ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Rasilez 150 mg film-coated tablets
2.
Each film-coated tablet contains 150 mg aliskiren (as hemifumarate).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Light-pink, biconvex, round tablet, imprinted “IL” on one side and “NVR” on the other side.
4.
Treatment of essential hypertension.
The recommended dose of Rasilez is 150 mg once daily. In patients whose blood pressure is not
adequately controlled, the dose may be increased to 300 mg once daily.
The antihypertensive effect is substantially present within two weeks (85-90%) after initiating therapy
with 150 mg once daily.
Rasilez may be used alone or in combination with other antihypertensive agents (see sections 4.4 and
5.1).
Rasilez should be taken with a light meal once a day, preferably at the same time each day. Grapefruit
juice should not be taken together with Rasilez.
Renal impairment
No adjustment of the initial dose is required for patients with mild to severe renal impairment (see
sections 4.4 and 5.2).
Hepatic impairment
No adjustment of the initial dose is required for patients with mild to severe hepatic impairment (see
section 5.2).
Elderly patients (over 65 years)
No adjustment of the initial dose is required for elderly patients.
Paediatric patients (below 18 years)
Rasilez is not recommended for use in children and adolescents below age 18 due to a lack of data on
safety and efficacy (see section 5.2).
2
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, a highly potent P-gp inhibitor, and other potent P-
gp inhibitors (quinidine, verapamil), is contraindicated (see section 4.5).
Patients receiving other medicinal products inhibiting the renin-angiotensin system (RAS), and/or
those with reduced kidney function and/or diabetes mellitus are at an increased risk of hyperkalaemia
during aliskiren therapy.
Aliskiren should be used with caution in patients with serious congestive heart failure (New York
Heart Association (NYHA) functional class III-IV).
In the event of severe and persistent diarrhoea, Rasilez therapy should be stopped.
Angioedema
As with other agents acting on the renin-angiotensin system, angioedema has been reported in patients
treated with aliskiren. 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 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 Rasilez. This condition should
be corrected prior to administration of Rasilez, or the treatment should start under close medical
supervision.
Renal impairment
In clinical studies Rasilez has not been investigated in hypertensive patients with severe renal
impairment (serum creatinine ≥ 150 μmol/l or 1.70 mg/dl in women and ≥ 177 μmol/l or 2.00 mg/dl in
men and/or estimated glomerular filtration rate (GFR) < 30 ml/min), history of dialysis, nephrotic
syndrome or renovascular hypertension. Caution should be exercised in hypertensive patients with
severe renal impairment due to the lack of safety information for Rasilez.
As for other agents acting on the renin-angiotensin system, caution should be exercised when aliskiren
is given in the presence of conditions pre-disposing to kidney dysfunction such as hypovolaemia (eg.
due to blood loss, severe prolonged diarrhoea, prolonged vomiting, etc.), heart disease, liver disease or
kidney disease. Acute renal failure, reversible upon discontinuation of treatment, has been reported in
at-risk patients receiving aliskiren in post-marketing experience. In the event that any signs of renal
failure occur, aliskiren should be promptly discontinued.
Renal artery stenosis
No controlled clinical data are available on the use of Rasilez in patients with unilateral or bilateral
renal artery stenosis, or stenosis to a solitary kidney. However, as with other agents acting on the
renin-angiotensin system, there is an increased risk of renal insufficiency, including acute renal failure,
when patients with renal artery stenosis are treated with aliskiren. Therefore, caution should be
exercised in these patients. If renal failure occurs, treatment should be discontinued.
3
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).
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 bioavailability may be slightly decreased by Rasilez.
Preliminary data suggest that irbesartan may decrease Rasilez AUC and C
max
.
In experimental animals, it has been shown that P-gp is a major determinant of Rasilez bioavailability.
Inducers of P-gp (St. John’s wort, rifampicin) might therefore decrease the bioavailability of Rasilez.
CYP450 interactions
Aliskiren does not inhibit the CYP450 isoenzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A).
Aliskiren does not induce CYP3A4. Therefore aliskiren is not expected to affect the systemic exposure
of substances that inhibit, induce or are metabolised by these enzymes. Aliskiren is metabolised
minimally by the cytochrome P450 enzymes. Hence, interactions due to inhibition or induction of
CYP450 isoenzymes are not expected. However, CYP3A4 inhibitors often also affect P-gp. Increased
aliskiren exposure during co-administration of CYP3A4 inhibitors that also inhibit P-gp can therefore
be expected (see P-glycoprotein interactions below).
P-glycoprotein interactions
MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption and
biliary excretion of aliskiren in preclinical studies. 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 C
max
increased by
50%.
