Enviage

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Enviage 150 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 150 mg aliskiren (as hemifumarate). 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet 
 
Light-pink, biconvex, round tablet, imprinted “IL” on one side and “NVR” on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of essential hypertension. 
 
4.2 Posology and method of administration 
 
The recommended dose of Enviage 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. 
 
Enviage may be used alone or in combination with other antihypertensive agents (see sections 4.4 and 
5.1). 
 
Enviage 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 Enviage. 
 
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) 
No adjustment of the initial dose is required for elderly patients. 
 
Paediatric patients (below 18 years) 
Enviage 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). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients. 

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History of angioedema with aliskiren. 
 
Second and third trimesters of pregnancy (see section 4.6). 
 
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). 
 
4.4 Special warnings and precautions for use 
 
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, Enviage therapy should be stopped. 
 
Angioedema 
As with other agents acting on the renin-angiotensin system, angioedema has been reported in patients 
treated with aliskiren. If angioedema occurs, Enviage 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 patient 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 Enviage. This condition should 
be corrected prior to administration of Enviage, or the treatment should start under close medical 
supervision. 
 
Renal impairment 
In clinical studies Enviage 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 Enviage. 
 
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 Enviage 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 resulted in a 76% increase in 
aliskiren AUC but P-gp inhibitors such as ketoconazole are expected to increase tissue concentrations  

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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). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Enviage 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 Cmax or AUC of Enviage. When 
administered with atorvastatin, steady-state Enviage AUC and Cmax increased by 50%. Co-
administration of Enviage had no significant impact on atorvastatin, valsartan, metformin or 
amlodipine pharmacokinetics. As a result no dose adjustment for Enviage or these co-administered 
medicinal products is necessary. 
 
Digoxin bioavailability may be slightly decreased by Enviage. 
 
Preliminary data suggest that irbesartan may decrease Enviage AUC and Cmax. 
 
In experimental animals, it has been shown that P-gp is a major determinant of Enviage 
bioavailability. Inducers of P-gp (St. John’s wort, rifampicin) might therefore decrease the 
bioavailability of Enviage. 
 
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. Inducers of P-gp (St. John’s wort, rifampicin) 
might therefore decrease the bioavailability of Enviage. 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 

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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). 
 
Furosemide 
When aliskiren was co-administered with furosemide, the AUC and Cmax 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 
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 Enviage. 
 
Warfarin 
The effects of Enviage on warfarin pharmacokinetics have not been evaluated. 
 
Food intake 
Meals with a high fat content have been shown to reduce the absorption of Enviage substantially. 
 
4.6 Pregnancy and lactation 
 
Pregnancy 
There are no data on the use of aliskiren in pregnant women. Enviage 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, 
Enviage 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, Enviage should be discontinued accordingly. 
 
Lactation 
It is not known whether aliskiren is excreted in human milk. Enviage was secreted in the milk of 
lactating rats. Its use is therefore not recommended in women who are breast-feeding. 

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4.7 Effects on ability to drive and use machines 
 
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. Enviage has negligible influence 
on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Enviage 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 Enviage 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 incidence of cough was similar in placebo (0.6%) and Enviage treated (0.9%) patients. 
 
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), including isolated reports. 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 
 
Table 1 
 
Gastrointestinal disorders 
 Common: Diarrhoea 
Skin and subcutaneous tissue disorders 
 Uncommon: Rash 
 Rare: Angioedema 

 
Angioedema has occurred during treatment with Enviage. In controlled clinical trials, angioedema 
occurred rarely during treatment with Enviage with rates comparable to treatment with placebo or 
hydrochlorothiazide. Cases of angioedema have also been reported in post-marketing experience 
(frequency unknown). 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). 
 
Laboratory findings 
In controlled clinical trials, clinically relevant changes in standard laboratory parameters were 
uncommonly associated with the administration of Enviage. In clinical studies in hypertensive 
patients, Enviage 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. 
 
Serum potassium: Increases in serum potassium were minor and infrequent in patients with essential 
hypertension treated with Enviage alone (0.9% compared to 0.6% with placebo). However, in one 
study where Enviage 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. 

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In post-marketing experience, renal dysfunction and cases of acute renal failure have been reported in 
patients at risk (see section 4.4). 
 
4.9 Overdose 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
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 Enviage 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. Enviage has been studied in 1,864 patients aged 65 years or older, and in 426 patients aged 
75 years or older. 
 
Enviage 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), Enviage 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, 
Enviage monotherapy was safe and effective. 
 
Combination therapy studies are available for Enviage 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. Enviage 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 Enviage 
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%). Enviage 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. 
 
