▼Rasilez 150 mg film-coated tablets

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

For the full list of excipients, see section 6.1.

Film-coated tablet

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

Treatment of essential hypertension in adults.

Posology

The recommended dose of Rasilez is 150 mg once daily. In patients whose blood pressure is not adequately controlled, the dose may be increased to 300 mg once daily.

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

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

Special populations

Renal impairment

No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see sections 4.4 and 5.2). Rasilez is not recommended in patients with severe renal impairment (GFR < 30 ml/min/1.73 m²). Concomitant use of Rasilez with ARBs or ACEIs is contraindicated in patients with renal impairment (GFR < 60 ml/min/1.73 m²) (see section 4.3).

Hepatic impairment

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

Elderly patients aged 65 years and over

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

Paediatric population

The safety and efficacy of Rasilez in children aged below 18 years have not yet been established. Currently available data are described in sections 4.8 and 5.2 but no recommendation on a posology can be made.

Method of administration

Oral use. The tablets should be swallowed whole with some water. Rasilez should be taken with a light meal once a day, preferably at the same time each day. Grapefruit juice should not be taken together with Rasilez (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-gp inhibitors, and other potent P-gp inhibitors (e.g. quinidine), is contraindicated (see section 4.5).

- The concomitant use of aliskiren with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) (see sections 4.2, 4.4, 4.5 and 5.1).

General

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).

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

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Hypotension, syncope, stroke, hyperkalaemia, and changes in renal function (including acute renal failure) have been reported in susceptible individuals, especially if combining medicinal products that affect this system (see section 5.1). Dual blockade of the renin-angiotensin-aldosterone system by combining aliskiren with an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) is therefore not recommended.

The use of aliskiren in combination with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) (see section 4.3).

Anaphylactic reactions and angioedema

Anaphylactic reactions have been observed during treatment with aliskiren from post-marketing experience (see section 4.8). As with other medicinal products acting on the renin-angiotensin system, angioedema or symptoms suggestive of angioedema (swelling of the face, 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 medicines that can cause angioedema, including RAAS blockers (angiotensin converting enzyme inhibitors or angiotensin receptor blockers) (see section 4.8).

In post-marketing experience, angioedema or angioedema-like reactions have been reported when aliskiren was co-administered with ACEIs and/or ARBs (see section 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 during treatment with aliskiren (see sections 4.3 and 4.8). Caution should therefore be exercised when prescribing aliskiren to patients with a history of angioedema, and such patients should be closely monitored during treatment (see section 4.8) especially at the beginning of the treatment.

If anaphylactic reactions or angioedema occur, Rasilez should be promptly discontinued and appropriate therapy and monitoring provided until complete and sustained resolution of signs and symptoms has occurred. Patients should be informed to report to the physician any signs suggestive of allergic 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 be administered. In addition, measures necessary to maintain patent airways should be provided.

Sodium and/or volume depleted patients

In patients with marked volume- and/or salt-depletion (e.g. those receiving high doses of diuretics) symptomatic hypotension could occur after initiation of treatment with Rasilez. This condition should be corrected prior to administration of Rasilez, or the treatment should start under close medical supervision.

Renal impairment

In clinical studies Rasilez has not been investigated in hypertensive patients with severe renal impairment (serum creatinine ≥ 150 μmol/l or 1.70 mg/dl in women and ≥ 177 μmol/l or 2.00 mg/dl in men and/or estimated GFR < 30 ml/min/1.73 m²), history of dialysis, nephrotic syndrome or renovascular hypertension. Rasilez 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 exercised when aliskiren is given in the presence of conditions pre-disposing to kidney dysfunction such as hypovolaemia (eg. due to blood loss, severe prolonged diarrhoea, prolonged vomiting, etc.), heart disease, liver disease, diabetes mellitus or kidney disease. The concomitant use of aliskiren and ACEIs or ARBs is contraindicated in patients with renal impairment (GFR < 60 ml/min/1.73 m²). Acute renal failure, reversible upon discontinuation of treatment, has been reported in at-risk patients receiving aliskiren in post-marketing experience. In the event that any signs of renal failure occur, aliskiren should be promptly discontinued.