4
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. 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 C
max
of furosemide were reduced
by 28% and 49%, respectively. It is therefore recommended that the effects be monitored when
initiating and adjusting furosemide therapy to avoid possible under-utilisation in clinical situations of
volume overload.
Non-steroidal anti-inflammatory drugs (NSAIDs)
As with other agents acting on the renin-angiotensin system, NSAIDs may reduce the anti-
hypertensive effect of aliskiren. In some patients with compromised renal function (dehydrated
patients or elderly patients) aliskiren given concomitantly with NSAIDs may result in further
deterioration of renal function, including possible acute renal failure, which is usually reversible.
Therefore the combination of aliskiren with an NSAID requires caution, especially in elderly patients.
Potassium and potassium-sparing diuretics
Based on experience with the use of other substances that affect the renin-angiotensin system,
concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing
potassium or other substances that may increase serum potassium levels (e.g. heparin) may lead to
increases in serum potassium. If co-medication is considered necessary, caution is advisable.
Grapefruit juice
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.
Warfarin
The effects of Rasilez on warfarin pharmacokinetics have not been evaluated.
Food intake
Meals with a high fat content have been shown to reduce the absorption of Rasilez substantially.
Pregnancy
There are no data on the use of aliskiren in pregnant women. Rasilez was not teratogenic in rats or
rabbits (see section 5.3). Other substances that act directly on the RAS have been associated with
serious foetal malformations and neonatal death. As for any medicine that acts directly on the RAS,
Rasilez should not be used during the first trimester of pregnancy or in women planning to become
pregnant and is contraindicated during the second and third trimesters (see section 4.3). Healthcare
professionals prescribing any agents acting on the RAS should counsel women of childbearing
5
potential about the potential risk of these agents during pregnancy.
If pregnancy is detected during
therapy, Rasilez should be discontinued accordingly.
Lactation
It is not known whether aliskiren is excreted in human milk. Rasilez was secreted in the milk of
lactating rats. Its use is therefore not recommended in women who are breast-feeding.
No studies on the effects on the ability to drive and use machines have been performed. However,
when driving vehicles or operating machinery it must be borne in mind that dizziness or weariness
may occasionally occur when taking any antihypertensive therapy. Rasilez has negligible influence on
the ability to drive and use machines.
Rasilez has been evaluated for safety in more than 7,800 patients, including over 2,300 treated for over
6 months, and more than 1,200 for over 1 year. The incidence of adverse reactions showed no
association with gender, age, body mass index, race or ethnicity. Treatment with Rasilez resulted in an
overall incidence of adverse reactions similar to placebo up to 300 mg. Adverse reactions have
generally been mild and transient in nature and have only infrequently required discontinuation of
therapy. The most common adverse drug reaction is diarrhoea.
The incidence of cough was similar in placebo (0.6%) and Rasilez 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:
Angioedema
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 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 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.
6
Rare:
Rash
Serum potassium
: Increases in serum potassium were minor and infrequent in patients with essential
hypertension treated with Rasilez alone (0.9% compared to 0.6% with placebo). However, in one
study where Rasilez was used in combination with an ACEI in a diabetic population, increases in
serum potassium were more frequent (5.5%). Therefore as with any agent acting on the RAS system,
routine monitoring of electrolytes and renal function is indicated in patients with diabetes mellitus,
kidney disease, or heart failure.
In post-marketing experience, renal dysfunction and cases of acute renal failure have been reported in
patients at risk (see section 4.4). There have also been reports of peripheral oedema (frequency not
known).
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.
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 Rasilez at doses of 150 mg and 300 mg provided
dose-dependent reductions in both systolic and diastolic blood pressure that were maintained over the
entire 24-hour dose interval (maintaining benefit in the early morning) with a mean peak to trough
ratio for diastolic response of up to 98% for the 300 mg dose. 85 to 90% of the maximal blood-
pressure-lowering effect was observed after 2 weeks. The blood-pressure-lowering effect was
sustained during long-term treatment, and was independent of age, gender, body mass index and
ethnicity. Rasilez has been studied in 1,864 patients aged 65 years or older, and in 426 patients aged
75 years or older.
Rasilez monotherapy studies have shown blood pressure lowering effects comparable to other classes
of antihypertensive agents including ACEI and ARB. Compared to a diuretic (hydrochlorothiazide -
HCTZ), Rasilez 300 mg lowered systolic/diastolic blood pressure by 17.0/12.3 mmHg, compared to
14.4/10.5 mmHg for HCTZ 25 mg after 12 weeks of treatment. In diabetic hypertensive patients,
Rasilez monotherapy was safe and effective.