In obese hypertensive patients who did not adequately respond to HCTZ 25 mg, add-on treatment with 
Enviage 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, Enviage 

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provided additive blood pressure reductions when added to ramipril, while the combination of Enviage 
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 Enviage 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 3-month study of 302 patients with mild stable heart failure, all of whom were receiving standard 
therapy for stable heart failure, addition of Enviage 150 mg was well tolerated. B-type natriuretic 
peptide (BNP) levels were reduced by 25% in the Enviage 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 
Enviage 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 Enviage and placebo, respectively. The 
clinical relevance of a reduction in UACR is not established in the absence of an effect on blood 
pressure. Enviage 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 Enviage 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. 
 
5.2 Pharmacokinetic properties 
 
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 Cmax 
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 

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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 Cmax, 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 Cmax 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 Enviage 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. 
 
5.3 Preclinical safety data 
 
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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Crospovidone 
Magnesium stearate 
Cellulose, microcrystalline 
Povidone 
Silica, colloidal anhydrous 

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Hypromellose 
Macrogol 
Talc 
Iron oxide, black (E 172) 
Iron oxide, red (E 172) 
Titanium dioxide (E 171) 
 
6.2 Incompatibilities 
 
Not applicable 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
Do not store above 30°C. Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
PA/Alu/PVC 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. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Novartis Europharm Limited 
Wimblehurst Road 
Horsham 
West Sussex, RH12 5AB 
United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/406/001-010 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
22.08.2007 
 
 
10. DATE OF REVISION OF THE TEXT 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Enviage 300 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 300 mg aliskiren (as hemifumarate). 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet 
 
Light-red, biconvex, ovaloid tablet, imprinted “IU” on one side and “NVR” on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of essential hypertension. 
 
4.2 Posology and method of administration 
 
The recommended dose of Enviage 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. 
 
Enviage may be used alone or in combination with other antihypertensive agents (see sections 4.4 and 
5.1). 
 
Enviage 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 Enviage. 
 
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) 
No adjustment of the initial dose is required for elderly patients. 
 
Paediatric patients (below 18 years) 
Enviage 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). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients. 

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History of angioedema with aliskiren. 
 
Second and third trimesters of pregnancy (see section 4.6). 
 
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). 
 
4.4 Special warnings and precautions for use 
 
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, Enviage therapy should be stopped. 
 
Angioedema 
As with other agents acting on the renin-angiotensin system, angioedema has been reported in patients 
treated with aliskiren. If angioedema occurs, Enviage 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 patient 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 Enviage. This condition should 
be corrected prior to administration of Enviage, or the treatment should start under close medical 
supervision. 
 
Renal impairment 
In clinical studies Enviage 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 Enviage. 
 
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 Enviage 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 resulted in a 76% increase in 
aliskiren AUC but P-gp inhibitors such as ketoconazole are expected to increase tissue concentrations  

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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). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Enviage 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 Cmax or AUC of Enviage. When 
administered with atorvastatin, steady-state Enviage AUC and Cmax increased by 50%. Co-
administration of Enviage had no significant impact on atorvastatin, valsartan, metformin or 
amlodipine pharmacokinetics. As a result no dose adjustment for Enviage or these co-administered 
medicinal products is necessary. 
 
Digoxin bioavailability may be slightly decreased by Enviage. 
 
Preliminary data suggest that irbesartan may decrease Enviage AUC and Cmax. 
 
In experimental animals, it has been shown that P-gp is a major determinant of Enviage 
bioavailability. Inducers of P-gp (St. John’s wort, rifampicin) might therefore decrease the 
bioavailability of Enviage. 
 
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. Inducers of P-gp (St. John’s wort, rifampicin) 
might therefore decrease the bioavailability of Enviage. 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 

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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). 
 
Furosemide 
When aliskiren was co-administered with furosemide, the AUC and Cmax 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 
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 Enviage. 
 
Warfarin 
The effects of Enviage on warfarin pharmacokinetics have not been evaluated. 
 
Food intake 
Meals with a high fat content have been shown to reduce the absorption of Enviage substantially. 
 
4.6 Pregnancy and lactation 
 
Pregnancy 
There are no data on the use of aliskiren in pregnant women. Enviage 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, 
Enviage 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, Enviage should be discontinued accordingly. 
 
Lactation 
It is not known whether aliskiren is excreted in human milk. Enviage was secreted in the milk of 
lactating rats. Its use is therefore not recommended in women who are breast-feeding. 

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4.7 Effects on ability to drive and use machines 
 
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. Enviage has negligible influence 
on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Enviage 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 Enviage 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 incidence of cough was similar in placebo (0.6%) and Enviage treated (0.9%) patients. 
 
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), including isolated reports. 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 
 
Table 1 
 
Gastrointestinal disorders 
 Common: Diarrhoea 
Skin and subcutaneous tissue disorders 
 Uncommon: Rash 
 Rare: Angioedema 

 
Angioedema has occurred during treatment with Enviage. In controlled clinical trials, angioedema 
occurred rarely during treatment with Enviage with rates comparable to treatment with placebo or 
hydrochlorothiazide. Cases of angioedema have also been reported in post-marketing experience 
(frequency unknown). 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). 
 
