angioedema, including RAAS blockers(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).

Laboratory findings

In controlled clinical trials, clinically relevant changes in standard laboratory parameters wereuncommonly associated with the administration of aliskiren. In clinical studies in hypertensivepatients, Rasilez had no clinically important effects on total cholesterol, high density lipoproteincholesterol (HDL-C), fasting triglycerides, fasting glucose or uric acid.

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 ifco-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 week 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 on 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).

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.

Limited data are available related to overdose in humans. The most likely manifestations ofoverdosage would be hypotension, related to the antihypertensive effect of aliskiren.

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: C09XA02

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 and angiotensin

II. Whereas other agents that inhibit the RAAS (ACEI and angiotensin II receptor blockers (ARB))cause a compensatory rise in plasma renin activity (PRA), treatment with aliskiren decreases PRA inhypertensive patients by approximately 50 to 80%. Similar reductions were found when aliskiren wascombined with other antihypertensive agents. The clinical implications of the differences in effect 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 maximalblood-pressure-lowering effect was observed after 2 weeks. The blood-pressure-lowering effect wassustained during long-term treatment, and was independent of age, gender, body mass index andethnicity. Aliskiren has been studied in 1,864 patients aged 65 years or older, and in 426 patients aged75 years or older.

Aliskiren monotherapy studies have shown blood pressure lowering effects comparable to otherclasses of antihypertensive agents including ACEI and ARB. Compared to a diuretic(hydrochlorothiazide - HCTZ), Rasilez 300 mg lowered systolic/diastolic blood pressure by17.0/12.3 mmHg, compared to 14.4/10.5 mmHg for HCTZ 25 mg after 12 weeks of treatment.

Combination therapy studies are available for aliskiren added to the diuretic hydrochlorothiazide, thecalcium channel blocker amlodipine and the beta blocker atenolol. These combinations were welltolerated. It induced an additive blood-pressure-lowering effect when added to hydrochlorothiazide. Inpatients who did not adequately respond to 5 mg of the calcium channel blocker amlodipine, theaddition of aliskiren 150 mg had a blood-pressure-lowering effect similar to that obtained byincreasing amlodipine dose to 10 mg, but had a lower incidence of oedema (aliskiren150 mg/amlodipine 5 mg 2.1% vs. amlodipine 10 mg 11.2%).

The efficacy and safety of aliskiren-based therapy were compared to ramipril-based therapy in a9-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 studies 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).

In obese hypertensive patients who did not adequately respond to HCTZ 25 mg, add-on treatment withaliskiren 300 mg provided additional blood pressure reduction that was comparable to add-ontreatment with irbesartan 300 mg or amlodipine 10 mg.

There has been no evidence of first-dose hypotension and no effect on pulse rate in patients treated incontrolled clinical studies. Excessive hypotension was uncommonly (0.1%) seen in patients withuncomplicated hypertension treated with aliskiren alone. Hypotension was also uncommon (<1%)during combination therapy with other antihypertensive agents. With cessation of treatment, bloodpressure gradually returned towards baseline levels over a period of several weeks, with no evidenceof a rebound effect for blood pressure or PRA.

In a 36-week study involving 820 patients with ischaemic left ventricular dysfunction, no changes inventricular re-modelling 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.

No effect on QT interval was reported in a randomised, double-blind, placebo, and active-controlledstudy using standard and Holter electrocardiography.

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 deferred the obligation to submit the results of studies withaliskiren in one or more subsets of the paediatric population in 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 takenwith a light 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.

Approximately 1.4% of the total oral dose is metabolised. The enzyme responsible for this metabolismis CYP3A4.

The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as unchangedcompound in the faeces (78%). Approximately 0.6% of the dose is recovered in urine following oraladministration. Following intravenous administration, the mean plasma clearance is approximately9 l/h.

Exposure to aliskiren increased more than in proportion to the increase in dose. After single doseadministration 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. At steady state the non-linearity may be morepronounced. Mechanisms responsible for deviation from linearity have not been identified. A possiblemechanism is saturation of transporters at the absorption site or at the hepatobiliary clearance route.

Aliskiren is an effective once-a-day antihypertensive treatment in adult patients, regardless of gender,age, body mass index and ethnicity.

The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renalinsufficiency. Relative AUC and Cmax of aliskiren in subjects with renal impairment ranged between0.8 to 2 times the levels in healthy subjects following single dose administration and at steady state.

These observed changes, however, did not correlate with the severity of renal impairment. Noadjustment of the initial dosage of treatment is required in patients with mild to moderate renalimpairment (see sections 4.2 and 4.4). It is not recommended in patients with severe renal impairment(glomerular filtration rate (GFR) < 30 ml/min/1.73 m2).

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).

The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe liverdisease. Consequently, no adjustment of the initial dose of aliskiren is required in patients with mild tosevere hepatic impairment.

Elderly patients aged 65 years and over

The AUC is 50% higher in elderly (> 65 years) than in young subjects. Gender, weight and ethnicityhave no clinically relevant influence on aliskiren pharmacokinetics.

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 (see section 5.1).

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).

Safety pharmacology studies did not reveal any adverse effects on central nervous, respiratory orcardiovascular function. Findings during repeat-dose toxicity studies in animals were consistent withthe known local (gastrointestinal tract) irritation potential or the expected pharmacological effects ofaliskiren.

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 beappropriate at 9-11-fold based on faecal concentrations or 6-fold based on mucosa concentrations incomparison with 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, thanthe maximum recommended human dose (300 mg).

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).

Crospovidone, type A

Magnesium stearate

Microcrystalline cellulose

Povidone, K-30

Colloidal anhydrous silica

Hypromellose substitution type 2910 (3 mPa·s)

Macrogol 4000

Talc

Black iron oxide (E 172)

Red iron oxide (E 172)

Titanium dioxide (E 171)

Not applicable.

3 years

Do not store above 25°C. Store in the original package in order to protect from moisture.

Rasilez 150 mg film-coated tablets

PVC/polychlorotrifluoroethylene (PCTFE) - Alu blisters:

Unit packs containing 14, 28, 30, 50, 56, 90 or 98 tablets.

Unit packs containing 56x1 tablets in perforated unit dose blisters.

Multipacks containing 280 (20x14) tablets.

Multipacks containing 98 (2x49x1) tablets in perforated unit dose blisters.

Rasilez 300 mg film-coated tablets

PVC/polychlorotrifluoroethylene (PCTFE) - Alu blisters:

Unit packs containing 14, 28, 30, 50, 56, 90 or 98 tablets.

Unit packs containing 56x1 tablets in perforated unit dose blisters.

Multipacks containing 280 (20x14) tablets.

Multipacks containing 98 (2x49x1) tablets in perforated unit dose blisters.

Not all pack sizes 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

Rasilez 150 mg film-coated tablets

EU/1/07/405/021-030

Rasilez 300 mg film-coated tablets

EU/1/07/405/031-040

Date of first authorisation: 22 August 2007

Date of latest renewal: 22 May 2017

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

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