Combination therapy studies are available for Rasilez added to the diuretic hydrochlorothiazide, the
ACEI ramipril, the calcium channel blocker amlodipine, the angiotensin receptor antagonist valsartan,
and the beta blocker atenolol. These combinations were well tolerated. Rasilez induced an additive
blood-pressure-lowering effect when added to hydrochlorothiazide and to ramipril. In patients who did
not adequately respond to 5 mg of the calcium channel blocker amlodipine, the addition of Rasilez
7
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.
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 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 6.0 mmol/l,
although this was not statistically significant.
Beneficial effects of Rasilez on mortality and cardiovascular morbidity and target organ damage are
currently unknown.
Cardiac electrophysiology
No effect on QT interval was reported in a randomised, double-blind, placebo, and active-controlled
study using standard and Holter electrocardiography.
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 C
max
by 85% and AUC by 70%. Steady-state-plasma concentrations are reached within 5-7 days following
once-daily administration and steady-state levels are approximately 2-fold greater than with the initial
dose.
Distribution
Following intravenous administration, the mean volume of distribution at steady state is approximately
135 litres, indicating that aliskiren distributes extensively into the extravascular space. Aliskiren
plasma protein binding is moderate (47-51%) and independent of the concentration.
8
Metabolism and elimination
The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as unchanged
compound in the faeces (78%). Approximately 1.4% of the total oral dose is metabolised. The enzyme
responsible for this metabolism is CYP3A4. Approximately 0.6% of the dose is recovered in urine
following oral administration. Following intravenous administration, the mean plasma clearance is
approximately 9 l/h.
Linearity/non-linearity
Exposure to aliskiren increased more than in proportion to the increase in dose. After single dose
administration in the dose range of 75 to 600 mg, a 2-fold increase in dose results in a ~2.3 and 2.6-
fold increase in AUC and C
max
, respectively. At steady state the non-linearity may be more
pronounced. Mechanisms responsible for deviation from linearity have not been identified. A possible
mechanism is saturation of transporters at the absorption site or at the hepatobiliary clearance route.
Characteristics in patients
Aliskiren is an effective once-a-day antihypertensive treatment in adult patients, regardless of gender,
age, body mass index and ethnicity.
The AUC is 50% higher in elderly (>65 years) than in young subjects. Gender, weight and ethnicity
have no clinically relevant influence on aliskiren pharmacokinetics.
The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renal
insufficiency. Relative AUC and C
max
of aliskiren in subjects with renal impairment ranged between
0.8 to 2 times the levels in healthy subjects following single dose administration and at steady state.
These observed changes, however, did not correlate with the severity of renal impairment. No
adjustment of the initial dosage of Rasilez is required in patients with mild to severe renal impairment,
however caution should be exercised in patients with severe renal impairment.
The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe liver
disease. Consequently, no adjustment of the initial dose of aliskiren is required in patients with mild to
severe hepatic impairment.
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.
9
6.
6.1 List of excipients
Crospovidone
Magnesium stearate
Cellulose, microcrystalline
Povidone
Silica, colloidal anhydrous
Hypromellose
Macrogol
Talc
Iron oxide, black (E 172)
Iron oxide, red (E 172)
Titanium dioxide (E 171)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 30C. Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
PA/Alu/PVC – Alu blisters:
Packs containing 7, 14, 28, 30, 50, 56, 84, 90, 98 or 280 tablets.
Packs containing 84 (3x28), 98 (2x49) or 280 (20x14) tablets are multi-packs.
PVC/polychlorotrifluoroethylene (PCTFE) – Alu blisters:
Packs containing 14, 28, 30, 50, 56, 90, 98 or 280 tablets.
Packs containing 98 (2x49) or 280 (20x14) tablets are multi-packs.
Packs containing 56 (8x7) and 98 (2x49) tablets are perforated unit-dose blisters.
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.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
10
8.
EU/1/07/405/001-010
EU/1/07/405/021-030
9.
22.08.2007
11
1.
Rasilez 300 mg film-coated tablets
2.
Each film-coated tablet contains 300 mg aliskiren (as hemifumarate).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Light-red, biconvex, ovaloid tablet, imprinted “IU” on one side and “NVR” on the other side.
4.
Treatment of essential hypertension.
The recommended dose of Rasilez is 150 mg once daily. In patients whose blood pressure is not
adequately controlled, the dose may be increased to 300 mg once daily.
The antihypertensive effect is substantially present within two weeks (85-90%) after initiating therapy
with 150 mg once daily.
Rasilez may be used alone or in combination with other antihypertensive agents (see sections 4.4 and
5.1).
Rasilez should be taken with a light meal once a day, preferably at the same time each day. Grapefruit
juice should not be taken together with Rasilez.