Laboratory findings 
In controlled clinical trials, clinically relevant changes in standard laboratory parameters were 
uncommonly associated with the administration of Enviage. In clinical studies in hypertensive 
patients, Enviage 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. 
 
Serum potassium: Increases in serum potassium were minor and infrequent in patients with essential 
hypertension treated with Enviage alone (0.9% compared to 0.6% with placebo). However, in one 
study where Enviage 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, 
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In post-marketing experience, renal dysfunction and cases of acute renal failure have been reported in 
patients at risk (see section 4.4). 
 
4.9 Overdose 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
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 Enviage 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. Enviage has been studied in 1,864 patients aged 65 years or older, and in 426 patients aged 
75 years or older. 
 
Enviage 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), Enviage 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, 
Enviage monotherapy was safe and effective. 
 
Combination therapy studies are available for Enviage 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. Enviage 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 Enviage 
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%). Enviage 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. 
 
In obese hypertensive patients who did not adequately respond to HCTZ 25 mg, add-on treatment with 
Enviage 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, Enviage 

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provided additive blood pressure reductions when added to ramipril, while the combination of Enviage 
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 Enviage 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 3-month study of 302 patients with mild stable heart failure, all of whom were receiving standard 
therapy for stable heart failure, addition of Enviage 150 mg was well tolerated. B-type natriuretic 
peptide (BNP) levels were reduced by 25% in the Enviage 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 
Enviage 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 Enviage and placebo, respectively. The 
clinical relevance of a reduction in UACR is not established in the absence of an effect on blood 
pressure. Enviage 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 Enviage 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. 
 
5.2 Pharmacokinetic properties 
 
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 Cmax 
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 

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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 Cmax, 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 Cmax 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 Enviage 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. 
 
5.3 Preclinical safety data 
 
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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Crospovidone 
Magnesium stearate 
Cellulose, microcrystalline 
Povidone 
Silica, colloidal anhydrous 

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Hypromellose 
Macrogol 
Talc 
Iron oxide, black (E 172) 
Iron oxide, red (E 172) 
Titanium dioxide (E 171) 
 
6.2 Incompatibilities 
 
Not applicable 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
Do not store above 30°C. Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
PA/Alu/PVC blisters 
 
Packs containing 7, 14, 28, 30, 50, 56, 84, 90, 98 or 280 tablets. 
Packs containing 84 (3x28), 90 (3x30), 98 (2x49) or 280 (20x14) tablets are multi-packs. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Novartis Europharm Limited 
Wimblehurst Road 
Horsham 
West Sussex, RH12 5AB 
United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/406/011-020 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
22.08.2007 
 
 
10. DATE OF REVISION OF THE TEXT 
 

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ANNEX II 
 

A. MANUFACTURING AUTHORISATION HOLDER 
RESPONSIBLE FOR BATCH RELEASE 

 
B. CONDITIONS OF THE MARKETING AUTHORISATION 

 

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A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH 
RELEASE 

 
Name and address of the manufacturer responsible for batch release 
 
Novartis Farma S.p.A. 
Via Provinciale Schito 131 
I-80058 Torre Annunziata/NA 
Italy 
 
 
B. CONDITIONS OF THE MARKETING AUTHORISATION 
 
• CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON 

THE MARKETING AUTHORISATION HOLDER 
 
Medicinal product subject to medical prescription. 
 
• CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
Not applicable. 
 
• OTHER CONDITIONS 
 
Pharmacovigilance system 
The MAH must ensure that the system of pharmacovigilance, as described in version 8.0 presented in 
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and 
whilst the product is on the market. 
 
Risk Management Plan 
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in 
the Pharmacovigilance Plan, as agreed in version 30 May 2007 of the Risk Management Plan (RMP) 
presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of 
the RMP agreed by the CHMP. 
 
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the 
updated RMP should be submitted at the same time as the next Periodic Safety Update Report 
(PSUR). 
 
In addition, an updated RMP should be submitted 
• When new information is received that may impact on the current Safety Specification, 

Pharmacovigilance Plan or risk minimisation activities. 
• Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being 

reached. 
• At the request of the EMEA. 
 

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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

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A. LABELLING 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
FOLDING BOX FOR UNIT PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Enviage 150 mg film-coated tablets 
Aliskiren 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 150 mg aliskiren (as hemifumarate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
7 film-coated tablets 
14 film-coated tablets 
28 film-coated tablets 
30 film-coated tablets 
50 film-coated tablets 
56 film-coated tablets 
90 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 

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9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
Store in the original package in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Novartis Europharm Limited 
Wimblehurst Road 
Horsham 
West Sussex, RH12 5AB 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/406/001 7 film-coated tablets 
EU/1/07/406/002 14 film-coated tablets 
EU/1/07/406/003 28 film-coated tablets 
EU/1/07/406/004 30 film-coated tablets 
EU/1/07/406/005 50 film-coated tablets 
EU/1/07/406/006 56 film-coated tablets 
EU/1/07/406/008 90 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Enviage 150 mg 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
BLISTER (CALENDAR) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Enviage 150 mg film-coated tablets 
Aliskiren 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Novartis Europharm Limited 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
INTERMEDIATE CARTON OF MULTIPACKS (WITHOUT BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Enviage 150 mg film-coated tablets 
Aliskiren 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 150 mg aliskiren (as hemifumarate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 film-coated tablets 
Component of a multipack comprising 20 packs, each containing 14 tablets. 
28 film-coated tablets 
Component of a multipack comprising 3 packs, each containing 28 tablets. 
49 film-coated tablets 
Component of a multipack comprising 2 packs, each containing 49 tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
Store in the original package in order to protect from moisture. 