Increases in serum potassium have been observed with aliskiren in post-marketing experience and these may be exacerbated by concomitant use of other agents acting on the RAAS or by non-steroidal anti-inflammatory drugs (NSAIDs). Consistent with standard medical practice, periodic determination of 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 Rasilez in patients with unilateral or bilateral renal artery stenosis, or stenosis to a solitary kidney. However, as with other medicinal products acting on the renin-angiotensin system, there is an increased risk of renal insufficiency, including acute renal failure, when patients with renal artery stenosis are treated with aliskiren. Therefore, caution should be exercised in these patients. If renal failure occurs, treatment should be discontinued.

Contraindicated (see section 4.3)

Dual RAAS blockade

The combination of aliskiren with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) and is not recommended in other patients (see sections 4.3, 4.4 and 5.1).

P-glycoprotein (P-gp) potent inhibitors

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

Not recommended (see section 4.2)

Grapefruit juice

Administration of grapefruit juice with aliskiren resulted in a decrease in AUC and C_max of aliskiren. Co-administration 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. This decrease is likely due to an inhibition of organic anion transporting polypeptide-mediated uptake of aliskiren by grapefruit juice in the gastrointestinal tract. Therefore, because of the risk of therapeutic failure, grapefruit juice should not be taken together with Rasilez.

Caution required with concomitant use

P-gp interactions

MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption and biliary excretion of aliskiren in preclinical studies. 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 Rasilez. Although this has not been investigated for aliskiren, it is known that P-gp also controls tissue uptake of a variety of substrates and P-gp inhibitors can increase the tissue-to-plasma concentration ratios. Therefore, P-gp inhibitors may increase tissue levels more than plasma levels. The potential for drug interactions at the P-gp site will likely depend on the degree of inhibition of this transporter.

Moderate P-gp inhibitors

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

Medicinal products affecting serum potassium levels

Concomitant use of other agents affecting 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 to increases in serum potassium. If co-medication with an agent affecting the level of serum potassium is considered necessary, caution is advisable. The combination of aliskiren with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) and is not recommended in other patients (see sections 4.3, 4.4 and 5.1).

Non-steroidal anti-inflammatory drugs (NSAIDs)

As with other agents acting on the renin-angiotensin system, NSAIDs may reduce the anti-hypertensive effect of aliskiren. In some patients with compromised renal function (dehydrated patients or elderly patients) aliskiren given concomitantly with NSAIDs may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore the combination of aliskiren with an NSAID requires caution, especially in elderly patients.

Furosemide

Oral co-administration of aliskiren and furosemide had no effect on the pharmacokinetics of aliskiren but reduced exposure to furosemide by 20-30% (the effect of aliskiren on furosemide administered intramuscularly 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 urinary sodium 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 treated with furosemide and 300 mg aliskiren (84.6 kg) was higher than the weight of patients treated with furosemide alone (83.4 kg). Smaller changes in furosemide pharmacokinetics and efficacy were observed with aliskiren 150 mg/day. In patients treated with both aliskiren and oral furosemide, it is therefore recommended that the effects of furosemide be monitored when initiating and adjusting furosemide or aliskiren therapy to avoid changes in extracellular fluid volume and possible situations of volume overload (see section 4.4).

Warfarin

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

Food interactions

Meals (low or high fat content) have been shown to reduce the absorption of Rasilez substantially (see section 4.2).

No interactions

- Compounds that have been investigated in clinical pharmacokinetic studies include acenocoumarol, atenolol, celecoxib, pioglitazone, allopurinol, isosorbide-5-mononitrate and hydrochlorothiazide. No interactions have been identified.

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

- Digoxin and verapamil bioavailability may be slightly decreased by Rasilez.

- CYP450 interactions

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 systemic exposure of substances that inhibit, induce or are metabolised by these enzymes. Aliskiren is metabolised minimally by the cytochrome P450 enzymes. Hence, interactions due to inhibition or induction 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).

- P-gp substrates or weak inhibitors

No relevant interactions with atenolol, digoxin, amlodipine or cimetidine have been observed. When administered with atorvastatin (80 mg), steady-state aliskiren (300 mg) AUC and C_max increased by 50%. In experimental animals, it has been shown that P-gp is a major determinant of Rasilez bioavailability. Inducers of P-gp (St. John's wort, rifampicin) might therefore decrease the bioavailability of Rasilez.