Renal impairment
No adjustment of the initial dose is required for patients with mild to severe renal impairment (see
sections 4.4 and 5.2).
Hepatic impairment
No adjustment of the initial dose is required for patients with mild to severe hepatic impairment (see
section 5.2).
Elderly patients (over 65 years)
No adjustment of the initial dose is required for elderly patients.
Paediatric patients (below 18 years)
Rasilez is not recommended for use in children and adolescents below age 18 due to a lack of data on
safety and efficacy (see section 5.2).
12
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, a highly potent P-gp inhibitor, and other potent P-
gp inhibitors (quinidine, verapamil), is contraindicated (see section 4.5).
Patients receiving other medicinal products inhibiting the renin-angiotensin system (RAS), and/or
those with reduced kidney function and/or diabetes mellitus are at an increased risk of hyperkalaemia
during aliskiren therapy.
Aliskiren should be used with caution in patients with serious congestive heart failure (New York
Heart Association (NYHA) functional class III-IV).
In the event of severe and persistent diarrhoea, Rasilez therapy should be stopped.
Angioedema
As with other agents acting on the renin-angiotensin system, angioedema has been reported in patients
treated with aliskiren. 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 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 Rasilez. This condition should
be corrected prior to administration of Rasilez, or the treatment should start under close medical
supervision.
Renal impairment
In clinical studies Rasilez has not been investigated in hypertensive patients with severe renal
impairment (serum creatinine ≥ 150 μmol/l or 1.70 mg/dl in women and ≥ 177 μmol/l or 2.00 mg/dl in
men and/or estimated glomerular filtration rate (GFR) < 30 ml/min), history of dialysis, nephrotic
syndrome or renovascular hypertension. Caution should be exercised in hypertensive patients with
severe renal impairment due to the lack of safety information for Rasilez.
As for other agents acting on the renin-angiotensin system, caution should be exercised when aliskiren
is given in the presence of conditions pre-disposing to kidney dysfunction such as hypovolaemia (eg.
due to blood loss, severe prolonged diarrhoea, prolonged vomiting, etc.), heart disease, liver disease or
kidney disease. Acute renal failure, reversible upon discontinuation of treatment, has been reported in
at-risk patients receiving aliskiren in post-marketing experience. In the event that any signs of renal
failure occur, aliskiren should be promptly discontinued.
Renal artery stenosis
No controlled clinical data are available on the use of Rasilez in patients with unilateral or bilateral
renal artery stenosis, or stenosis to a solitary kidney. However, as with other agents acting on the
renin-angiotensin system, there is an increased risk of renal insufficiency, including acute renal failure,
when patients with renal artery stenosis are treated with aliskiren. Therefore, caution should be
exercised in these patients. If renal failure occurs, treatment should be discontinued.
13
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).
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 bioavailability may be slightly decreased by Rasilez.
Preliminary data suggest that irbesartan may decrease Rasilez AUC and C
max
.
In experimental animals, it has been shown that P-gp is a major determinant of Rasilez bioavailability.
Inducers of P-gp (St. John’s wort, rifampicin) might therefore decrease the bioavailability of Rasilez.
CYP450 interactions
Aliskiren does not inhibit the CYP450 isoenzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A).
Aliskiren does not induce CYP3A4. Therefore aliskiren is not expected to affect the systemic exposure
of substances that inhibit, induce or are metabolised by these enzymes. Aliskiren is metabolised
minimally by the cytochrome P450 enzymes. Hence, interactions due to inhibition or induction of
CYP450 isoenzymes are not expected. However, CYP3A4 inhibitors often also affect P-gp. Increased
aliskiren exposure during co-administration of CYP3A4 inhibitors that also inhibit P-gp can therefore
be expected (see P-glycoprotein interactions below).
P-glycoprotein interactions
MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption and
biliary excretion of aliskiren in preclinical studies. 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 C
max
increased by
50%.
14
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. 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 C
max
of furosemide were reduced
by 28% and 49%, respectively. It is therefore recommended that the effects be monitored when
initiating and adjusting furosemide therapy to avoid possible under-utilisation in clinical situations of
volume overload.
Non-steroidal anti-inflammatory drugs (NSAIDs)
As with other agents acting on the renin-angiotensin system, NSAIDs may reduce the anti-
hypertensive effect of aliskiren. In some patients with compromised renal function (dehydrated
patients or elderly patients) aliskiren given concomitantly with NSAIDs may result in further
deterioration of renal function, including possible acute renal failure, which is usually reversible.
Therefore the combination of aliskiren with an NSAID requires caution, especially in elderly patients.