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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Novartis Europharm Limited 
Wimblehurst Road 
Horsham 
West Sussex, RH12 5AB 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/406/007 84 film-coated tablets (3x28) 
EU/1/07/406/009 98 film-coated tablets (2x49) 
EU/1/07/406/010 280 film-coated tablets (20x14) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Enviage 150 mg 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON OF MULTIPACKS (INCLUDING BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Enviage 150 mg film-coated tablets 
Aliskiren 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 150 mg aliskiren (as hemifumarate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
84 film-coated tablets 
Multipack comprising 3 packs, each containing 28 tablets. 
98 film-coated tablets 
Multipack comprising 2 packs, each containing 49 tablets. 
280 film-coated tablets 
Multipack comprising 20 packs, each containing 14 tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
Store in the original package in order to protect from moisture. 

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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Novartis Europharm Limited 
Wimblehurst Road 
Horsham 
West Sussex, RH12 5AB 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/406/007 84 film-coated tablets (3x28) 
EU/1/07/406/009 98 film-coated tablets (2x49) 
EU/1/07/406/010 280 film-coated tablets (20x14) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Enviage 150 mg 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
FOLDING BOX FOR UNIT PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Enviage 300 mg film-coated tablets 
Aliskiren 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 300 mg aliskiren (as hemifumarate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
7 film-coated tablets 
14 film-coated tablets 
28 film-coated tablets 
30 film-coated tablets 
50 film-coated tablets 
56 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
Store in the original package in order to protect from moisture. 

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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Novartis Europharm Limited 
Wimblehurst Road 
Horsham 
West Sussex, RH12 5AB 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/406/011 7 film-coated tablets 
EU/1/07/406/012 14 film-coated tablets 
EU/1/07/406/013 28 film-coated tablets 
EU/1/07/406/014 30 film-coated tablets 
EU/1/07/406/015 50 film-coated tablets 
EU/1/07/406/016 56 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Enviage 300 mg 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
BLISTER (CALENDAR) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Enviage 300 mg film-coated tablets 
Aliskiren 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Novartis Europharm Limited 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
INTERMEDIATE CARTON OF MULTIPACKS (WITHOUT BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Enviage 300 mg film-coated tablets 
Aliskiren 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 300 mg aliskiren (as hemifumarate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 film-coated tablets 
Component of a multipack comprising 20 packs, each containing 14 tablets. 
28 film-coated tablets 
Component of a multipack comprising 3 packs, each containing 28 tablets. 
30 film-coated tablets 
Component of a multipack comprising 3 packs, each containing 30 tablets. 
49 film-coated tablets 
Component of a multipack comprising 2 packs, each containing 49 tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 

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9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
Store in the original package in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Novartis Europharm Limited 
Wimblehurst Road 
Horsham 
West Sussex, RH12 5AB 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/406/017 84 film-coated tablets (3x28) 
EU/1/07/406/018 90 film-coated tablets (3x30) 
EU/1/07/406/019 98 film-coated tablets (2x49) 
EU/1/07/406/020 280 film-coated tablets (20x14) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Enviage 300 mg 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON OF MULTIPACKS (INCLUDING BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Enviage 300 mg film-coated tablets 
Aliskiren 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 300 mg aliskiren (as hemifumarate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
84 film-coated tablets 
Multipack comprising 3 packs, each containing 28 tablets. 
90 film-coated tablets 
Multipack comprising 3 packs, each containing 30 tablets. 
98 film-coated tablets 
Multipack comprising 2 packs, each containing 49 tablets. 
280 film-coated tablets 
Multipack comprising 20 packs, each containing 14 tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 

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9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
Store in the original package in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Novartis Europharm Limited 
Wimblehurst Road 
Horsham 
West Sussex, RH12 5AB 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/406/017 84 film-coated tablets (3x28) 
EU/1/07/406/018 90 film-coated tablets (3x30) 
EU/1/07/406/019 98 film-coated tablets (2x49) 
EU/1/07/406/020 280 film-coated tablets (20x14) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Enviage 300 mg 
 

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B. PACKAGE LEAFLET 
 

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PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

Enviage 150 mg film-coated tablets 
Aliskiren 

 
Read all of this leaflet carefully before you start taking this medicine. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even 

if their symptoms are the same as yours. 
- If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 

please tell your doctor or pharmacist. 
 
