Novartis Pharmaceuticals UK Ltd

Section 4.3

The following at the end of section:

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).

Section 4.4

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.

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).

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 RAAS blockers (angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs)) (see section 4.8).

as present....until......

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/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).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, 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.

as present to end of section.

Section 4.5

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).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.

as present until.........

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.

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 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 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).

as present until end of section.

Section 4.6

Changes RAS to RAAS.

Section 4.8

Table 1

change RAS to RAAS.

As present until.....

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 NSAIDswere 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. 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).

last paragraph unchanged.

Section 5.1

Changes RAS to RAAS.

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.

as present until......

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%).

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. Preliminary study results indicated a hazard ratio for the primary endpoint of 1.09 in favour of placebo (95% Confidence Interval: 0.97, 1.22, 2-sided p=0.17). In addition, an increased incidence of serious adverse outcomes was observed with aliskiren compared to placebo for renal complications (4.7% versus 3.3%), hyperkalaemia (36.9% versus 27.1%), hypotension (18.4% versus 14.6%) and stroke (2.7% versus 2.0%). The increased incidence of non-fatal stroke was greater in patients with renal insufficiency.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 ³6.0 mmol/l, although this was not statistically significant.

as present to end.

Section 5.2

Paragraph changed as follows:

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

Rash, severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN) and oral mucosal reactions

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

 
The final paragraph has had the following text added shown below:

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,  and increase in blood creatinine and severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN) and oral mucosal reactions.

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.

The concomitant use of aliskiren with ciclosporin and itraconazole, two highly potent P-gp inhibitors, and other potent P-gp inhibitors (e.g. quinidine, verapamil), is contraindicated (see section 4.5).

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 but P-gp inhibitors such as ketoconazole are expected to increase tissue concentrations more than plasma concentrations. Therefore caution should be exercised when aliskiren is administered with moderate P-gp inhibitors such as ketoconazole or verapamil (see section 4.5).

Digoxin and verapamil bioavailability may be slightly decreased by Rasilez.

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 iInducers of P-gp (St. John’s wort, rifampicin) might therefore 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%.

Moderate P-gp inhibitors

Co-administration of ketoconazole (200 mg) with aliskiren (300 mg) resulted in an 80% increase in plasma levels of aliskiren (AUC and C_max). Preclinical studies indicate that aliskiren and ketoconazole co-administration enhances aliskiren gastrointestinal absorption and decreases biliary excretion. The change in plasma levels of aliskiren in the presence of ketoconazole 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. Yet, P-gp inhibitors are expected to increase tissue concentrations more than plasma concentrations. Therefore, caution should be exercised when aliskiren is administered with ketoconazole or other moderate pgp inhibitors (itraconazol, clarithromycin, telithromycin, erythromycin, amiodarone).

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).

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).

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).

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.

Packs containing 56 (8x7) and 98 (2x49) tablets are perforated unit-dose blisters.

4.8         Undesirable effects

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 (quinidine, verapamil), is contraindicated (see section 4.5).

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) havehas 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 ensure maintain patient airways should be provided.

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 (frequency not known). 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).

In the event of any signs suggesting a hypersensitivity reaction/angioedema an allergic reaction (in particular difficulties in breathing, or swallowing, or swelling of the face, extremities, eyes, lips and/or tongue) patients should discontinue treatment and contact the physician (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 angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers ARBs.

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

History of angioedema with aliskiren.

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 (quinidine, verapamil), is contraindicated (see section 4.5).

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).

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.

Angioedema has occurred during treatment with Rasilez. In controlled clinical trials, angioedema occurred rarely during treatment with Rasilez with rates comparable to treatment with placebo or hydrochlorothiazide. Cases of angioedema have also been reported in post-marketing experience (frequency not known). In the event of any signs suggesting an allergic reaction (in particular difficulties in breathing, or swallowing, or swelling of the face, extremities, eyes, lips and/or tongue) patients should discontinue treatment and contact the physician (see section 4.4).

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

There have also been reports of peripheral oedema (frequency not known).

at the end of end of section 4.8.

SECTION 2

The following has been added:

(as hemifumarate)

SECTION 4.2

The following has been added:

Grapefruit juice should not be taken together with Rasilez

SECTION 4.3

The following has been added:

The concomitant use of aliskiren with ciclosporin, a highly potent P-gp inhibitor, and other potent P-gp inhibitors (quinidine, verapamil), is contraindicated (see section 4.5).

SECTION 4.4

The following has been added:

Moderate P-gp inhibitors
Co-administration of aliskiren 300 mg with ketoconazole 200 mg resulted in a 76% increase in aliskiren AUC but P-gp inhibitors such as ketoconazole are expected to increase tissue concentrations more than plasma concentrations. Therefore caution should be exercised when aliskiren is administered with moderate P-gp inhibitors such as ketoconazole (see section 4.5).

SECTION 4.5

The following has been added:

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. Inducers of P-gp (St. John’s wort, rifampicin) might therefore 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 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 Cmax increased by 50%.

Moderate P-gp inhibitors
Co-administration of ketoconazole (200 mg) with aliskiren (300 mg) resulted in an 80% increase in plasma levels of aliskiren (AUC and Cmax). Preclinical studies indicate that aliskiren and ketoconazole co-administration enhances aliskiren gastrointestinal absorption and decreases biliary excretion. The change in plasma levels of aliskiren in the presence of ketoconazole 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. Yet, P-gp inhibitors are expected to increase tissue concentrations more than plasma concentrations. Therefore, caution should be exercised when aliskiren is administered with ketoconazole or other moderate pgp inhibitors (itraconazol, clarithromycin, telithromycin, erythromycin, amiodarone).

P-gp potent inhibitors
A single dose drug 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 increase may be higher with higher aliskiren doses. Therefore, concomitant use of aliskiren and P-gp potent inhibitors is contraindicated (see section 4.3).

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
Due to the lack of data a potential interaction between grapefruit juice and aliskiren cannot be excluded. Grapefruit juice should not be taken together with Rasilez.

The following has been deleted:

Ketoconazole
Co-administration of ketoconazole 200 mg twice daily with Rasilez resulted in a 1.8-fold increase in plasma levels of Rasilez (AUC and Cmax). The change in plasma levels in the presence of ketoconazole is expected to be within the range that would be achieved if the dose were doubled; Rasilez doses of up to 600 mg, or twice the highest recommended therapeutic dose, have been found to be safe in well-controlled clinical trials. Preclinical studies indicate that Rasilez and ketoconazole co-administration enhances Rasilez gastrointestinal absorption and decreases biliary excretion.

SECTION 10

The date of revision has been changed from 09 Jul 2008  to 28 Aug 2008

SECTION 4.4

The following sentence has been added:

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

The following sentence has been deleted:

Aliskiren should be used with caution in patients with heart failure due to limited clinical efficacy and safety data.

SECTION 5.1

The following paragraphs have been added:

In a 3-month study of 302 patients with mild stable heart failure, all of whom were receiving standard therapy for stable heart failure, addition of Rasilez 150 mg was well tolerated. B-type natriuretic peptide (BNP) levels were reduced by 25% in the Rasilez arm compared to placebo. However the clinical significance of this reduction is unknown.

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 (³6.0 mmol/l), although this was not statistically significant.