- Organic anion transporting polypeptide (OATP) inhibitors

Preclinical studies indicate that aliskiren might be a substrate of organic anion transporting polypeptides. Therefore, the potential exists for interactions between OATP inhibitors and aliskiren when administered concomitantly (see interaction with Grapefruit juice).

Pregnancy

There are no data on the use of aliskiren in pregnant women. Rasilez was not teratogenic in rats or rabbits (see section 5.3). Other substances that act directly on the RAAS have been associated with serious foetal malformations and neonatal death. As for any medicine that acts directly on the RAAS, Rasilez should not be used during the first trimester of pregnancy or in women planning to become pregnant and is contraindicated during the second and third trimesters (see section 4.3). Healthcare professionals prescribing any agents acting on the RAAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy. If pregnancy is detected during therapy, Rasilez should be discontinued accordingly.

Breast-feeding

It is not known whether aliskiren is excreted in human milk. Rasilez was secreted in the milk of lactating rats. Its use is therefore not recommended in women who are breast-feeding.

Fertility

There are no clinical data on fertility.

Rasilez has negligible influence on the ability to drive and use machines. However, when driving vehicles or operating machinery it must be borne in mind that dizziness or weariness may occasionally occur when taking Rasilez.

Summary of the safety profile

Rasilez has been evaluated for safety in more than 7,800 patients, including over 2,300 treated for over 6 months, and more than 1,200 for over 1 year. The incidence of adverse reactions showed no association with gender, age, body mass index, race or ethnicity. Serious adverse reactions include anaphylactic reaction and angioedema which have been reported in post-marketing experience and may occur rarely (less than 1 case per 1,000 patients). The most common adverse reaction is diarrhoea.

Tabulated list of adverse reactions:

The adverse drug reactions (Table 1) are ranked under heading of 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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1

Description of selected adverse reactions

Hypersensitivity reactions including anaphylactic reactions and angioedema have occurred during treatment with aliskiren.

In controlled clinical trials, angioedema and hypersensitivity reactions occurred rarely during treatment 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/or tongue) have also been reported in post-marketing experience. A number of these patients had a history of angioedema or symptoms suggestive of angioedema which in some cases was associated with 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 reported when aliskiren was co-administered with ACEIs and/or ARBs.

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

In the event of any signs suggesting a hypersensitivity reaction/angioedema (in particular difficulties in breathing or swallowing, rash, itching, hives or swelling of the face, extremities, eyes, lips and/or tongue, 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 a hypersensitivity reaction.

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

Laboratory findings

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

Haemoglobin and haematocrit: Small decreases in haemoglobin and haematocrit (mean decreases of approximately 0.05 mmol/l and 0.16 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.

Serum potassium: Increases in serum potassium have been observed with aliskiren and these may be exacerbated by concomitant use of other agents acting on the RAAS or by NSAIDs. Consistent with standard medical practice, periodic determination of renal function including serum electrolytes is advised if co-administration is considered necessary. The combination of aliskiren with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) and is not recommended in other patients (see sections 4.3, 4.4 and 5.1).

Paediatric population

Based on the limited amount of safety data available from a pharmacokinetic study of aliskiren treatment in 39 hypertensive children 6-17 years of age, the frequency, type and severity of adverse reactions in children are expected to be similar to that seen in hypertensive adults. As for other RAAS blockers, headache is a common adverse event in children treated with aliskiren.

Symptoms

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

Treatment

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

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

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system; renin inhibitor, ATC code: 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 the conversion 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 in hypertensive patients by approximately 50 to 80%. Similar reductions were found when aliskiren was combined with other antihypertensive agents. The clinical implications of the differences in effect on PRA are not known at the present time.

Hypertension

In hypertensive patients, once-daily administration of Rasilez at doses of 150 mg and 300 mg provided dose-dependent reductions in both systolic and diastolic blood pressure that were maintained over the entire 24-hour dose interval (maintaining benefit in the early morning) with a mean peak to trough 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 was sustained during long-term treatment, and was independent of age, gender, body mass index and ethnicity. Rasilez has been studied in 1,864 patients aged 65 years or older, and in 426 patients aged 75 years or older.

Rasilez monotherapy studies have shown blood pressure lowering effects comparable to other classes of antihypertensive agents including ACEI and ARB. Compared to a diuretic (hydrochlorothiazide - HCTZ), Rasilez 300 mg lowered systolic/diastolic blood pressure by 17.0/12.3 mmHg, compared to 14.4/10.5 mmHg for HCTZ 25 mg after 12 weeks of treatment.

Combination therapy studies are available for Rasilez added to the diuretic hydrochlorothiazide, the calcium channel blocker amlodipine and the beta blocker atenolol. These combinations were well tolerated. Rasilez induced an additive blood-pressure-lowering effect when added to hydrochlorothiazide. In patients who did not adequately respond to 5 mg of the calcium channel blocker amlodipine, the addition of Rasilez 150 mg had a blood-pressure-lowering effect similar to that obtained by increasing amlodipine dose to 10 mg, but had a lower incidence of oedema (aliskiren 150 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 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 for 36 weeks with optional add-on therapy of hydrochlorothiazide (12.5 mg or 25 mg) at week 12, and amlodipine (5 mg or 10 mg) at week 22. Over the 12 week period, aliskiren monotherapy lowered systolic/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 dosages chosen and the differences in systolic and diastolic blood pressure were statistically significant. Tolerability was comparable in both treatment arms, however cough was more often reported with the ramipril regimen than the aliskiren regimen (14.2% vs. 4.4%), whilst diarrhoea was more common with the aliskiren regimen than for the ramipril 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 in blood pressure (both systolic and diastolic) when compared to placebo. No additional blood pressure lowering effect was detected with 300 mg aliskiren compared to 150 mg aliskiren. All three doses were well tolerated in both elderly and very elderly patients.

In obese hypertensive patients who did not adequately respond to HCTZ 25 mg, add-on treatment with Rasilez 300 mg provided additional blood pressure reduction that was comparable to add-on treatment 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 in controlled clinical studies. Excessive hypotension was uncommonly (0.1%) seen in patients with uncomplicated hypertension treated with Rasilez alone. Hypotension was also uncommon (<1%) during combination therapy with other antihypertensive agents. With cessation of treatment, blood pressure gradually returned towards baseline levels over a period of several weeks, with no evidence of a rebound effect for blood pressure or PRA.

In a 36-week study involving 820 patients with ischaemic left ventricular dysfunction, no changes in ventricular remodelling as assessed by left ventricular end systolic volume were detected with aliskiren 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 controlled randomised trial in 8,606 patients with type 2 diabetes and chronic kidney disease (evidenced by proteinuria and/or GFR < 60 ml/min/1.73 m²) with or without cardiovascular disease. In most patients arterial blood pressure was well controlled at baseline. The primary endpoint was a composite of cardiovascular and renal complications.

In this study, aliskiren 300 mg was compared to placebo when added to standard of care which included either an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. The study was discontinued prematurely because the participants were unlikely to benefit from aliskiren. Study results indicated a hazard ratio for the primary endpoint of 1.11 in favour of placebo (95% Confidence Interval: 1.00, 1.23, 2-sided p=0.05). In addition, an increased incidence of adverse events was observed with aliskiren compared to placebo (37.9% versus 30.2%). In particular there was an increased incidence of renal dysfunction (14.0% versus 12.1%), hyperkalaemia (38.9% versus 28.8%), hypotension-related events (19.7% versus 16.2%) and adjudicated stroke endpoints (3.4% versus 2.6%). The increased incidence of stroke was greater in patients with renal insufficiency.

Effects of Rasilez on mortality and cardiovascular morbidity are currently unknown.

Cardiac electrophysiology

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

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Rasilez in one or more subsets of the paediatric population in hypertension (see section 4.2 for information on paediatric use).

Absorption

Following oral absorption, peak plasma concentrations of aliskiren are reached after 1-3 hours. The absolute bioavailability of aliskiren is approximately 2-3%. Meals with a high fat content reduce C_max by 85% and AUC by 70%. At steady state meals with low fat content reduce C_max by 76% and AUC_0-tau by 67% in hypertensive patients. Steady-state-plasma concentrations are reached within 5-7 days following once-daily administration and steady-state levels are approximately 2-fold greater than with the initial dose.

Distribution

Following intravenous administration, the mean volume of distribution at steady state is approximately 135 litres, indicating that aliskiren distributes extensively into the extravascular space. Aliskiren plasma protein binding is moderate (47-51%) and independent of the concentration.