 
In this leaflet: 
1. What Enviage is and what it is used for 
2. Before you take Enviage 
3. How to take Enviage 
4. Possible side effects 
5. How to store Enviage 
6. Further information 
 
 
 
1. WHAT ENVIAGE IS AND WHAT IT IS USED FOR 
 
Enviage belongs to a new class of medicines called renin inhibitors. Enviage helps to lower high blood 
pressure. Renin inhibitors reduce the amount of angiotensin II the body can produce. Angiotensin II 
causes blood vessels to tighten, which increases the blood pressure. Reducing the amount of 
angiotensin II allows the blood vessels to relax, which lowers blood pressure. 
 
High blood pressure increases the workload of the heart and arteries. If this continues for a long time, 
it can damage the blood vessels of the brain, heart and kidneys, and may result in a stroke, heart 
failure, heart attack or kidney failure. Lowering the blood pressure to a normal level reduces the risk 
of developing these disorders. 
 
 
2. BEFORE YOU TAKE ENVIAGE 
 
Do not take Enviage 
- if you are allergic (hypersensitive) to aliskiren or any of the other ingredients of Enviage. If you 

think you may be allergic, ask your doctor for advice. 
- if you have already experienced angioedema (difficulties in breathing, or swallowing, or 

swelling of the face, hands and feet, eyes, lips and/or tongue) when taking aliskiren. 
- during the last 6 months of pregnancy or if you are breast-feeding, see section Pregnancy and 

breastfeeding. 
- if you are taking ciclosporin (a medicine used in transplantation to prevent organ rejection or for 

other conditions, e.g. rheumathoid arthritis or atopic dermatitis) or verapamil (a medicine used 
to lower blood pressure, to correct hearth rhythm or to treat angina pectoris) or quinidine (a 
medicine used to correct heart rhythm). 

 
Take special care with Enviage 
- if you are taking a diuretic (a type of medicine also known as “water” tablets which increases 

the amount of urine you produce). 
- if you have impaired kidney function. 
- if you experience angioedema (difficulties in breathing, or swallowing, or swelling of the face, 

hands and feet, eyes, lips and/or tongue). 

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If any of these apply to you, tell your doctor before you take Enviage. 
 
The use of Enviage in children and adolescents is not recommended. 
There are no special dose recommendations for patients aged 65 years or older. 
 
Using other medicines 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription. 
 
Your doctor may need to change your dose and/or to take other precautions if you are taking one of 
the following medicines: 
- medicines that increase the amount of potassium in your blood. These include potassium-

sparing diuretics, potassium supplements. 
- furosemide, a medicine belonging to the type known as diuretics, or “water” tablets, which is 

used to increase the amount of urine you produce. 
- ketoconazole, a medicine used to treat fungal infections. 
- certain types of pain killers called non-steroidal anti-inflammatory medicines (NSAIDs). 
 
Taking Enviage with food and drink 
You should take Enviage with a light meal once a day, preferably at the same time each day. You 
should not take Enviage together with grapefruit juice. 
 
Pregnancy and breast-feeding 
Do not take Enviage if you are pregnant. It is important to talk to your doctor immediately if you think 
you may be pregnant or are planning to become pregnant. Do not breast-feed if you are taking 
Enviage. 
 
Ask your doctor or pharmacist for advice before taking any medicine. 
 
Driving and using machines 
You may feel dizzy and this can affect your ability to concentrate. Before you drive a vehicle, use 
machinery, or carry out other activities that require concentration, you should make sure you know 
how you react to the effects of Enviage. 
 
 
3. HOW TO TAKE ENVIAGE 
 
Always take Enviage exactly as your doctor has told you. You should check with your doctor or 
pharmacist if you are not sure. 
 
People who have high blood pressure often do not notice any signs of the problem. Many may feel 
quite normal. It is very important that you take this medicine exactly as your doctor tells you to get the 
best results and reduce the risk of side effects. Keep your appointments with the doctor even if you are 
feeling well. 
 
The usual starting dose is one 150 mg tablet once daily. 
 
Depending on how you respond to the treatment your doctor may prescribe a higher dose of one 
300 mg tablet once daily. Your doctor may prescribe Enviage together with other medicines used to 
treat high blood pressure. 
 
Method of administration 
It is recommended that you take the tablets with some water. You should take Enviage with a light 
meal once a day, preferably at the same time each day. You should not take Enviage together with 
grapefruit juice. 

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If you take more Enviage than you should 
If you have accidentally taken too many Enviage tablets, consult a doctor immediately. You may 
require medical attention. 
 
If you forget to take Enviage 
If you forget to take a dose of Enviage, take it as soon as you remember and then take the next dose at 
its usual time. However, if it is almost time for your next dose you should simply take the next tablet 
at the usual time. Do not take a double dose to make up for a forgotten dose. 
 
