Rasilez 150 mg film-coated tablets

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

For a 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.

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 (see sections 4.4 and 5.1).

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.

Renal impairment

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

Hepatic impairment

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

Elderly patients (over 65 years)

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 patients (below 18 years)

Rasilez is not recommended for use in children and adolescents below age 18 due to a lack of data on safety and efficacy (see section 5.2).

Hypersensitivity to the active substance or to any of the excipients.

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).

Patients receiving other medicinal products inhibiting the renin-angiotensin system (RAS), and/or those with reduced kidney function and/or diabetes mellitus are at an increased risk of hyperkalaemia during aliskiren therapy.

Aliskiren should be used with caution in patients with serious congestive heart failure (New York Heart Association (NYHA) functional class III-IV).

In the event of severe and persistent diarrhoea, Rasilez therapy should be stopped.

Angioedema

As with other agents 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 RAS blockers (angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs)) (see section 4.8).

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 angioedema occurs, Rasilez should be promptly discontinued and appropriate therapy and monitoring provided until complete and sustained resolution of signs and symptoms has occurred. 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 glomerular filtration rate (GFR) < 30 ml/min), history of dialysis, nephrotic syndrome or renovascular hypertension. Caution should be exercised in hypertensive patients with severe renal impairment due to the lack of safety information for Rasilez.

As for other agents 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 or kidney disease. 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.

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 agents 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.

Moderate P-gp inhibitors

Co-administration of aliskiren 300 mg with ketoconazole 200 mg or verapamil 240 mg resulted in a 76% or 97% increase in aliskiren AUC, respectively. Therefore caution should be exercised when aliskiren is administered with moderate P-gp inhibitors such as ketoconazole or verapamil (see section 4.5).

Rasilez has no known clinically relevant interactions with medicinal products commonly used to treat hypertension or diabetes.

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

Co-administration of aliskiren with either valsartan (28%), 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, valsartan, 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.

Preliminary data suggest that irbesartan may decrease Rasilez AUC and C_max.

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.

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 P-glycoprotein interactions below).

P-glycoprotein 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.

P-gp potent inhibitors

A single dose drug 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).

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).

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%.

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).

Furosemide

When aliskiren was co-administered with furosemide, the AUC and C_max of furosemide were reduced by 28% and 49%, respectively. It is therefore recommended that the effects be monitored when initiating and adjusting furosemide therapy to avoid possible under-utilisation in clinical situations of volume overload.

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.

Potassium and potassium-sparing diuretics

Based on experience with the use of other substances that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other substances that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium. If co-medication is considered necessary, caution is advisable.

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.

Warfarin

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

Food intake

Meals with a high fat content have been shown to reduce the absorption of Rasilez substantially.

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 RAS have been associated with serious foetal malformations and neonatal death. As for any medicine that acts directly on the RAS, 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 RAS 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.

No studies on the effects on the ability to drive and use machines have been performed. However, when driving vehicles or operating machinery it must be borne in mind that dizziness or weariness may occasionally occur when taking any antihypertensive therapy. Rasilez has negligible influence on the ability to drive and use machines.

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. Treatment with Rasilez resulted in an overall incidence of adverse reactions similar to placebo up to 300 mg. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The most common adverse drug reaction is diarrhoea.

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, <1/10); uncommon (1/1,000, <1/100); rare (1/10,000, <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

Angioedema and hypersensitivity reactions 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 RAS blockers (ACE inhibitors or ARBs).

Hypersensitivity reactions have also been reported in post-marketing experience.

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.

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 ACEI and ARBs.

Serum potassium: Increases in serum potassium were minor and infrequent in patients with essential hypertension treated with Rasilez alone (0.9% compared to 0.6% with placebo). However, in one study where Rasilez was used in combination with an ACEI in a diabetic population, increases in serum potassium were more frequent (5.5%). Therefore as with any agent acting on the RAS system, routine monitoring of electrolytes and renal function is indicated in patients with diabetes mellitus, kidney disease, or heart failure.

In post-marketing experience, renal dysfunction and cases of acute renal failure have been reported in patients at risk (see section 4.4). There have also been reports of peripheral oedema, increase in blood creatinine and severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN) and oral mucosal reactions.

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

Pharmacotherapeutic group: 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 RAS 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 RAS (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. In diabetic hypertensive patients, Rasilez monotherapy was safe and effective.

Combination therapy studies are available for Rasilez added to the diuretic hydrochlorothiazide, the ACEI ramipril, the calcium channel blocker amlodipine, the angiotensin receptor antagonist valsartan, and the beta blocker atenolol. These combinations were well tolerated. Rasilez induced an additive blood-pressure-lowering effect when added to hydrochlorothiazide and to ramipril. 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%). Rasilez in combination with the angiotensin receptor antagonist valsartan showed an additive antihypertensive effect in the study specifically designed to investigate the effect of the combination therapy.

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. In diabetic hypertensive patients, Rasilez provided additive blood pressure reductions when added to ramipril, while the combination of Rasilez and ramipril had a lower incidence of cough (1.8%) than ramipril (4.7%).

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.

In a 6-month study of 599 patients with hypertension, type 2 diabetes mellitus, and nephropathy, all of whom were receiving losartan 100 mg and optimised antihypertensive background therapy, addition of Rasilez 300 mg achieved a 20% reduction versus placebo in urinary albumin:creatinine ratio (UACR), i.e. from 58 mg/mmol to 46 mg/mmol. The proportion of patients who had UACR reduced at least 50% from baseline to endpoint was 24.7% and 12.5% for Rasilez and placebo, respectively.

The clinical relevance of a reduction in UACR is not established in the absence of an effect on blood pressure. Rasilez did not affect the serum concentration of creatinine but was associated with an increased frequency (4.2% vs. 1.9% for placebo) of serum potassium concentration 6.0 mmol/l, although this was not statistically significant.

Beneficial effects of Rasilez on mortality and cardiovascular morbidity and target organ damage 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.

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%. 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.

Metabolism 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/non-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.

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.

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 severe renal impairment, however caution should be exercised in patients with severe renal 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.

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 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

22.08.2007

22.11.2011

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

POM