Biotransformation and elimination

The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as unchanged compound in the faeces (78%). Approximately 1.4% of the total oral dose is metabolised. The enzyme responsible for this metabolism is CYP3A4. Approximately 0.6% of the dose is recovered in urine following oral administration. Following intravenous administration, the mean plasma clearance is approximately 9 l/h.

Linearity

Exposure to aliskiren increased more than in proportion to the increase in dose. After single dose administration in the dose range of 75 to 600 mg, a 2-fold increase in dose results in a ~2.3 and 2.6-fold increase in AUC and C_max, respectively. At steady state the non-linearity may be more pronounced. Mechanisms responsible for deviation from linearity have not been identified. A possible mechanism is saturation of transporters at the absorption site or at the hepatobiliary clearance route.

Characteristics in patients

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

Renal impairment

The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renal insufficiency. Relative AUC and C_max of aliskiren in subjects with renal impairment ranged between 0.8 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. No adjustment of the initial dosage of Rasilez is required in patients with mild to moderate renal impairment (see sections 4.2 and 4.4). Rasilez is not recommended in patients with severe renal impairment (glomerular filtration rate (GFR) < 30 ml/min/1.73 m²). Concomitant use of Rasilez with ARBs or ACEIs is contraindicated in patients with renal impairment (GFR < 60 ml/min/1.73 m²) (see section 4.3).

The pharmacokinetics of aliskiren were evaluated in patients with end stage renal disease receiving haemodialysis. Administration of a single oral dose of 300 mg aliskiren was associated with very minor changes in the pharmacokinetics of aliskiren (change in C_max of less than 1.2 fold; increase in AUC of up to 1.6 fold) compared to matched healthy subjects. Timing of haemodialysis did not significantly alter the pharmacokinetics of aliskiren in ESRD patients. Therefore,if administration of aliskiren in ESRD patients receiving haemodialysis is considered necessary, no dose adjustment is warranted in these patients. However, the use of aliskiren is not recommended in patients with severe renal impairment (see section 4.4).

Hepatic impairment

The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe liver disease. Consequently, no adjustment of the initial dose of aliskiren is required in patients with mild to severe 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 ethnicity have no clinically relevant influence on aliskiren pharmacokinetics.

Paediatric population

In a pharmacokinetic study of aliskiren treatment in 39 paediatric hypertensive patients (aged 6-17 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 available data did not suggest that age, body weight or gender have any significant effect on aliskiren systemic exposure (see section 4.2).

Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic mouse study. No carcinogenic potential was detected. One colonic adenoma and one caecal adenocarcinoma recorded in rats at the dose of 1,500 mg/kg/day were not statistically significant. Although aliskiren has known irritation potential, safety margins obtained in humans at the dose of 300 mg during a study in healthy volunteers were considered to be appropriate at 9-11-fold based on faecal concentrations or 6-fold based on mucosa concentrations in comparison 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. The assays included in vitro assays in bacterial and mammalian cells and in vivo assessments in rats.

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

Safety pharmacology studies did not reveal any adverse effects on central nervous, respiratory or cardiovascular function. Findings during repeat-dose toxicity studies in animals were consistent with the known local irritation potential or the expected pharmacological effects of aliskiren.

Crospovidone

Magnesium stearate

Cellulose, microcrystalline

Povidone

Silica, colloidal anhydrous

Hypromellose

Macrogol

Talc

Iron oxide, black (E 172)

Iron oxide, red (E 172)

Titanium dioxide (E 171)

Not applicable

2 years

Do not store above 30°C. Store in the original package in order to protect from moisture.

PA/Alu/PVC – Alu blisters:

Packs containing 7, 14, 28, 30, 50, 56, 84, 90, 98 or 280 tablets.

Packs containing 84 (3x28), 98 (2x49) or 280 (20x14) tablets are multi-packs.

PVC/polychlorotrifluoroethylene (PCTFE) – Alu blisters:

Packs containing 14, 28, 30, 50, 56, 90, 98 or 280 tablets.

Packs containing 98 (2x49) or 280 (20x14) tablets are multi-packs.

Packs containing 56 and 98 (2x49) tablets are 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 local requirements.

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

EU/1/07/405/001-010

EU/1/07/405/021-030

Date of first authorisation: 22 August 2007

Date of latest renewal: 24 August 2012

18 February 2013

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

POM