 
4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, Enviage can cause side effects, although not everybody gets them. 
 
Common (affecting less than 1 in 10 patients): Diarrhoea. 
Uncommon (affecting less than 1 in 100 patients): Skin rash. 
Rare (affecting less than 1 in 1,000 patients): Angioedema (difficulties in breathing, or swallowing, or 
swelling of the face, hands and feet, eyes, lips and/or tongue). 
Not known (frequency cannot be estimated from the available data): Kidney problems. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor or pharmacist. 
 
 
5. HOW TO STORE ENVIAGE 
 
Keep out of the reach and sight of children. 
Do not use Enviage after the expiry date which is stated on the carton and blister. The expiry date 
refers to the last day of that month. 
Do not store above 30°C. 
Store in the original package in order to protect from moisture. 
 
 
6. FURTHER INFORMATION 
 
What Enviage contains 
- The active substance is aliskiren (as hemifumarate) 150 mg. 
- The other ingredients are crospovidone, hypromellose, magnesium stearate, macrogol, 

microcrystalline cellulose, povidone, colloidal anhydrous silica, talc, titanium dioxide (E 171), 
black iron oxide (E 172), red iron oxide (E 172). 

 
What Enviage looks like and contents of the pack 
Enviage 150 mg film coated tablets are light-pink, biconvex round tablets, imprinted “IL” on one side 
and “NVR” on the other side. 
 
Enviage is available in 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. Not all pack sizes may be 
available in your country. 
 
Marketing Authorisation Holder 
Novartis Europharm Limited 
Wimblehurst Road 
Horsham 
West Sussex, RH12 5AB 
United Kingdom 

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Manufacturer 
Novartis Farma S.p.A. 
Via Provinciale Schito 131 
I-80058 Torre Annunziata/NA 
Italy 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Novartis Pharma N.V. 
Tél/Tel: +32 2 246 16 11 
 

Luxembourg/Luxemburg 
Novartis Pharma GmbH 
Tél/Tel: +49 911 273 0 
 

България 
Novartis Pharma Services Inc. 
Тел.: +359 2 489 98 28 
 

Magyarország 
Novartis Hungária Kft. Pharma 
Tel.: +36 1 457 65 00 

Česká republika 
Novartis s.r.o. 
Tel: +420 225 775 111 
 

Malta 
Novartis Pharma Services Inc. 
Tel: +356 2298 3217 

Danmark 
Novartis Healthcare A/S 
Tlf: +45 39 16 84 00 
 

Nederland 
Novartis Pharma B.V. 
Tel: +31 26 37 82 111 

Deutschland 
Novartis Pharma GmbH 
Tel: +49 911 273 0 
 

Norge 
Novartis Norge AS 
Tlf: +47 23 05 20 00 

Eesti 
Novartis Pharma Services Inc. 
Tel: +372 60 62 400 
 

Österreich 
Novartis Pharma GmbH 
Tel: +43 1 86 6570 

Ελλάδα 
Novartis (Hellas) A.E.B.E. 
Τηλ: +30 210 281 17 12 
 

Polska 
Novartis Poland Sp. z o.o. 
Tel.: +48 22 550 8888 

España 
Novartis Farmacéutica, S.A. 
Tel: +34 93 306 42 00 
 

Portugal 
Novartis Farma - Produtos Farmacêuticos, S.A. 
Tel: +351 21 000 8600 

France 
 Novartis Pharma S.A.S.

él: +33 1 55 47 66 00 T
 

România 
Novartis Pharma Services Inc. 
Tel: +40 21 31299 01 

Ireland 
d Novartis Ireland Limite

el: +353 1 260 12 55 T
 

Slovenija 
es Inc. Novartis Pharma Servic

Tel: +386 1 300 75 77 

Ísland 
Vistor hf. 

ími: +354 535 7000 S
 

Slovenská republika 
Novartis Slovakia s.r.o. 

el: +421 2 5542 5439 T
 

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Italia 
Novartis Farma S.p.A. 
Tel: +39 02 96 54 1 

Suomi/Finland 
Novartis Finland Oy 
Puh/Tel: +358 9 61 33 22 11 
 

Κύπρος 
Δημητριάδης και Παπαέλληνας Λτδ 
Τηλ: +357 22 690 690 
 

Sverige 
Novartis Sverige AB 
Tel: +46 8 732 32 00 
 

Latvija 
Novartis Pharma Services Inc. 
Tel: +371 7 887 070 
 

United Kingdom 
Novartis Pharmaceuticals UK Ltd. 
Tel: +44 1276 698370 
 

Lietuva 
Novartis Pharma Services Inc. 
Tel: +370 5 269 16 50 
 

 

 
This leaflet was last approved in 

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PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

Enviage 300 mg film-coated tablets 
Aliskiren 

 
Read all of this leaflet carefully before you start taking this medicine. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even 

if their symptoms are the same as yours. 
- If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 

please tell your doctor or pharmacist. 
 