Potassium and potassium-sparing diuretics
Based on experience with the use of other substances that affect the renin-angiotensin system,
concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing
potassium or other substances that may increase serum potassium levels (e.g. heparin) may lead to
increases in serum potassium. If co-medication is considered necessary, caution is advisable.
Grapefruit juice
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.
Warfarin
The effects of Rasilez on warfarin pharmacokinetics have not been evaluated.
Food intake
Meals with a high fat content have been shown to reduce the absorption of Rasilez substantially.
Pregnancy
There are no data on the use of aliskiren in pregnant women. Rasilez was not teratogenic in rats or
rabbits (see section 5.3). Other substances that act directly on the RAS have been associated with
serious foetal malformations and neonatal death. As for any medicine that acts directly on the RAS,
Rasilez should not be used during the first trimester of pregnancy or in women planning to become
pregnant and is contraindicated during the second and third trimesters (see section 4.3). Healthcare
professionals prescribing any agents acting on the RAS should counsel women of childbearing
15
potential about the potential risk of these agents during pregnancy.
If pregnancy is detected during
therapy, Rasilez should be discontinued accordingly.
Lactation
It is not known whether aliskiren is excreted in human milk. Rasilez was secreted in the milk of
lactating rats. Its use is therefore not recommended in women who are breast-feeding.
No studies on the effects on the ability to drive and use machines have been performed. However,
when driving vehicles or operating machinery it must be borne in mind that dizziness or weariness
may occasionally occur when taking any antihypertensive therapy. Rasilez has negligible influence on
the ability to drive and use machines.
Rasilez has been evaluated for safety in more than 7,800 patients, including over 2,300 treated for over
6 months, and more than 1,200 for over 1 year. The incidence of adverse reactions showed no
association with gender, age, body mass index, race or ethnicity. Treatment with Rasilez resulted in an
overall incidence of adverse reactions similar to placebo up to 300 mg. Adverse reactions have
generally been mild and transient in nature and have only infrequently required discontinuation of
therapy. The most common adverse drug reaction is diarrhoea.
The incidence of cough was similar in placebo (0.6%) and Rasilez 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:
Angioedema
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 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 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.
16
Rare:
Rash
Serum potassium
: Increases in serum potassium were minor and infrequent in patients with essential
hypertension treated with Rasilez alone (0.9% compared to 0.6% with placebo). However, in one
study where Rasilez was used in combination with an ACEI in a diabetic population, increases in
serum potassium were more frequent (5.5%). Therefore as with any agent acting on the RAS system,
routine monitoring of electrolytes and renal function is indicated in patients with diabetes mellitus,
kidney disease, or heart failure.
In post-marketing experience, renal dysfunction and cases of acute renal failure have been reported in
patients at risk (see section 4.4). There have also been reports of peripheral oedema (frequency not
known).
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.
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 Rasilez at doses of 150 mg and 300 mg provided
dose-dependent reductions in both systolic and diastolic blood pressure that were maintained over the
entire 24-hour dose interval (maintaining benefit in the early morning) with a mean peak to trough
ratio for diastolic response of up to 98% for the 300 mg dose. 85 to 90% of the maximal blood-
pressure-lowering effect was observed after 2 weeks. The blood-pressure-lowering effect was
sustained during long-term treatment, and was independent of age, gender, body mass index and
ethnicity. Rasilez has been studied in 1,864 patients aged 65 years or older, and in 426 patients aged
75 years or older.
Rasilez monotherapy studies have shown blood pressure lowering effects comparable to other classes
of antihypertensive agents including ACEI and ARB. Compared to a diuretic (hydrochlorothiazide -
HCTZ), Rasilez 300 mg lowered systolic/diastolic blood pressure by 17.0/12.3 mmHg, compared to
14.4/10.5 mmHg for HCTZ 25 mg after 12 weeks of treatment. In diabetic hypertensive patients,
Rasilez monotherapy was safe and effective.
Combination therapy studies are available for Rasilez added to the diuretic hydrochlorothiazide, the
ACEI ramipril, the calcium channel blocker amlodipine, the angiotensin receptor antagonist valsartan,
and the beta blocker atenolol. These combinations were well tolerated. Rasilez induced an additive
blood-pressure-lowering effect when added to hydrochlorothiazide and to ramipril. In patients who did
not adequately respond to 5 mg of the calcium channel blocker amlodipine, the addition of Rasilez
17
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.
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 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 6.0 mmol/l,
although this was not statistically significant.
Beneficial effects of Rasilez on mortality and cardiovascular morbidity and target organ damage are
currently unknown.
Cardiac electrophysiology
No effect on QT interval was reported in a randomised, double-blind, placebo, and active-controlled
study using standard and Holter electrocardiography.
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 C
max
by 85% and AUC by 70%. Steady-state-plasma concentrations are reached within 5-7 days following
once-daily administration and steady-state levels are approximately 2-fold greater than with the initial
dose.
Distribution
Following intravenous administration, the mean volume of distribution at steady state is approximately
135 litres, indicating that aliskiren distributes extensively into the extravascular space. Aliskiren
plasma protein binding is moderate (47-51%) and independent of the concentration.
18
Metabolism and elimination
The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as unchanged
compound in the faeces (78%). Approximately 1.4% of the total oral dose is metabolised. The enzyme
responsible for this metabolism is CYP3A4. Approximately 0.6% of the dose is recovered in urine
following oral administration. Following intravenous administration, the mean plasma clearance is
approximately 9 l/h.
Linearity/non-linearity
Exposure to aliskiren increased more than in proportion to the increase in dose. After single dose
administration in the dose range of 75 to 600 mg, a 2-fold increase in dose results in a ~2.3 and 2.6-
fold increase in AUC and C
max
, respectively. At steady state the non-linearity may be more
pronounced. Mechanisms responsible for deviation from linearity have not been identified. A possible
mechanism is saturation of transporters at the absorption site or at the hepatobiliary clearance route.
Characteristics in patients
Aliskiren is an effective once-a-day antihypertensive treatment in adult patients, regardless of gender,
age, body mass index and ethnicity.
The AUC is 50% higher in elderly (>65 years) than in young subjects. Gender, weight and ethnicity
have no clinically relevant influence on aliskiren pharmacokinetics.
The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renal
insufficiency. Relative AUC and C
max
of aliskiren in subjects with renal impairment ranged between
0.8 to 2 times the levels in healthy subjects following single dose administration and at steady state.
These observed changes, however, did not correlate with the severity of renal impairment. No
adjustment of the initial dosage of Rasilez is required in patients with mild to severe renal impairment,
however caution should be exercised in patients with severe renal impairment.
The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe liver
disease. Consequently, no adjustment of the initial dose of aliskiren is required in patients with mild to
severe hepatic impairment.
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.
19
6.
6.1 List of excipients
Crospovidone
Magnesium stearate
Cellulose, microcrystalline
Povidone
Silica, colloidal anhydrous
Hypromellose
Macrogol
Talc
Iron oxide, black (E 172)
Iron oxide, red (E 172)
Titanium dioxide (E 171)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 30C. Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
PA/Alu/PVC – Alu 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.
PVC/polychlorotrifluoroethylene (PCTFE) – Alu blisters:
Packs containing 14, 28, 30, 50, 56, 90, 98 or 280 tablets.
Packs containing 98 (2x49) or 280 (20x14) tablets are multi-packs.
Packs containing 56 (8x7) and 98 (2x49) tablets are perforated unit-dose blisters.
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.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
20
8.
EU/1/07/405/011-020
EU/1/07/405/031-040
9.
22.08.2007
21
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
22
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
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.
23
ANNEX III
LABELLING AND PACKAGE LEAFLET
24
A. LABELLING
25
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
FOLDING BOX FOR UNIT PACK CONTAINING PA/ALU/PVC BLISTERS
1.
Rasilez 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.
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
26
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
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/405/001
7 film-coated tablets
EU/1/07/405/002
14 film-coated tablets
EU/1/07/405/003
28 film-coated tablets
EU/1/07/405/005
50 film-coated tablets
EU/1/07/405/006
56 film-coated tablets
EU/1/07/405/008
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
Rasilez 150 mg
27
EU/1/07/405/004
30 film-coated tablets
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
FOLDING BOX FOR UNIT PACK CONTAINING PCTFE/PVC BLISTERS
1.
Rasilez 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.
14 film-coated tablets
28 film-coated tablets
30 film-coated tablets
50 film-coated tablets
56 film-coated tablets
90 film-coated tablets
98 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
28
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
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/405/021
14 film-coated tablets
EU/1/07/405/022
28 film-coated tablets
EU/1/07/405/023
30 film-coated tablets
EU/1/07/405/025
56 film-coated tablets
EU/1/07/405/026
56 film-coated tablets (perforated unit-dose blister)
EU/1/07/405/027
90 film-coated tablets
EU/1/07/405/028
98 film-coated tablets
EU/1/07/405/000
98 film-coated tablets (perforated unit-dose blister)
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Rasilez 150 mg
29
EU/1/07/405/024
50 film-coated tablets
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
BLISTER (CALENDAR)
1.
Rasilez 150 mg film-coated tablets
Aliskiren
2.
Novartis Europharm Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
Sunday
30
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
INTERMEDIATE CARTON OF MULTIPACKS (WITHOUT BLUE BOX) CONTAINING
PA/ALU/PVC BLISTERS
1.
Rasilez 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.
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
31
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
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/405/007
84 film-coated tablets (3x28)
EU/1/07/405/009
98 film-coated tablets (2x49)
EU/1/07/405/010
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
Rasilez 150 mg
32
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON OF MULTIPACKS (INCLUDING BLUE BOX) CONTAINING
PA/ALU/PVC BLISTERS
1.
Rasilez 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.
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
33
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
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/405/007
84 film-coated tablets (3x28)
EU/1/07/405/009
98 film-coated tablets (2x49)
EU/1/07/405/010
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
Rasilez 150 mg
34
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
INTERMEDIATE CARTON OF MULTIPACKS (WITHOUT BLUE BOX) CONTAINING
PCTFE/PVC BLISTERS
1.
Rasilez 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.
14 film-coated tablets
Component of a multipack comprising 20 packs, each containing 14 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.
35
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/405/029
98 film-coated tablets (2x49)
EU/1/07/405/030
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
Rasilez 150 mg
36
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON OF MULTIPACKS (INCLUDING BLUE BOX) CONTAINING
PCTFE/PVC BLISTERS
1.
Rasilez 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.
280 film-coated tablets
Multipack comprising 20 packs, each containing 14 tablets.
98 film-coated tablets
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.
37
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/405/029
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
Rasilez 150 mg
38
EU/1/07/405/030
98 film-coated tablets (2x49)
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
FOLDING BOX FOR UNIT PACK CONTAINING PA/ALU/PVC BLISTERS
1.
Rasilez 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.
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.
39
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/405/011
14 film-coated tablets
EU/1/07/405/013
28 film-coated tablets
EU/1/07/405/014
30 film-coated tablets
EU/1/07/405/015
50 film-coated tablets
EU/1/07/405/016
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
Rasilez 300 mg
40
EU/1/07/405/012
7 film-coated tablets
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
FOLDING BOX FOR UNIT PACK CONTAINING PCTFE/PVC BLISTERS
1.
Rasilez 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.
14 film-coated tablets
28 film-coated tablets
30 film-coated tablets
50 film-coated tablets
56 film-coated tablets
90 film-coated tablets
98 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
41
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
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/405/031
14 film-coated tablets
EU/1/07/405/032
28 film-coated tablets
EU/1/07/405/033
30 film-coated tablets
EU/1/07/405/035
56 film-coated tablets
EU/1/07/405/036
56 film-coated tablets (perforated unit-dose blister)
EU/1/07/405/037
90 film-coated tablets
EU/1/07/405/038
98 film-coated tablets
EU/1/07/405/000
98 film-coated tablets (perforated unit-dose blister)
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Rasilez 300 mg
42
EU/1/07/405/034
50 film-coated tablets
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
BLISTER (CALENDAR)
1.
Rasilez 300 mg film-coated tablets
Aliskiren
2.
Novartis Europharm Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
Sunday
43
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
INTERMEDIATE CARTON OF MULTIPACKS (WITHOUT BLUE BOX) CONTAINING
PA/ALU/PVC BLISTERS
1.
Rasilez 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.
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
44
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
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/405/017
84 film-coated tablets (3x28)
EU/1/07/405/018
90 film-coated tablets (3x30)
EU/1/07/405/019
98 film-coated tablets (2x49)
EU/1/07/405/020
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
Rasilez 300 mg
45
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON OF MULTIPACKS (INCLUDING BLUE BOX) CONTAINING
PA/ALU/PVC BLISTERS
1.
Rasilez 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.
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
46
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
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/405/017
84 film-coated tablets (3x28)
EU/1/07/405/018
90 film-coated tablets (3x30)
EU/1/07/405/019
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
Rasilez 300 mg
47
EU/1/07/405/020
98 film-coated tablets (2x49)
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
INTERMEDIATE CARTON OF MULTIPACKS (WITHOUT BLUE BOX) CONTAINING
PCTFE/PVC BLISTERS
1.
Rasilez 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.
14 film-coated tablets
Component of a multipack comprising 20 packs, each containing 14 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.
48
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/405/039
98 film-coated tablets (2x49)
EU/1/07/405/040
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
Rasilez 300 mg
49
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON OF MULTIPACKS (INCLUDING BLUE BOX) CONTAINING
PCTFE/PVC BLISTERS
1.
Rasilez 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.
280 film-coated tablets
Multipack comprising 20 packs, each containing 14 tablets.
98 film-coated tablets
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.
50
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/405/039
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
Rasilez 300 mg
51
EU/1/07/405/040
98 film-coated tablets (2x49)
B. PACKAGE LEAFLET
52
PACKAGE LEAFLET: INFORMATION FOR THE USER
Rasilez 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 Rasilez is and what it is used for
3.
How to take Rasilez
4.
Possible side effects
5.
How to store Rasilez
6.
Further information
1.
WHAT RASILEZ IS AND WHAT IT IS USED FOR
Rasilez belongs to a new class of medicines called renin inhibitors. Rasilez 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 RASILEZ
Do not take Rasilez
-
if you are allergic (hypersensitive) to aliskiren or any of the other ingredients of Rasilez. 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 Rasilez
- 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).
53
2.
Before you take Rasilez
-
If any of these apply to you, tell your doctor before you take Rasilez.
The use of Rasilez 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.
-
certain types of pain killers called non-steroidal anti-inflammatory medicines (NSAIDs).
Taking Rasilez with food and drink
You should take Rasilez with a light meal once a day, preferably at the same time each day. You
should not take Rasilez together with grapefruit juice.
Pregnancy and breast-feeding
Do not take Rasilez 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 Rasilez.
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 Rasilez.
3.
HOW TO TAKE RASILEZ
Always take Rasilez 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 Rasilez 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 Rasilez with a light
meal once a day, preferably at the same time each day. You should not take Rasilez together with
grapefruit juice.
54
-
ketoconazole, a medicine used to treat fungal infections.
If you take more Rasilez than you should
If you have accidentally taken too many Rasilez tablets, consult a doctor immediately. You may
require medical attention.
If you forget to take Rasilez
If you forget to take a dose of Rasilez, 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, Rasilez 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, swelling of
hands, ankles or feet (peripheral oedema).
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 RASILEZ
Keep out of the reach and sight of children.
Do not use Rasilez 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 Rasilez 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 Rasilez looks like and contents of the pack
Rasilez 150 mg film coated tablets are light-pink, biconvex round tablets, imprinted “IL” on one side
and “NVR” on the other side.
Rasilez 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
55
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
Ελλά
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
Novartis Ireland Limited
Tel: +353 1 260 12 55
Slovenija
Novartis Pharma Services Inc.
Tel: +386 1 300 75 77
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Novartis Slovakia s.r.o.
Tel: +421 2 5542 5439
56
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
Κύπρς
Δημητριάης κι Ππέλληνς Λτ
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
57
PACKAGE LEAFLET: INFORMATION FOR THE USER
Rasilez 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 Rasilez is and what it is used for
3.
How to take Rasilez
4.
Possible side effects
5.
How to store Rasilez
6.
Further information
1.
WHAT RASILEZ IS AND WHAT IT IS USED FOR
Rasilez belongs to a new class of medicines called renin inhibitors. Rasilez 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 RASILEZ
Do not take Rasilez
-
if you are allergic (hypersensitive) to aliskiren or any of the other ingredients of Rasilez. 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 Rasilez
- 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).
58
2.
Before you take Rasilez
-
If any of these apply to you, tell your doctor before you take Rasilez.
The use of Rasilez 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.
-
certain types of pain killers called non-steroidal anti-inflammatory medicines (NSAIDs).
Taking Rasilez with food and drink
You should take Rasilez with a light meal once a day, preferably at the same time each day. You
should not take Rasilez together with grapefruit juice.
Pregnancy and breast-feeding
Do not take Rasilez 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 Rasilez.
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 Rasilez.
3.
HOW TO TAKE RASILEZ
Always take Rasilez 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 Rasilez 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 Rasilez with a light
meal once a day, preferably at the same time each day. You should not take Rasilez together with
grapefruit juice.
59
-
ketoconazole, a medicine used to treat fungal infections.
If you take more Rasilez than you should
If you have accidentally taken too many Rasilez tablets, consult a doctor immediately. You may
require medical attention.
If you forget to take Rasilez
If you forget to take a dose of Rasilez, 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, Rasilez 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, swelling of
hands, ankles or feet (peripheral oedema).
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 RASILEZ
Keep out of the reach and sight of children.
Do not use Rasilez 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 Rasilez 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 Rasilez looks like and contents of the pack
Rasilez 300 mg film coated tablets are light-red, biconvex, ovaloid tablets, imprinted “IU” on one side
and “NVR” on the other side.
Rasilez 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
60
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
Ελλά
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
Novartis Ireland Limited
Tel: +353 1 260 12 55
Slovenija
Novartis Pharma Services Inc.
Tel: +386 1 300 75 77
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Novartis Slovakia s.r.o.
Tel: +421 2 5542 5439
61
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
Κύπρς
Δημητριάης κι Ππέλληνς Λτ
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
62
Source: European Medicines Agency
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