 
In this leaflet: 
1. What Enviage is and what it is used for 
2. Before you take Enviage 
3. How to take Enviage 
4. Possible side effects 
5. How to store Enviage 
6. Further information 
 
 
 
1. WHAT ENVIAGE IS AND WHAT IT IS USED FOR 
 
Enviage belongs to a new class of medicines called renin inhibitors. Enviage helps to lower high blood 
pressure. Renin inhibitors reduce the amount of angiotensin II the body can produce. Angiotensin II 
causes blood vessels to tighten, which increases the blood pressure. Reducing the amount of 
angiotensin II allows the blood vessels to relax, which lowers blood pressure. 
 
High blood pressure increases the workload of the heart and arteries. If this continues for a long time, 
it can damage the blood vessels of the brain, heart and kidneys, and may result in a stroke, heart 
failure, heart attack or kidney failure. Lowering the blood pressure to a normal level reduces the risk 
of developing these disorders. 
 
 
2. BEFORE YOU TAKE ENVIAGE 
 
Do not take Enviage 
- if you are allergic (hypersensitive) to aliskiren or any of the other ingredients of Enviage. If you 

think you may be allergic, ask your doctor for advice. 
- if you have already experienced angioedema (difficulties in breathing, or swallowing, or 

swelling of the face, hands and feet, eyes, lips and/or tongue) when taking aliskiren. 
- during the last 6 months of pregnancy or if you are breast-feeding, see section Pregnancy and 

breastfeeding. 
- if you are taking ciclosporin (a medicine used in transplantation to prevent organ rejection or for 

other conditions, e.g. rheumathoid arthritis or atopic dermatitis) or verapamil (a medicine used 
to lower blood pressure, to correct hearth rhythm or to treat angina pectoris) or quinidine (a 
medicine used to correct heart rhythm). 

 
Take special care with Enviage 
- if you are taking a diuretic (a type of medicine also known as “water” tablets which increases 

the amount of urine you produce). 
- if you have impaired kidney function. 
- if you experience angioedema (difficulties in breathing, or swallowing, or swelling of the face, 

hands and feet, eyes, lips and/or tongue). 

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If any of these apply to you, tell your doctor before you take Enviage. 
 
The use of Enviage in children and adolescents is not recommended. 
There are no special dose recommendations for patients aged 65 years or older. 
 
Using other medicines 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription. 
 
Your doctor may need to change your dose and/or to take other precautions if you are taking one of 
the following medicines: 
- medicines that increase the amount of potassium in your blood. These include potassium-

sparing diuretics, potassium supplements. 
- furosemide, a medicine belonging to the type known as diuretics, or “water” tablets, which is 

used to increase the amount of urine you produce. 
- ketoconazole, a medicine used to treat fungal infections. 
- certain types of pain killers called non-steroidal anti-inflammatory medicines (NSAIDs). 
 
Taking Enviage with food and drink 
You should take Enviage with a light meal once a day, preferably at the same time each day. You 
should not take Enviage together with grapefruit juice. 
 
Pregnancy and breast-feeding 
Do not take Enviage if you are pregnant. It is important to talk to your doctor immediately if you think 
you may be pregnant or are planning to become pregnant. Do not breast-feed if you are taking 
Enviage. 
 
Ask your doctor or pharmacist for advice before taking any medicine. 
 
Driving and using machines 
You may feel dizzy and this can affect your ability to concentrate. Before you drive a vehicle, use 
machinery, or carry out other activities that require concentration, you should make sure you know 
how you react to the effects of Enviage. 
 
 
3. HOW TO TAKE ENVIAGE 
 
Always take Enviage exactly as your doctor has told you. You should check with your doctor or 
pharmacist if you are not sure. 
 
People who have high blood pressure often do not notice any signs of the problem. Many may feel 
quite normal. It is very important that you take this medicine exactly as your doctor tells you to get the 
best results and reduce the risk of side effects. Keep your appointments with the doctor even if you are 
feeling well. 
 
The usual starting dose is one 150 mg tablet once daily. 
 
Depending on how you respond to the treatment your doctor may prescribe a higher dose of one 
300 mg tablet once daily. Your doctor may prescribe Enviage together with other medicines used to 
treat high blood pressure. 
 
Method of administration 
It is recommended that you take the tablets with some water. You should take Enviage with a light 
meal once a day, preferably at the same time each day. You should not take Enviage together with 
grapefruit juice. 

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If you take more Enviage than you should 
If you have accidentally taken too many Enviage tablets, consult a doctor immediately. You may 
require medical attention. 
 
If you forget to take Enviage 
If you forget to take a dose of Enviage, take it as soon as you remember and then take the next dose at 
its usual time. However, if it is almost time for your next dose you should simply take the next tablet 
at the usual time. Do not take a double dose to make up for a forgotten dose. 
 
 
4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, Enviage can cause side effects, although not everybody gets them. 
 
Common (affecting less than 1 in 10 patients): Diarrhoea. 
Uncommon (affecting less than 1 in 100 patients): Skin rash. 
Rare (affecting less than 1 in 1,000 patients): Angioedema (difficulties in breathing, or swallowing, or 
swelling of the face, hands and feet, eyes, lips and/or tongue). 
Not known (frequency cannot be estimated from the available data): Kidney problems. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor or pharmacist. 
 
 
5. HOW TO STORE ENVIAGE 
 
Keep out of the reach and sight of children. 
Do not use Enviage after the expiry date which is stated on the carton and blister. The expiry date 
refers to the last day of that month. 
Do not store above 30°C. 
Store in the original package in order to protect from moisture. 
 
 
6. FURTHER INFORMATION 
 
What Enviage contains 
- The active substance is aliskiren (as hemifumarate) 300 mg. 
- The other ingredients are crospovidone, hypromellose, magnesium stearate, macrogol, 

microcrystalline cellulose, povidone, colloidal anhydrous silica, talc, titanium dioxide (E 171), 
black iron oxide (E 172), red iron oxide (E 172). 

 
What Enviage looks like and contents of the pack 
Enviage 300 mg film coated tablets are light-red, biconvex, ovaloid tablets, imprinted “IU” on one 
side and “NVR” on the other side. 
 
Enviage is available in packs containing 7, 14, 28, 30, 50, 56, 84, 90, 98 or 280 tablets. Packs 
containing 84 (3x28), 90 (3x30), 98 (2x49) or 280 (20x14) tablets are multi-packs. Not all pack sizes 
may be available in your country. 
 
 
Marketing Authorisation Holder 
Novartis Europharm Limited 
Wimblehurst Road 
Horsham 
West Sussex, RH12 5AB 
United Kingdom 

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Manufacturer 
Novartis Farma S.p.A. 
Via Provinciale Schito 131 
I-80058 Torre Annunziata/NA 
Italy 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Novartis Pharma N.V. 
Tél/Tel: +32 2 246 16 11 
 

Luxembourg/Luxemburg 
Novartis Pharma GmbH 
Tél/Tel: +49 911 273 0 
 

България 
Novartis Pharma Services Inc. 
Тел.: +359 2 489 98 28 
 

Magyarország 
Novartis Hungária Kft. Pharma 
Tel.: +36 1 457 65 00 

Česká republika 
Novartis s.r.o. 
Tel: +420 225 775 111 
 

Malta 
Novartis Pharma Services Inc. 
Tel: +356 2298 3217 

Danmark 
Novartis Healthcare A/S 
Tlf: +45 39 16 84 00 
 

Nederland 
Novartis Pharma B.V. 
Tel: +31 26 37 82 111 

Deutschland 
Novartis Pharma GmbH 
Tel: +49 911 273 0 
 

Norge 
Novartis Norge AS 
Tlf: +47 23 05 20 00 

Eesti 
Novartis Pharma Services Inc. 
Tel: +372 60 62 400 
 

Österreich 
Novartis Pharma GmbH 
Tel: +43 1 86 6570 

Ελλάδα 
Novartis (Hellas) A.E.B.E. 
Τηλ: +30 210 281 17 12 
 

Polska 
Novartis Poland Sp. z o.o. 
Tel.: +48 22 550 8888 

España 
Novartis Farmacéutica, S.A. 
Tel: +34 93 306 42 00 
 

Portugal 
Novartis Farma - Produtos Farmacêuticos, S.A. 
Tel: +351 21 000 8600 

France 
Novartis Pharma S.A.S. 
Tél: +33 1 55 47 66 00 
 

România 
Novartis Pharma Services Inc. 
Tel: +40 21 31299 01 

Ireland 
d Novartis Ireland Limite

el: +353 1 260 12 55 T
 

Slovenija 
es Inc. Novartis Pharma Servic

Tel: +386 1 300 75 77 

Ísland 
Vistor hf. 

ími: +354 535 7000 S
 

Slovenská republika 
Novartis Slovakia s.r.o. 

el: +421 2 5542 5439 T
 

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Italia 
Novartis Farma S.p.A. 
Tel: +39 02 96 54 1 

Suomi/Finland 
Novartis Finland Oy 
Puh/Tel: +358 9 61 33 22 11 
 

Κύπρος 
Δημητριάδης και Παπαέλληνας Λτδ 
Τηλ: +357 22 690 690 
 

Sverige 
Novartis Sverige AB 
Tel: +46 8 732 32 00 
 

Latvija 
Novartis Pharma Services Inc. 
Tel: +371 7 887 070 
 

United Kingdom 
Novartis Pharmaceuticals UK Ltd. 
Tel: +44 1276 698370 
 

Lietuva 
Novartis Pharma Services Inc. 
Tel: +370 5 269 16 50 
 

 

 
This leaflet was last approved in 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OF THE MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET