ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Rasilez HCT 150 mg/12.5 mg film-coated tablets
2.
Each film-coated tablet contains 150 mg aliskiren (as hemifumarate) and 12.5 mg hydrochlorothiazide.
Excipients: Each tablet contains 25 mg lactose monohydrate and 24.5 mg wheat starch.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
White, biconvex, ovaloid film-coated tablet imprinted with “LCI” on one side and “NVR” on the
other.
4.
Treatment of essential hypertension in adults.
Rasilez HCT is indicated in patients whose blood pressure is not adequately controlled on aliskiren or
hydrochlorothiazide used alone.
Rasilez HCT is indicated as substitution therapy in patients adequately controlled with aliskiren and
hydrochlorothiazide, given concurrently, at the same dose level as in the combination.
The recommended dose of Rasilez HCT is one tablet per day. Rasilez HCT 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 HCT.
The antihypertensive effect is largely manifested within 1 week and the maximum effect is generally
seen within 4 weeks.
Posology in patients not adequately controlled with aliskiren or hydrochlorothiazide monotherapy
Individual dose titration with each of the two components may be recommended before changing to
the fixed combination. When clinically appropriate, direct change from monotherapy to the fixed
combination may be considered.
Rasilez HCT 150 mg /12.5 mg may be administered in patients whose blood pressure is not adequately
controlled with aliskiren 150 mg or hydrochlorothiazide 12.5 mg alone.
If blood pressure remains uncontrolled after 2-4 weeks of therapy, the dose may be titrated up to a
maximum of Rasilez HCT 300 mg/25 mg daily. Dosing should be individualised and adjusted
according to the patient’s clinical response.
2
Posology as substitution therapy
For convenience, patients receiving aliskiren and hydrochlorothiazide from separate tablets may be
switched to a fixed combination tablet of Rasilez HCT containing the same component doses.
Renal impairment
No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see
sections 4.4 and 5.2). Due to the hydrochlorothiazide component, Rasilez HCT is contraindicated for
use in patients with severe renal impairment (glomerular filtration rate (GFR) < 30 ml/min/1.73 m
2
)
(see sections 4.3 and 5.2).
Hepatic impairment
Thiazides should be used with caution in patients with impaired hepatic function. No adjustment of the
initial dose is required for patients with mild to moderate hepatic impairment (see section 5.2). Due to
the hydrochlorothiazide component, Rasilez HCT is contraindicated in patients with severe hepatic
impairment (see sections 4.3 and 4.4).
Elderly patients (over 65 years)
No adjustment of the initial dose is required in elderly patients.
Paediatric patients
Rasilez HCT is not recommended for use in children and adolescents below age 18 due to a lack of
data on safety and efficacy (see section 5.2).
Hypersensitivity to the active substances or to any of the excipients (see section 6.1), or to other
sulphonamide-derived substances.
History of angioedema with aliskiren.
Second and third trimesters of pregnancy, lactation (see section 4.6).
Severe renal impairment (GFR < 30 ml/min/1.73 m
2
).
Refractory hypokalaemia, hypercalcaemia.
Severe hepatic impairment.
The concomitant use of aliskiren with ciclosporin, a highly potent P-glycoprotein (P-gp)
inhibitor, and other potent P-gp inhibitors (quinidine, verapamil), is contraindicated (see section
4.5).
Heart failure
Aliskiren should be used with caution in patients with serious congestive heart failure (New York
Heart Association (NYHA) functional class III-IV). Rasilez HCT should be used with caution in
patients with heart failure due to limited clinical efficacy and safety data.
Angioedema
As with other agents acting on the renin -angiotensin system, angioedema has been reported in patients
treated with aliskiren. If angioedema occurs, Rasilez HCT 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.
Intravascular volume depletion
Symptomatic hypotension may occur in patients who are volume and/or sodium depleted as a result of
vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be
corrected before the administration of Rasilez HCT.
3
Electrolyte imbalance
As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be
performed at appropriate intervals. Thiazides, including hydrochlorothiazide, can cause fluid or
electrolyte imbalance (including hypokalaemia, hyponatraemia and hypochloraemic alkalosis).
Warning signs of fluid or electrolyte imbalance are dry mouth, thirst, weakness, lethargy, drowsiness,
restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and
gastrointestinal disturbances such as nausea or vomiting (see section 4.8).
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with
aliskiren may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in patients
with cirrhosis of the liver, patients experiencing brisk diuresis, patients with inadequate oral
electrolyte intake and patients receiving concomitant therapy with corticosteroids or
adrenocorticotropic hormone (ACTH) (see sections 4.5 and 4.8).
Conversely, due to the aliskiren component of Rasilez HCT, hyperkalaemia might occur. Although
clinically significant hyperkalaemia has not been documented with Rasilez HCT, risk factors for the
development of hyperkalaemia include renal insufficiency and/or heart failure, and diabetes mellitus.
Adequate monitoring of serum potassium in patients at risk is recommended. Caution is required when
co-administering potassium-sparing diuretics, potassium supplements or potassium-containing salts
substitutes with Rasilez HCT (see sections 4.5 and 4.8).
There is no evidence that Rasilez HCT would reduce or prevent diuretic-induced hyponatraemia.
Chloride deficit is generally mild and usually does not require treatment.
Thiazides may reduce urinary calcium excretion and cause an intermittent and slight elevation of
serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia
may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out
tests for parathyroid function.
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in
hypomagnesaemia (see also section 4.5).
Renal impairment and kidney transplantation
When Rasilez HCT is used in patients with impaired renal function, periodic monitoring of potassium,
creatinine and uric acid serum levels is recommended. There is no experience regarding the
administration of Rasilez HCT in patients who have recently undergone kidney transplantation. No
dosage adjustment is necessary in patients with renal impairment whose GFR is ≥ 30 ml/min/1.73 m
2
.
However, in patients with mild to moderate renal impairment (GFR ≥ 30 ml/min/1.73 m
2
but
< 60 ml/min/1.73 m
2
), Rasilez HCT should be administered with caution.
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 (e.g.
due to blood loss, severe or 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.
Hepatic impairment
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver
disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
There is no clinical experience with Rasilez HCT in patients with hepatic impairment.
4
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).
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral
stenosis, or obstructive hypertrophic cardiomyopathy.
Renal artery stenosis and renovascular hypertension
No controlled clinical data are available on the use of Rasilez HCT 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 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.
Metabolic and endocrine effects
Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or
oral hypoglycaemic agents may be required. Latent diabetes mellitus may occur during thiazide
therapy. To date, no data are available from clinical studies that were specifically-designed to evaluate
the safety of Rasilez HCT in diabetic patients.
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy.
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide
therapy.
General
In the event of severe and persistent diarrhoea, Rasilez HCT therapy should be stopped.
As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischaemic
cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of
allergy or bronchial asthma, but are more likely in patients with such a history. Exacerbation or
activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.
Excipients
Rasilez HCT contains lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Rasilez HCT contains wheat starch. It is suitable for people with coeliac disease. Patients with wheat
allergy (different from coeliac disease) should not take this medicine.
Medicinal products affecting potassium
: The potassium-depleting effect of hydrochlorothiazide is
attenuated by the potassium-sparing effect of aliskiren. However, this effect of hydrochlorothiazide on
serum potassium would be expected to be potentiated by other medicinal products associated with
potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin,
carbenoxolone, penicillin G sodium, corticosteroids, ACTH, salicylic acid derivatives). Conversely,
based on experience with the use of other medicinal products that blunt the renin-angiotensin system
(RAS), concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes
containing potassium or other medicinal products that may increase serum potassium levels (e.g.
heparin sodium) may lead to increases in serum potassium. Adequate monitoring of serum potassium
in patients at risk is recommended (see sections 4.4 and 4.8).
5
Medicinal products affected by serum potassium disturbances
: Periodic monitoring of serum
potassium is recommended when Rasilez HCT is administered with medicinal products affected by
serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).
Other antihypertensive agents:
The antihypertensive effect of Rasilez HCT may be increased with the
concomitant use of other antihypertensive agents.
Additional information on aliskiren interactions
Aliskiren has no known clinically relevant interactions with medicinal products commonly used to
treat hypertension or diabetes.
Compounds that have been investigated in aliskiren clinical pharmacokinetic studies include
acenocoumarol, atenolol, celecoxib, fenofibrate, pioglitazone, allopurinol, isosorbide-5-mononitrate,
irbesartan, digoxin, ramipril, valsartan, metformin, amlodipine, atorvastatin, cimetidine and
hydrochlorothiazide. No clinically relevant interactions have been identified. As a result no dose
adjustment for aliskiren or these co-administered medicinal products is necessary.
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 aliskiren. Although this
has not been investigated for aliskiren, it is known that P-gp also controls tissue uptake of a variety of
substrates and P-gp inhibitors can increase the tissue-to-plasma concentration ratios. Therefore, P-gp
inhibitors may increase tissue levels more than plasma levels. The potential for drug interactions at the
P-gp site will likely depend on the degree of inhibition of this transporter.
P-gp potent inhibitors
: A single dose drug interaction study in healthy subjects has shown that
ciclosporin (200 and 600 mg) increases C
max
of aliskiren 75 mg approximately 2.5-fold and AUC
approximately 5-fold
.
The increase may be higher with higher aliskiren doses. Therefore, concomitant
use of aliskiren and P-gp potent inhibitors is contraindicated (see section 4.3).
Moderate P-gp inhibitors
: Co-administration of ketoconazole (200 mg) 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 P-gp inhibitors (itraconazol, clarithromycin,
telithromycin, erythromycin, amiodarone).
P-gp substrates or weak inhibitors
: No relevant interactions with atenolol, digoxin, amlodipine or
cimetidine have been observed. When administered with atorvastatin (80 mg), steady-state aliskiren
(300 mg) AUC and C
max
increased by 50%.
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 HCT.
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 to monitor the effects when
initiating and adjusting furosemide therapy to avoid possible underutilisation in clinical situations of
volume overload.
6
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.
Warfarin:
The effects of aliskiren on warfarin pharmacokinetics have not been evaluated.
Food interactions:
Meals with a high fat content have been shown to reduce the absorption of aliskiren
substantially.
Additional information on hydrochlorothiazide interactions
When administered concurrently, the following medicinal products may interact with thiazide
diuretics:
Lithium:
Renal clearance of lithium is reduced by thiazides, therefore the risk of lithium toxicity may
be increased with hydrochlorothiazide. Co-administration of lithium and hydrochlorothiazide is not
recommended. If this combination proves essential, careful monitoring of serum lithium level is
recommended during concomitant use.
Alcohol
: Potentiation of orthostatic hypotension may occur.
Antidiabetic medicinal products (oral agents and insulins)
: Dosage adjustment of the antidiabetic
medicinal product may be required (see section 4.4).
Cholestyramine and colestipol resins:
Absorption of hydrochlorothiazide is impaired in the presence
of anionic exchange resins.
Digitalis glycosides:
Thiazide-induced hypokalaemia or hypomagnesaemia favour the onset of
digitalis-induced cardiac arrhythmias (see section 4.4).
NSAIDs:
The administration of an NSAID may reduce the diuretic, natriuretic and antihypertensive
effects of thiazide diuretics in some patients.
Pressor amines (e.g. noradrenaline):
The effect of pressor amines may be decreased.
Antigout medicine:
Dosage adjustments of antigout medications may be necessary as
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or
sulfinpyrazone may be necessary. Co
-
administration of thiazide diuretics may increase the incidence
of hypersensitivity reactions to allopurinol.
Calcium salts:
Thiazide diuretics may increase serum calcium levels due to decreased excretion. If
calcium supplements or calcium-sparing medicinal products (e.g. vitamin D therapy) must be
prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.
Curare derivatives (e.g. tubocurarine):
The effect of non-depolarising skeletal muscle relaxants may
be potentiated by hydrochlorothiazide.
Other interactions:
The hyperglycaemic effect of beta blockers and diazoxide may be enhanced by
thiazides. Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide-
type diuretics by decreasing gastrointestinal motility and stomach-emptying rate. Thiazides may
increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal excretion of
cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their
myelosuppressive effects.
7
Pregnancy
There are no data on the use of aliskiren in pregnant women. Aliskiren 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 when used during second and third trimesters.
Prolonged exposure to thiazides during the third trimester of pregnancy can reduce maternal plasma
volume as well as uteroplacental blood flow, which may cause a foeto-placental ischaemia and growth
retardation. Moreover, rare cases of hypoglycaemia and thrombocytopenia in neonates have been
reported following exposure near term.
No specific clinical studies have been performed with this combination, therefore Rasilez HCT 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). A switch to a suitable
alternative treatment should be carried out in advance of a planned pregnancy. If pregnancy is detected
during therapy, Rasilez HCT should be discontinued as soon as possible.
Lactation
Rasilez HCT is contraindicated during lactation (see section 4.3). It is not known whether aliskiren is
excreted in human milk. Aliskiren was secreted in the milk of lactating rats. Thiazides appear in
human milk and may inhibit lactation. They can produce adverse biological effects including
hypokalaemia, haemolysis (glucose-6-phosphate dehydrogenase (G6PD) defect) and hypersensitivity
due to sulphonamide properties.
No studies on the effect on the ability to drive and use machines have been performed. Rasilez HCT is
unlikely to affect the ability to drive and use machines. However, when driving vehicles or operating
machinery it must be borne in mind that dizziness or drowsiness may occasionally occur when taking
antihypertensive therapy.
Aliskiren/hydrochlorothiazide combination
The safety of Rasilez HCT has been evaluated in 9 clinical trials with more than 3,900 patients,
including over 700 treated for over 6 months, and 190 for over 1 year. The incidence of adverse
reactions showed no association with gender, age, body mass index, race or ethnicity. Treatment with
Rasilez HCT had an overall incidence of adverse experiences at doses up to 300 mg/25 mg similar to
placebo. 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 frequency of adverse reactions listed below is defined using the following convention: very
common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to
< 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within
each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Gastrointestinal disorders
Common:
Diarrhoea
Diarrhoea
: Diarrhoea is a dose-related adverse drug reaction for aliskiren. In controlled clinical trials,
the incidence of diarrhoea in Rasilez HCT-treated patients was 1.3% compared to 1.4% for aliskiren-
or 1.9% for hydrochlorothiazide-treated patients.
8
Serum potassium
: In a large placebo-controlled clinical trial, the opposite effects of aliskiren (150 mg
or 300 mg) and hydrochlorothiazide (12.5 mg or 25 mg) on serum potassium approximately balanced
each other in many patients. In other patients, one or the other effect may be dominant. Periodic
determinations of serum potassium to detect possible electrolyte imbalance should be performed in
patients at risk at appropriate intervals (see sections 4.4 and 4.5).
Additional information on individual components
Adverse reactions previously reported with one of the individual components may occur with Rasilez
HCT even if not observed in clinical trials.
Aliskiren
Treatment with Aliskiren up to 300 mg resulted in an overall incidence of adverse reactions similar to
placebo. 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 known aliskiren adverse drug reactions are presented in the table below using the same
convention as described previously for the fixed combination.
Gastrointestinal disorders
Common: Diarrhoea
Skin and subcutaneous tissue disorders
Rash
Rare:
Angioedema
In controlled clinical trials, angioedema occurred rarely during treatment with aliskiren 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 patients should discontinue treatment and contact the physician (see section 4.4).
The incidence of cough was similar in placebo (0.6%) and aliskiren-treated (0.9%) patients.
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 RAS,
such as ACEIs and angiotensin receptor blockers.
Serum potassium
: Increases in serum potassium were minor and infrequent in patients with essential
hypertension treated with aliskiren alone (0.9% compared to 0.6% with placebo). However, in one
study where aliskiren 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, 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).
9
Uncommon:
Hydrochlorothiazide
Adverse events (regardless of relationship to medicinal product) reported with the use of
hydrochlorothiazide alone include:
Blood and lymphatic system disorders
Aplastic anaemia, bone marrow depression,
neutropenia/agranulocytosis, haemolytic anaemia, leucopenia,
thrombocytopenia
Psychiatric disorders
Not known:
Depression, sleep disturbances
Nervous system disorders
Not known:
Restlessness, light-headedness, vertigo, paraesthesia, dizziness
Eye disorders
Cardiac disorders
Transient blurred vision, xanthopsia
Not known:
Cardiac arrhythmias
Vascular disorders
Not known: Postural hypotension
Respiratory, thoracic and mediastinal disorders
Not known:
Respiratory distress (including pneumonitis and pulmonary oedema)
Gastrointestinal disorders
Not known:
Pancreatitis, anorexia, diarrhoea, constipation, gastric irritation,
sialadenitis, loss of appetite
Hepatobiliary disorders
Not known: Jaundice (intrahepatic cholestatic jaundice)
Skin and subcutaneous tissue disorders
Not known: Anaphylactic reactions, toxic epidermal necrolysis, necrotising angiitis
(vasculitis, cutaneous vasculitis), cutaneous lupus erythematosus-like
reactions, reactivation of cutaneous lupus erythematosus,
photosensitivity reactions, rash, urticaria
Musculoskeletal and connective tissue disorders
Not known: Weakness, muscle spasm
Renal and urinary disorders
Not known: Interstitial nephritis, renal dysfunction
General disorders and administration site conditions
Not known:
Fever
Investigations
Not known:
Electrolyte imbalance, including hypokalaemia and hyponatraemia (see
section 4.4), hyperuricaemia, glycosuria, hyperglycaemia, increases in
cholesterol and triglycerides
No information is available on the treatment of overdose with Rasilez HCT. The most likely
manifestation of overdose would be hypotension, related to the antihypertensive effect of aliskiren.
hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. The most
common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in
muscle spasms and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis
glycosides or certain antiarrhythmic medicinal products. If symptomatic hypotension should occur,
supportive treatment should be initiated.
10
Not known:
Not known:
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Renin inhibitor (aliskiren) combinations with diuretics
(hydrochlorothiazide), ATC code: C09XA52
Rasilez HCT combines two antihypertensive compounds to control blood pressure in patients with
essential hypertension: Aliskiren belongs to the class of direct renin inhibitors and hydrochlorothiazide
to the class of thiazide diuretics. The combination of these substances with complementary
mechanisms of action provides an additive antihypertensive effect, reducing blood pressure to a
greater degree than either component alone.
Aliskiren
Aliskiren is an orally active, non-peptide, potent and selective direct inhibitor of human renin.
By inhibiting the enzyme renin, aliskiren inhibits the renin-angiotensin system (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 (angiotensin converting
enzyme inhibitors (ACEI) and angiotension 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 effects on PRA are not known at the present
time.
In hypertensive patients, once-daily administration of aliskiren 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 (12 months), and was independent of age, gender, body mass
index and ethnicity.
There has been no evidence of first-dose hypotension and no effect on pulse rate in patients treated in
controlled clinical studies. 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 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
aliskiren 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 aliskiren and placebo, respectively. The
clinical relevance of a reduction in UACR is not established in the absence of an effect on blood
pressure. Aliskiren 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.
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 aliskiren 150 mg was well tolerated. B-type natriuretic
peptide (BNP) levels were reduced by 25% in the aliskiren arm compared to placebo. However the
clinical significance of this reduction is unknown.
Combination therapy studies are available for aliskiren added to the diuretic hydrochlorothiazide, the
ACEI ramipril, the calcium channel blocker amlodipine, the ARB valsartan, and the beta blocker
atenolol. These combinations were efficacious and well tolerated.
11
Hydrochlorothiazide
The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been
shown that there is a high-affinity receptor in the renal cortex as the primary binding site for the
thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule. The mode of
action of thiazides is through inhibition of the Na+Cl- symporter by competing for the Cl- site, thereby
affecting electrolyte reabsorption mechanisms: directly increasing sodium and chloride excretion to an
approximately equal extent, and indirectly by this diuretic action reducing plasma volume, with
consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and a
decrease in serum potassium.
Aliskiren/hydrochlorothiazide
Over 3,900 hypertensive patients received Rasilez HCT once daily in clinical trials.
In hypertensive patients, once-daily administration of Rasilez HCT provided dose-dependent
reductions in both systolic and diastolic blood pressure that were maintained over the entire 24-hour
dose interval. The antihypertensive effect is largely manifested within 1 week and the maximum effect
is generally seen within 4 weeks.The blood-pressure-lowering effect was sustained during long-term
treatment, and was independent of age, gender, body mass index and ethnicity. The antihypertensive
effect of a single dose of the combination persisted for 24 hours. Upon withdrawal of the aliskiren
treatment (aliskiren with or without hydrochlorothiazide add-on), the return of blood pressure towards
baseline was gradual (3-4 weeks) with no evidence of the rebound effect.
Rasilez HCT was studied in a placebo-controlled trial including 2,762 hypertensive patients with
diastolic blood pressure ≥ 95 mmHg and < 110 mmHg (mean baseline blood pressure of
153.6/99.2 mmHg). In this study, Rasilez HCT in doses from 150 mg/12.5 mg to 300 mg/25 mg
produced dose-dependent blood pressure reductions (systolic/diastolic) from 17.6/11.9 mmHg to
21.2/14.3 mmHg, respectively, compared to 7.5/6.9 mmHg with placebo. The greater blood pressure
reductions with these combination doses were also significantly greater than the respective doses of
aliskiren and hydrochlorothiazide when used alone. The combination of aliskiren and
hydrochlorothiazide neutralised the reactive increase of PRA caused by hydrochlorothiazide.
When administered in hypertensive patients with markedly elevated blood pressure (systolic blood
pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg), Rasilez HCT in doses from
150 mg/12.5 mg to 300 mg/25 mg administered without up-titration from monotherapy demonstrated
significantly greater systolic/diastolic blood pressure control rates (< 140/90 mmHg) as compared to
the respective monotherapies. In this population, Rasilez HCT 150 mg/12.5 mg to 300 mg/25 mg
provided dose-dependent systolic/diastolic blood pressure reduction from 20.6/12.4 mmHg to
24.8/14.5 mmHg, which were significantly superior to the respective monotherapies. The safety of the
combination therapy was similar to the respective monotherapies regardless of severity of
hypertension or of the presence or absence of additional cardiovascular risk. Hypotension and related
adverse events were uncommon with the combination treatment, with no increased incidence in
elderly patients.
In a study in 880 randomised patients not adequately responsive to aliskiren 300 mg treatment, the
combination of aliskiren/hydrochlorothiazide 300 mg/25 mg produced systolic/diastolic blood
pressure reductions of 15.8/11.0 mmHg, which were significantly greater than aliskiren 300 mg
monotherapy. In a study in 722 randomised patients not adequately responsive to hydrochlorothiazide
25 mg treatment, the combination of aliskiren/hydrochlorothiazide 300 mg/25 mg produced
systolic/diastolic blood pressure reductions of 16.78/10.7 mmHg, which were significantly greater
than hydrochlorothiazide 25 mg monotherapy.
In another clinical trial, the efficacy and safety of Rasilez HCT were also assessed in 489 obese
hypertensive patients who did not respond to hydrochlorothiazide 25 mg (baseline systolic/diastolic
blood pressure 149.4/96.8 mmHg). In this difficult-to-treat population, Rasilez HCT provided a blood
pressure reduction (systolic/diastolic) of 15.8/11.9 mmHg compared to 15.4/11.3 mmHg for
irbesartan/hydrochlorothiazide, 13.6/10.3 mmHg for amlodipine/hydrochlorothiazide and
12
8.6/7.9 mmHg for hydrochlorothiazide monotherapy, with similar safety to hydrochlorothiazide
monotherapy.
In a study in 183 randomised patients with severe hypertension (mean sitting diastolic blood pressure
≥ 105 and < 120 mmHg), aliskiren treatment regimen with optional addition of hydrochlorothiazide
25 mg was shown to be safe and efficacious in reducing blood pressure.
5.2 Pharmacokinetic properties
Aliskiren
Absorption
Following oral absorption, peak plasma concentrations of aliskiren are reached after 1-3 hours. The
absolute bioavailability of aliskiren is approximately 2-3%. Meals with a high fat content reduce C
max
by 85% and AUC by 70%. Steady-state-plasma concentrations are reached within 5-7 days following
once-daily administration and steady-state levels are approximately 2-fold greater than with the initial
dose.
Distribution
Following intravenous administration, the mean volume of distribution at steady state is approximately
135 litres, indicating that aliskiren distributes extensively into the extravascular space. Aliskiren
plasma protein binding is moderate (47-51%) and independent of the concentration.
Metabolism and elimination
The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as unchanged
compound in the faeces (oral radioactive dose recovery = 91%). Approximately 1.4% of the total oral
dose is metabolised. The enzyme responsible for this metabolism is CYP3A4. Approximately 0.6% of
the dose is recovered in urine following oral administration. Following intravenous administration, the
mean plasma clearance is approximately 9 l/h.
Linearity
Exposure to aliskiren increased slightly 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. Mechanisms responsible for the deviation from dose
proportionality have not been identified. A possible mechanism is saturation of transporters at the
absorption site or at the hepatobiliary clearance route.
Hydrochlorothiazide
Absorption
The absorption of hydrochlorothiazide, after an oral dose, is rapid (T
max
about 2 h), with similar
absorption characteristics for both suspension and tablet formulations. Absolute bioavailability of
hydrochlorothiazide is 60-80% after oral administration.
Concomitant administration with food has been reported to both increase and decrease the systemic
availability of hydrochlorothiazide compared with the fasted state. The magnitude of these effects is
small and has little clinical importance.
Distribution
The apparent volume of distribution is 4-8 l/kg. Circulating hydrochlorothiazide is bound to serum
proteins (40-70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at
approximately 3 times the level in plasma.
Metabolism and elimination
After oral administration, > 95% of the absorbed dose being excreted as unchanged compound in the
urine. The distribution and elimination kinetics have generally been described by a bi-exponential
decay function, with a terminal half-life of 6-15 h.
13
Linearity
The increase in mean AUC is linear and dose proportional in the therapeutic range. There is no change
in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed
once daily.
Aliskiren/hydrochlorothiazide
Following oral administration of Rasilez HCT tablets, the median peak plasma concentration time is
within 1 hour for aliskiren and 2.5 hours for hydrochlorothiazide.
The rate and extent of absorption of Rasilez HCT are equivalent to the bioavailability of aliskiren and
hydrochlorothiazide when administered as individual monotherapies. Similar food effect was observed
for Rasilez HCT as for the individual monotherapies.
Characteristics in patients
Rasilez HCT has been shown to be effective as a once-a-day antihypertensive treatment in adult
patients, regardless of gender, age, body mass index and ethnicity.
The pharmacokinetics of aliskiren and hydrochlorothiazide are not significantly affected in patients
with mild to moderate liver disease. Consequently, no initial dose adjustment of Rasilez HCT is
required in patients with mild to moderate hepatic impairment. No data are available on patients with
severe hepatic impairment treated by Rasilez HCT. However, due to its hydrochlorothiazide
component, Rasilez HCT is contraindicated in patients with severe hepatic impairment (see section
4.3).
No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see
sections 4.4 and 4.2). No data are available for Rasilez HCT in patients with severe renal impairment
(GFR < 30 ml/min/1.73 m
2
). However, as expected for a compound which is cleared almost
exclusively via the kidneys, renal function has a marked effect on the kinetics of hydrochlorothiazide.
Therefore, Rasilez HCT is contraindicated in patients with severe renal impairment (GFR
< 30 ml/min/1.73 m
2
) (see section 4.3).
No initial dose adjustment of Rasilez HCT is required in elderly patients.
No pharmacokinetic data are available in the paediatric population.
5.3 Preclinical safety data
Safety pharmacology studies with aliskiren 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. No carcinogenic potential for aliskiren was detected in a 2-year rat study and a 6-month
transgenic mouse study. One colonic adenoma and one caecal adenocarcinoma recorded in rats at the
dose of 1,500 mg/kg/day were not statistically significant. Aliskiren was devoid of any mutagenic
potential, embryo-foetal toxicity or teratogenicity. Fertility, prenatal development and postnatal
development were unaffected in rats.
Preclinical evaluations to support the administration of hydrochlorothiazide in humans included
in
vitro
genotoxicity assays and reproductive toxicity and carcinogenicity studies in rodents. Extensive
clinical data are available for hydrochlorothiazide and these are reflected in the relevant sections.
The findings observed in the 2-week and 13-week toxicity studies were consistent with those observed
previously with aliskiren or hydrochlorothiazide monotherapies. There were no new or unexpected
findings observed of relevance to human use. Increased cellular vacuolation of the adrenal gland zona
glomerulosa was observed during the 13-week toxicity study in rats. The finding was observed in
animals treated with hydrochlorothiazide but not in those animals receiving aliskiren alone or vehicle.
There was no evidence that this finding was enhanced in the aliskiren/hydrochlorothiazide
combination as it was only apparent at a minimal severity in all animals.
14
6.
6.1 List of excipients
Tablet core
:
Cellulose microcrystalline
Crospovidone
Lactose monohydrate
Wheat starch
Povidone
Magnesium stearate
Silica colloidal anhydrous
Talc
Coating
:
Talc
Hypromellose
Macrogol
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
24 months
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
PA/Alu/PVC – Alu blisters:
Single-packs containing 7, 14, 28, 30, 50 or 56 tablets.
Multi-packs containing 90, 98 or 280 tablets.
PVC/polychlorotrifluoroethylene (PCTFE) – Alu blisters:
Single-packs containing 7, 14, 28, 30, 50, 56, 90 or 98 tablets.
Single-packs (perforated unit dose blister) containing 56 x 1 tablets.
Multi-packs containing 280 tablets.
Multi-packs (perforated unit dose blister) containing 98 x 1 tablets.
Not all pack sizes or strengths may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
15
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/08/491/001-020
9.
16.01.2009
16
1.
Rasilez HCT 150 mg/25 mg film-coated tablets
2.
Each film-coated tablet contains 150 mg aliskiren (as hemifumarate) and 25 mg hydrochlorothiazide.
Excipients: Each tablet contains 50 mg lactose monohydrate and 49 mg wheat starch.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Pale yellow, biconvex, ovaloid film-coated tablet imprinted with “CLL” on one side and “NVR” on
the other.
4.
Treatment of essential hypertension in adults.
Rasilez HCT is indicated in patients whose blood pressure is not adequately controlled on aliskiren or
hydrochlorothiazide used alone.
Rasilez HCT is indicated as substitution therapy in patients adequately controlled with aliskiren and
hydrochlorothiazide, given concurrently, at the same dose level as in the combination.
The recommended dose of Rasilez HCT is one tablet per day. Rasilez HCT 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 HCT.
The antihypertensive effect is largely manifested within 1 week and the maximum effect is generally
seen within 4 weeks.
Posology in patients not adequately controlled with aliskiren or hydrochlorothiazide monotherapy
Individual dose titration with each of the two components may be recommended before changing to
the fixed combination. When clinically appropriate, direct change from monotherapy to the fixed
combination may be considered.
Rasilez HCT 150 mg /25 mg may be administered in patients whose blood pressure is not adequately
controlled with aliskiren 150 mg or hydrochlorothiazide 25 mg alone or by Rasilez HCT
150 mg/12.5 mg.
If blood pressure remains uncontrolled after 2-4 weeks of therapy, the dose may be titrated up to a
maximum of Rasilez HCT 300 mg/25 mg daily. Dosing should be individualised and adjusted
according to the patient’s clinical response.
17
Posology as substitution therapy
For convenience, patients receiving aliskiren and hydrochlorothiazide from separate tablets may be
switched to a fixed combination tablet of Rasilez HCT containing the same component doses.
Renal impairment
No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see
sections 4.4 and 5.2). Due to the hydrochlorothiazide component, Rasilez HCT is contraindicated for
use in patients with severe renal impairment (glomerular filtration rate (GFR) < 30 ml/min/1.73 m
2
)
(see sections 4.3 and 5.2).
Hepatic impairment
Thiazides should be used with caution in patients with impaired hepatic function. No adjustment of the
initial dose is required for patients with mild to moderate hepatic impairment (see section 5.2). Due to
the hydrochlorothiazide component, Rasilez HCT is contraindicated in patients with severe hepatic
impairment (see sections 4.3 and 4.4).
Elderly patients (over 65 years)
No adjustment of the initial dose is required in elderly patients.
Paediatric patients
Rasilez HCT is not recommended for use in children and adolescents below age 18 due to a lack of
data on safety and efficacy (see section 5.2).
Hypersensitivity to the active substances or to any of the excipients (see section 6.1), or to other
sulphonamide-derived substances.
History of angioedema with aliskiren.
Second and third trimesters of pregnancy, lactation (see section 4.6).
Severe renal impairment (GFR < 30 ml/min/1.73 m
2
).
Refractory hypokalaemia, hypercalcaemia.
Severe hepatic impairment.
The concomitant use of aliskiren with ciclosporin, a highly potent P-glycoprotein (P-gp)
inhibitor, and other potent P-gp inhibitors (quinidine, verapamil), is contraindicated (see section
4.5).
Heart failure
Aliskiren should be used with caution in patients with serious congestive heart failure (New York
Heart Association (NYHA) functional class III-IV). Rasilez HCT should be used with caution in
patients with heart failure due to limited clinical efficacy and safety data.
Angioedema
As with other agents acting on the renin -angiotensin system, angioedema has been reported in patients
treated with aliskiren. If angioedema occurs, Rasilez HCT 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.
Intravascular volume depletion
Symptomatic hypotension may occur in patients who are volume and/or sodium depleted as a result of
vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be
corrected before the administration of Rasilez HCT.
18
Electrolyte imbalance
As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be
performed at appropriate intervals. Thiazides, including hydrochlorothiazide, can cause fluid or
electrolyte imbalance (including hypokalaemia, hyponatraemia and hypochloraemic alkalosis).
Warning signs of fluid or electrolyte imbalance are dry mouth, thirst, weakness, lethargy, drowsiness,
restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and
gastrointestinal disturbances such as nausea or vomiting (see section 4.8).
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with
aliskiren may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in patients
with cirrhosis of the liver, patients experiencing brisk diuresis, patients with inadequate oral
electrolyte intake and patients receiving concomitant therapy with corticosteroids or
adrenocorticotropic hormone (ACTH) (see sections 4.5 and 4.8).
Conversely, due to the aliskiren component of Rasilez HCT, hyperkalaemia might occur. Although
clinically significant hyperkalaemia has not been documented with Rasilez HCT, risk factors for the
development of hyperkalaemia include renal insufficiency and/or heart failure, and diabetes mellitus.
Adequate monitoring of serum potassium in patients at risk is recommended. Caution is required when
co-administering potassium-sparing diuretics, potassium supplements or potassium-containing salts
substitutes with Rasilez HCT (see sections 4.5 and 4.8).
There is no evidence that Rasilez HCT would reduce or prevent diuretic-induced hyponatraemia.
Chloride deficit is generally mild and usually does not require treatment.
Thiazides may reduce urinary calcium excretion and cause an intermittent and slight elevation of
serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia
may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out
tests for parathyroid function.
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in
hypomagnesaemia (see also section 4.5).
Renal impairment and kidney transplantation
When Rasilez HCT is used in patients with impaired renal function, periodic monitoring of potassium,
creatinine and uric acid serum levels is recommended. There is no experience regarding the
administration of Rasilez HCT in patients who have recently undergone kidney transplantation. No
dosage adjustment is necessary in patients with renal impairment whose GFR is ≥ 30 ml/min/1.73 m
2
.
However, in patients with mild to moderate renal impairment (GFR ≥ 30 ml/min/1.73 m
2
but
< 60 ml/min/1.73 m
2
), Rasilez HCT should be administered with caution.
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 (e.g.
due to blood loss, severe or 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.
Hepatic impairment
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver
disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
There is no clinical experience with Rasilez HCT in patients with hepatic impairment.
19
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).
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral
stenosis, or obstructive hypertrophic cardiomyopathy.
Renal artery stenosis and renovascular hypertension
No controlled clinical data are available on the use of Rasilez HCT 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 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.
Metabolic and endocrine effects
Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or
oral hypoglycaemic agents may be required. Latent diabetes mellitus may occur during thiazide
therapy. To date, no data are available from clinical studies that were specifically-designed to evaluate
the safety of Rasilez HCT in diabetic patients.
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy.
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide
therapy.
General
In the event of severe and persistent diarrhoea, Rasilez HCT therapy should be stopped.
As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischaemic
cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of
allergy or bronchial asthma, but are more likely in patients with such a history. Exacerbation or
activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.
Excipients
Rasilez HCT contains lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Rasilez HCT contains wheat starch. It is suitable for people with coeliac disease. Patients with wheat
allergy (different from coeliac disease) should not take this medicine.
Medicinal products affecting potassium
: The potassium-depleting effect of hydrochlorothiazide is
attenuated by the potassium-sparing effect of aliskiren. However, this effect of hydrochlorothiazide on
serum potassium would be expected to be potentiated by other medicinal products associated with
potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin,
carbenoxolone, penicillin G sodium, corticosteroids, ACTH, salicylic acid derivatives). Conversely,
based on experience with the use of other medicinal products that blunt the renin-angiotensin system
(RAS), concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes
containing potassium or other medicinal products that may increase serum potassium levels (e.g.
heparin sodium) may lead to increases in serum potassium. Adequate monitoring of serum potassium
in patients at risk is recommended (see sections 4.4 and 4.8).
20
Medicinal products affected by serum potassium disturbances
: Periodic monitoring of serum
potassium is recommended when Rasilez HCT is administered with medicinal products affected by
serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).
Other antihypertensive agents:
The antihypertensive effect of Rasilez HCT may be increased with the
concomitant use of other antihypertensive agents.
Additional information on aliskiren interactions
Aliskiren has no known clinically relevant interactions with medicinal products commonly used to
treat hypertension or diabetes.
Compounds that have been investigated in aliskiren clinical pharmacokinetic studies include
acenocoumarol, atenolol, celecoxib, fenofibrate, pioglitazone, allopurinol, isosorbide-5-mononitrate,
irbesartan, digoxin, ramipril, valsartan, metformin, amlodipine, atorvastatin, cimetidine and
hydrochlorothiazide. No clinically relevant interactions have been identified. As a result no dose
adjustment for aliskiren or these co-administered medicinal products is necessary.
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 aliskiren. Although this
has not been investigated for aliskiren, it is known that P-gp also controls tissue uptake of a variety of
substrates and P-gp inhibitors can increase the tissue-to-plasma concentration ratios. Therefore, P-gp
inhibitors may increase tissue levels more than plasma levels. The potential for drug interactions at the
P-gp site will likely depend on the degree of inhibition of this transporter.
P-gp potent inhibitors
: A single dose drug interaction study in healthy subjects has shown that
ciclosporin (200 and 600 mg) increases C
max
of aliskiren 75 mg approximately 2.5-fold and AUC
approximately 5-fold
.
The increase may be higher with higher aliskiren doses. Therefore, concomitant
use of aliskiren and P-gp potent inhibitors is contraindicated (see section 4.3).
Moderate P-gp inhibitors
: Co-administration of ketoconazole (200 mg) 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 P-gp inhibitors (itraconazol, clarithromycin,
telithromycin, erythromycin, amiodarone).
P-gp substrates or weak inhibitors
: No relevant interactions with atenolol, digoxin, amlodipine or
cimetidine have been observed. When administered with atorvastatin (80 mg), steady-state aliskiren
(300 mg) AUC and C
max
increased by 50%.
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 HCT.
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 to monitor the effects when
initiating and adjusting furosemide therapy to avoid possible underutilisation in clinical situations of
volume overload.
21
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.
Warfarin:
The effects of aliskiren on warfarin pharmacokinetics have not been evaluated.
Food interactions:
Meals with a high fat content have been shown to reduce the absorption of aliskiren
substantially.
Additional information on hydrochlorothiazide interactions
When administered concurrently, the following medicinal products may interact with thiazide
diuretics:
Lithium:
Renal clearance of lithium is reduced by thiazides, therefore the risk of lithium toxicity may
be increased with hydrochlorothiazide. Co-administration of lithium and hydrochlorothiazide is not
recommended. If this combination proves essential, careful monitoring of serum lithium level is
recommended during concomitant use.
Alcohol
: Potentiation of orthostatic hypotension may occur.
Antidiabetic medicinal products (oral agents and insulins)
: Dosage adjustment of the antidiabetic
medicinal product may be required (see section 4.4).
Cholestyramine and colestipol resins:
Absorption of hydrochlorothiazide is impaired in the presence
of anionic exchange resins.
Digitalis glycosides:
Thiazide-induced hypokalaemia or hypomagnesaemia favour the onset of
digitalis-induced cardiac arrhythmias (see section 4.4).
NSAIDs:
The administration of an NSAID may reduce the diuretic, natriuretic and antihypertensive
effects of thiazide diuretics in some patients.
Pressor amines (e.g. noradrenaline):
The effect of pressor amines may be decreased.
Antigout medicine:
Dosage adjustments of antigout medications may be necessary as
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or
sulfinpyrazone may be necessary. Co
-
administration of thiazide diuretics may increase the incidence
of hypersensitivity reactions to allopurinol.
Calcium salts:
Thiazide diuretics may increase serum calcium levels due to decreased excretion. If
calcium supplements or calcium-sparing medicinal products (e.g. vitamin D therapy) must be
prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.
Curare derivatives (e.g. tubocurarine):
The effect of non-depolarising skeletal muscle relaxants may
be potentiated by hydrochlorothiazide.
Other interactions:
The hyperglycaemic effect of beta blockers and diazoxide may be enhanced by
thiazides. Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide-
type diuretics by decreasing gastrointestinal motility and stomach-emptying rate. Thiazides may
increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal excretion of
cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their
myelosuppressive effects.
22
Pregnancy
There are no data on the use of aliskiren in pregnant women. Aliskiren 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 when used during second and third trimesters.
Prolonged exposure to thiazides during the third trimester of pregnancy can reduce maternal plasma
volume as well as uteroplacental blood flow, which may cause a foeto-placental ischaemia and growth
retardation. Moreover, rare cases of hypoglycaemia and thrombocytopenia in neonates have been
reported following exposure near term.
No specific clinical studies have been performed with this combination, therefore Rasilez HCT 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). A switch to a suitable
alternative treatment should be carried out in advance of a planned pregnancy. If pregnancy is detected
during therapy, Rasilez HCT should be discontinued as soon as possible.
Lactation
Rasilez HCT is contraindicated during lactation (see section 4.3). It is not known whether aliskiren is
excreted in human milk. Aliskiren was secreted in the milk of lactating rats. Thiazides appear in
human milk and may inhibit lactation. They can produce adverse biological effects including
hypokalaemia, haemolysis (glucose-6-phosphate dehydrogenase (G6PD) defect) and hypersensitivity
due to sulphonamide properties.
No studies on the effect on the ability to drive and use machines have been performed. Rasilez HCT is
unlikely to affect the ability to drive and use machines. However, when driving vehicles or operating
machinery it must be borne in mind that dizziness or drowsiness may occasionally occur when taking
antihypertensive therapy.
Aliskiren/hydrochlorothiazide combination
The safety of Rasilez HCT has been evaluated in 9 clinical trials with more than 3,900 patients,
including over 700 treated for over 6 months, and 190 for over 1 year. The incidence of adverse
reactions showed no association with gender, age, body mass index, race or ethnicity. Treatment with
Rasilez HCT had an overall incidence of adverse experiences at doses up to 300 mg/25 mg similar to
placebo. 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 frequency of adverse reactions listed below is defined using the following convention: very
common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to
< 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within
each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Gastrointestinal disorders
Common:
Diarrhoea
Diarrhoea
: Diarrhoea is a dose-related adverse drug reaction for aliskiren. In controlled clinical trials,
the incidence of diarrhoea in Rasilez HCT-treated patients was 1.3% compared to 1.4% for aliskiren-
or 1.9% for hydrochlorothiazide-treated patients.
23
Serum potassium
: In a large placebo-controlled clinical trial, the opposite effects of aliskiren (150 mg
or 300 mg) and hydrochlorothiazide (12.5 mg or 25 mg) on serum potassium approximately balanced
each other in many patients. In other patients, one or the other effect may be dominant. Periodic
determinations of serum potassium to detect possible electrolyte imbalance should be performed in
patients at risk at appropriate intervals (see sections 4.4 and 4.5).
Additional information on individual components
Adverse reactions previously reported with one of the individual components may occur with Rasilez
HCT even if not observed in clinical trials.
Aliskiren
Treatment with Aliskiren up to 300 mg resulted in an overall incidence of adverse reactions similar to
placebo. 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 known aliskiren adverse drug reactions are presented in the table below using the same
convention as described previously for the fixed combination.
Gastrointestinal disorders
Common: Diarrhoea
Skin and subcutaneous tissue disorders
Rash
Rare:
Angioedema
In controlled clinical trials, angioedema occurred rarely during treatment with aliskiren 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 patients should discontinue treatment and contact the physician (see section 4.4).
The incidence of cough was similar in placebo (0.6%) and aliskiren-treated (0.9%) patients.
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 RAS,
such as ACEIs and angiotensin receptor blockers.
Serum potassium
: Increases in serum potassium were minor and infrequent in patients with essential
hypertension treated with aliskiren alone (0.9% compared to 0.6% with placebo). However, in one
study where aliskiren 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, 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).
24
Uncommon:
Hydrochlorothiazide
Adverse events (regardless of relationship to medicinal product) reported with the use of
hydrochlorothiazide alone include:
Blood and lymphatic system disorders
Aplastic anaemia, bone marrow depression,
neutropenia/agranulocytosis, haemolytic anaemia, leucopenia,
thrombocytopenia
Psychiatric disorders
Not known:
Depression, sleep disturbances
Nervous system disorders
Not known:
Restlessness, light-headedness, vertigo, paraesthesia, dizziness
Eye disorders
Cardiac disorders
Transient blurred vision, xanthopsia
Not known:
Cardiac arrhythmias
Vascular disorders
Not known: Postural hypotension
Respiratory, thoracic and mediastinal disorders
Not known:
Respiratory distress (including pneumonitis and pulmonary oedema)
Gastrointestinal disorders
Not known:
Pancreatitis, anorexia, diarrhoea, constipation, gastric irritation,
sialadenitis, loss of appetite
Hepatobiliary disorders
Not known: Jaundice (intrahepatic cholestatic jaundice)
Skin and subcutaneous tissue disorders
Not known: Anaphylactic reactions, toxic epidermal necrolysis, necrotising angiitis
(vasculitis, cutaneous vasculitis), cutaneous lupus erythematosus-like
reactions, reactivation of cutaneous lupus erythematosus,
photosensitivity reactions, rash, urticaria
Musculoskeletal and connective tissue disorders
Not known: Weakness, muscle spasm
Renal and urinary disorders
Not known: Interstitial nephritis, renal dysfunction
General disorders and administration site conditions
Not known:
Fever
Investigations
Not known:
Electrolyte imbalance, including hypokalaemia and hyponatraemia (see
section 4.4), hyperuricaemia, glycosuria, hyperglycaemia, increases in
cholesterol and triglycerides
No information is available on the treatment of overdose with Rasilez HCT. The most likely
manifestation of overdose would be hypotension, related to the antihypertensive effect of aliskiren.
hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. The most
common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in
muscle spasms and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis
glycosides or certain antiarrhythmic medicinal products. If symptomatic hypotension should occur,
supportive treatment should be initiated.
25
Not known:
Not known:
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Renin inhibitor (aliskiren) combinations with diuretics
(hydrochlorothiazide), ATC code: C09XA52
Rasilez HCT combines two antihypertensive compounds to control blood pressure in patients with
essential hypertension: Aliskiren belongs to the class of direct renin inhibitors and hydrochlorothiazide
to the class of thiazide diuretics. The combination of these substances with complementary
mechanisms of action provides an additive antihypertensive effect, reducing blood pressure to a
greater degree than either component alone.
Aliskiren
Aliskiren is an orally active, non-peptide, potent and selective direct inhibitor of human renin.
By inhibiting the enzyme renin, aliskiren inhibits the renin-angiotensin system (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 (angiotensin converting
enzyme inhibitors (ACEI) and angiotension 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 effects on PRA are not known at the present
time.
In hypertensive patients, once-daily administration of aliskiren 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 (12 months), and was independent of age, gender, body mass
index and ethnicity.
There has been no evidence of first-dose hypotension and no effect on pulse rate in patients treated in
controlled clinical studies. 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 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
aliskiren 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 aliskiren and placebo, respectively. The
clinical relevance of a reduction in UACR is not established in the absence of an effect on blood
pressure. Aliskiren 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.
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 aliskiren 150 mg was well tolerated. B-type natriuretic
peptide (BNP) levels were reduced by 25% in the aliskiren arm compared to placebo. However the
clinical significance of this reduction is unknown.
26
Combination therapy studies are available for aliskiren added to the diuretic hydrochlorothiazide, the
ACEI ramipril, the calcium channel blocker amlodipine, the ARB valsartan, and the beta blocker
atenolol. These combinations were efficacious and well tolerated.
Hydrochlorothiazide
The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been
shown that there is a high-affinity receptor in the renal cortex as the primary binding site for the
thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule. The mode of
action of thiazides is through inhibition of the Na+Cl- symporter by competing for the Cl- site, thereby
affecting electrolyte reabsorption mechanisms: directly increasing sodium and chloride excretion to an
approximately equal extent, and indirectly by this diuretic action reducing plasma volume, with
consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and a
decrease in serum potassium.
Aliskiren/hydrochlorothiazide
Over 3,900 hypertensive patients received Rasilez HCT once daily in clinical trials.
In hypertensive patients, once-daily administration of Rasilez HCT provided dose-dependent
reductions in both systolic and diastolic blood pressure that were maintained over the entire 24-hour
dose interval. The antihypertensive effect is largely manifested within 1 week and the maximum effect
is generally seen within 4 weeks.The blood-pressure-lowering effect was sustained during long-term
treatment, and was independent of age, gender, body mass index and ethnicity. The antihypertensive
effect of a single dose of the combination persisted for 24 hours. Upon withdrawal of the aliskiren
treatment (aliskiren with or without hydrochlorothiazide add-on), the return of blood pressure towards
baseline was gradual (3-4 weeks) with no evidence of the rebound effect.
Rasilez HCT was studied in a placebo-controlled trial including 2,762 hypertensive patients with
diastolic blood pressure ≥ 95 mmHg and < 110 mmHg (mean baseline blood pressure of
153.6/99.2 mmHg). In this study, Rasilez HCT in doses from 150 mg/12.5 mg to 300 mg/25 mg
produced dose-dependent blood pressure reductions (systolic/diastolic) from 17.6/11.9 mmHg to
21.2/14.3 mmHg, respectively, compared to 7.5/6.9 mmHg with placebo. The greater blood pressure
reductions with these combination doses were also significantly greater than the respective doses of
aliskiren and hydrochlorothiazide when used alone. The combination of aliskiren and
hydrochlorothiazide neutralised the reactive increase of PRA caused by hydrochlorothiazide.
When administered in hypertensive patients with markedly elevated blood pressure (systolic blood
pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg), Rasilez HCT in doses from
150 mg/12.5 mg to 300 mg/25 mg administered without up-titration from monotherapy demonstrated
significantly greater systolic/diastolic blood pressure control rates (< 140/90 mmHg) as compared to
the respective monotherapies. In this population, Rasilez HCT 150 mg/12.5 mg to 300 mg/25 mg
provided dose-dependent systolic/diastolic blood pressure reduction from 20.6/12.4 mmHg to
24.8/14.5 mmHg, which were significantly superior to the respective monotherapies. The safety of the
combination therapy was similar to the respective monotherapies regardless of severity of
hypertension or of the presence or absence of additional cardiovascular risk. Hypotension and related
adverse events were uncommon with the combination treatment, with no increased incidence in
elderly patients.
In a study in 880 randomised patients not adequately responsive to aliskiren 300 mg treatment, the
combination of aliskiren/hydrochlorothiazide 300 mg/25 mg produced systolic/diastolic blood
pressure reductions of 15.8/11.0 mmHg, which were significantly greater than aliskiren 300 mg
monotherapy. In a study in 722 randomised patients not adequately responsive to hydrochlorothiazide
25 mg treatment, the combination of aliskiren/hydrochlorothiazide 300 mg/25 mg produced
systolic/diastolic blood pressure reductions of 16.78/10.7 mmHg, which were significantly greater
than hydrochlorothiazide 25 mg monotherapy.
27
In another clinical trial, the efficacy and safety of Rasilez HCT were also assessed in 489 obese
hypertensive patients who did not respond to hydrochlorothiazide 25 mg (baseline systolic/diastolic
blood pressure 149.4/96.8 mmHg). In this difficult-to-treat population, Rasilez HCT provided a blood
pressure reduction (systolic/diastolic) of 15.8/11.9 mmHg compared to 15.4/11.3 mmHg for
irbesartan/hydrochlorothiazide, 13.6/10.3 mmHg for amlodipine/hydrochlorothiazide and
8.6/7.9 mmHg for hydrochlorothiazide monotherapy, with similar safety to hydrochlorothiazide
monotherapy.
In a study in 183 randomised patients with severe hypertension (mean sitting diastolic blood pressure
≥ 105 and < 120 mmHg), aliskiren treatment regimen with optional addition of hydrochlorothiazide
25 mg was shown to be safe and efficacious in reducing blood pressure.
5.2 Pharmacokinetic properties
Aliskiren
Absorption
Following oral absorption, peak plasma concentrations of aliskiren are reached after 1-3 hours. The
absolute bioavailability of aliskiren is approximately 2-3%. Meals with a high fat content reduce C
max
by 85% and AUC by 70%. Steady-state-plasma concentrations are reached within 5-7 days following
once-daily administration and steady-state levels are approximately 2-fold greater than with the initial
dose.
Distribution
Following intravenous administration, the mean volume of distribution at steady state is approximately
135 litres, indicating that aliskiren distributes extensively into the extravascular space. Aliskiren
plasma protein binding is moderate (47-51%) and independent of the concentration.
Metabolism and elimination
The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as unchanged
compound in the faeces (oral radioactive dose recovery = 91%). Approximately 1.4% of the total oral
dose is metabolised. The enzyme responsible for this metabolism is CYP3A4. Approximately 0.6% of
the dose is recovered in urine following oral administration. Following intravenous administration, the
mean plasma clearance is approximately 9 l/h.
Linearity
Exposure to aliskiren increased slightly 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. Mechanisms responsible for the deviation from dose
proportionality have not been identified. A possible mechanism is saturation of transporters at the
absorption site or at the hepatobiliary clearance route.
Hydrochlorothiazide
Absorption
The absorption of hydrochlorothiazide, after an oral dose, is rapid (T
max
about 2 h), with similar
absorption characteristics for both suspension and tablet formulations. Absolute bioavailability of
hydrochlorothiazide is 60-80% after oral administration.
Concomitant administration with food has been reported to both increase and decrease the systemic
availability of hydrochlorothiazide compared with the fasted state. The magnitude of these effects is
small and has little clinical importance.
Distribution
The apparent volume of distribution is 4-8 l/kg. Circulating hydrochlorothiazide is bound to serum
proteins (40-70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at
approximately 3 times the level in plasma.
28
Metabolism and elimination
After oral administration, > 95% of the absorbed dose being excreted as unchanged compound in the
urine. The distribution and elimination kinetics have generally been described by a bi-exponential
decay function, with a terminal half-life of 6-15 h.
Linearity
The increase in mean AUC is linear and dose proportional in the therapeutic range. There is no change
in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed
once daily.
Aliskiren/hydrochlorothiazide
Following oral administration of Rasilez HCT tablets, the median peak plasma concentration time is
within 1 hour for aliskiren and 2.5 hours for hydrochlorothiazide.
The rate and extent of absorption of Rasilez HCT are equivalent to the bioavailability of aliskiren and
hydrochlorothiazide when administered as individual monotherapies. Similar food effect was observed
for Rasilez HCT as for the individual monotherapies.
Characteristics in patients
Rasilez HCT has been shown to be effective as a once-a-day antihypertensive treatment in adult
patients, regardless of gender, age, body mass index and ethnicity.
The pharmacokinetics of aliskiren and hydrochlorothiazide are not significantly affected in patients
with mild to moderate liver disease. Consequently, no initial dose adjustment of Rasilez HCT is
required in patients with mild to moderate hepatic impairment. No data are available on patients with
severe hepatic impairment treated by Rasilez HCT. However, due to its hydrochlorothiazide
component, Rasilez HCT is contraindicated in patients with severe hepatic impairment (see section
4.3).
No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see
sections 4.4 and 4.2). No data are available for Rasilez HCT in patients with severe renal impairment
(GFR < 30 ml/min/1.73 m
2
). However, as expected for a compound which is cleared almost
exclusively via the kidneys, renal function has a marked effect on the kinetics of hydrochlorothiazide.
Therefore, Rasilez HCT is contraindicated in patients with severe renal impairment (GFR
< 30 ml/min/1.73 m
2
) (see section 4.3).
No initial dose adjustment of Rasilez HCT is required in elderly patients.
No pharmacokinetic data are available in the paediatric population.
5.3 Preclinical safety data
Safety pharmacology studies with aliskiren 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. No carcinogenic potential for aliskiren was detected in a 2-year rat study and a 6-month
transgenic mouse study. One colonic adenoma and one caecal adenocarcinoma recorded in rats at the
dose of 1,500 mg/kg/day were not statistically significant. Aliskiren was devoid of any mutagenic
potential, embryo-foetal toxicity or teratogenicity. Fertility, prenatal development and postnatal
development were unaffected in rats.
Preclinical evaluations to support the administration of hydrochlorothiazide in humans included
in
vitro
genotoxicity assays and reproductive toxicity and carcinogenicity studies in rodents. Extensive
clinical data are available for hydrochlorothiazide and these are reflected in the relevant sections.
29
The findings observed in the 2-week and 13-week toxicity studies were consistent with those observed
previously with aliskiren or hydrochlorothiazide monotherapies. There were no new or unexpected
findings observed of relevance to human use. Increased cellular vacuolation of the adrenal gland zona
glomerulosa was observed during the 13-week toxicity study in rats. The finding was observed in
animals treated with hydrochlorothiazide but not in those animals receiving aliskiren alone or vehicle.
There was no evidence that this finding was enhanced in the aliskiren/hydrochlorothiazide
combination as it was only apparent at a minimal severity in all animals.
6.
6.1 List of excipients
Tablet core
:
Cellulose microcrystalline
Crospovidone
Lactose monohydrate
Wheat starch
Povidone
Magnesium stearate
Silica colloidal anhydrous
Talc
Coating
:
Talc
Hypromellose
Macrogol
Titanium dioxide (E171)
Red iron oxide (E172)
Yellow iron oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
24 months
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
PA/Alu/PVC – Alu blisters:
Single-packs containing 7, 14, 28, 30, 50 or 56 tablets.
Multi-packs containing 90, 98 or 280 tablets.
PVC/polychlorotrifluoroethylene (PCTFE) – Alu blisters:
Single-packs containing 7, 14, 28, 30, 50, 56, 90 or 98 tablets.
Single-packs (perforated unit dose blister) containing 56 x 1 tablets.
Multi-packs containing 280 tablets.
Multi-packs (perforated unit dose blister) containing 98 x 1 tablets.
Not all pack sizes or strengths may be marketed.
30
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
8.
EU/1/08/491/021-040
9.
16.01.2009
31
1.
Rasilez HCT 300 mg/12.5 mg film-coated tablets
2.
Each film-coated tablet contains 300 mg aliskiren (as hemifumarate) and 12.5 mg hydrochlorothiazide.
Excipients: Each tablet contains 25 mg lactose monohydrate and 24.5 mg wheat starch.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Violet white, biconvex, ovaloid film-coated tablet imprinted with “CVI” on one side and “NVR” on
the other.
4.
Treatment of essential hypertension in adults.
Rasilez HCT is indicated in patients whose blood pressure is not adequately controlled on aliskiren or
hydrochlorothiazide used alone.
Rasilez HCT is indicated as substitution therapy in patients adequately controlled with aliskiren and
hydrochlorothiazide, given concurrently, at the same dose level as in the combination.
The recommended dose of Rasilez HCT is one tablet per day. Rasilez HCT 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 HCT.
The antihypertensive effect is largely manifested within 1 week and the maximum effect is generally
seen within 4 weeks.
Posology in patients not adequately controlled with aliskiren or hydrochlorothiazide monotherapy
Individual dose titration with each of the two components may be recommended before changing to
the fixed combination. When clinically appropriate, direct change from monotherapy to the fixed
combination may be considered.
Rasilez HCT 300 mg /12.5 mg may be administered in patients whose blood pressure is not adequately
controlled with aliskiren 300 mg or hydrochlorothiazide 12.5 mg alone or by Rasilez HCT
150 mg/12.5 mg.
If blood pressure remains uncontrolled after 2-4 weeks of therapy, the dose may be titrated up to a
maximum of Rasilez HCT 300 mg/25 mg daily. Dosing should be individualised and adjusted
according to the patient’s clinical response.
32
Posology as substitution therapy
For convenience, patients receiving aliskiren and hydrochlorothiazide from separate tablets may be
switched to a fixed combination tablet of Rasilez HCT containing the same component doses.
Renal impairment
No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see
sections 4.4 and 5.2). Due to the hydrochlorothiazide component, Rasilez HCT is contraindicated for
use in patients with severe renal impairment (glomerular filtration rate (GFR) < 30 ml/min/1.73 m
2
)
(see sections 4.3 and 5.2).
Hepatic impairment
Thiazides should be used with caution in patients with impaired hepatic function. No adjustment of the
initial dose is required for patients with mild to moderate hepatic impairment (see section 5.2). Due to
the hydrochlorothiazide component, Rasilez HCT is contraindicated in patients with severe hepatic
impairment (see sections 4.3 and 4.4).
Elderly patients (over 65 years)
No adjustment of the initial dose is required in elderly patients.
Paediatric patients
Rasilez HCT is not recommended for use in children and adolescents below age 18 due to a lack of
data on safety and efficacy (see section 5.2).
Hypersensitivity to the active substances or to any of the excipients (see section 6.1), or to other
sulphonamide-derived substances.
History of angioedema with aliskiren.
Second and third trimesters of pregnancy, lactation (see section 4.6).
Severe renal impairment (GFR < 30 ml/min/1.73 m
2
).
Refractory hypokalaemia, hypercalcaemia.
Severe hepatic impairment.
The concomitant use of aliskiren with ciclosporin, a highly potent P-glycoprotein (P-gp)
inhibitor, and other potent P-gp inhibitors (quinidine, verapamil), is contraindicated (see section
4.5).
Heart failure
Aliskiren should be used with caution in patients with serious congestive heart failure (New York
Heart Association (NYHA) functional class III-IV). Rasilez HCT should be used with caution in
patients with heart failure due to limited clinical efficacy and safety data.
Angioedema
As with other agents acting on the renin -angiotensin system, angioedema has been reported in patients
treated with aliskiren. If angioedema occurs, Rasilez HCT 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.
Intravascular volume depletion
Symptomatic hypotension may occur in patients who are volume and/or sodium depleted as a result of
vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be
corrected before the administration of Rasilez HCT.
33
Electrolyte imbalance
As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be
performed at appropriate intervals. Thiazides, including hydrochlorothiazide, can cause fluid or
electrolyte imbalance (including hypokalaemia, hyponatraemia and hypochloraemic alkalosis).
Warning signs of fluid or electrolyte imbalance are dry mouth, thirst, weakness, lethargy, drowsiness,
restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and
gastrointestinal disturbances such as nausea or vomiting (see section 4.8).
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with
aliskiren may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in patients
with cirrhosis of the liver, patients experiencing brisk diuresis, patients with inadequate oral
electrolyte intake and patients receiving concomitant therapy with corticosteroids or
adrenocorticotropic hormone (ACTH) (see sections 4.5 and 4.8).
Conversely, due to the aliskiren component of Rasilez HCT, hyperkalaemia might occur. Although
clinically significant hyperkalaemia has not been documented with Rasilez HCT, risk factors for the
development of hyperkalaemia include renal insufficiency and/or heart failure, and diabetes mellitus.
Adequate monitoring of serum potassium in patients at risk is recommended. Caution is required when
co-administering potassium-sparing diuretics, potassium supplements or potassium-containing salts
substitutes with Rasilez HCT (see sections 4.5 and 4.8).
There is no evidence that Rasilez HCT would reduce or prevent diuretic-induced hyponatraemia.
Chloride deficit is generally mild and usually does not require treatment.
Thiazides may reduce urinary calcium excretion and cause an intermittent and slight elevation of
serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia
may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out
tests for parathyroid function.
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in
hypomagnesaemia (see also section 4.5).
Renal impairment and kidney transplantation
When Rasilez HCT is used in patients with impaired renal function, periodic monitoring of potassium,
creatinine and uric acid serum levels is recommended. There is no experience regarding the
administration of Rasilez HCT in patients who have recently undergone kidney transplantation. No
dosage adjustment is necessary in patients with renal impairment whose GFR is ≥ 30 ml/min/1.73 m
2
.
However, in patients with mild to moderate renal impairment (GFR ≥ 30 ml/min/1.73 m
2
but
< 60 ml/min/1.73 m
2
), Rasilez HCT should be administered with caution.
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 (e.g.
due to blood loss, severe or 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.
Hepatic impairment
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver
disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
There is no clinical experience with Rasilez HCT in patients with hepatic impairment.
34
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).
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral
stenosis, or obstructive hypertrophic cardiomyopathy.
Renal artery stenosis and renovascular hypertension
No controlled clinical data are available on the use of Rasilez HCT 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 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.
Metabolic and endocrine effects
Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or
oral hypoglycaemic agents may be required. Latent diabetes mellitus may occur during thiazide
therapy. To date, no data are available from clinical studies that were specifically-designed to evaluate
the safety of Rasilez HCT in diabetic patients.
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy.
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide
therapy.
General
In the event of severe and persistent diarrhoea, Rasilez HCT therapy should be stopped.
As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischaemic
cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of
allergy or bronchial asthma, but are more likely in patients with such a history. Exacerbation or
activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.
Excipients
Rasilez HCT contains lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Rasilez HCT contains wheat starch. It is suitable for people with coeliac disease. Patients with wheat
allergy (different from coeliac disease) should not take this medicine.
Medicinal products affecting potassium
: The potassium-depleting effect of hydrochlorothiazide is
attenuated by the potassium-sparing effect of aliskiren. However, this effect of hydrochlorothiazide on
serum potassium would be expected to be potentiated by other medicinal products associated with
potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin,
carbenoxolone, penicillin G sodium, corticosteroids, ACTH, salicylic acid derivatives). Conversely,
based on experience with the use of other medicinal products that blunt the renin-angiotensin system
(RAS), concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes
containing potassium or other medicinal products that may increase serum potassium levels (e.g.
heparin sodium) may lead to increases in serum potassium. Adequate monitoring of serum potassium
in patients at risk is recommended (see sections 4.4 and 4.8).
35
Medicinal products affected by serum potassium disturbances
: Periodic monitoring of serum
potassium is recommended when Rasilez HCT is administered with medicinal products affected by
serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).
Other antihypertensive agents:
The antihypertensive effect of Rasilez HCT may be increased with the
concomitant use of other antihypertensive agents.
Additional information on aliskiren interactions
Aliskiren has no known clinically relevant interactions with medicinal products commonly used to
treat hypertension or diabetes.
Compounds that have been investigated in aliskiren clinical pharmacokinetic studies include
acenocoumarol, atenolol, celecoxib, fenofibrate, pioglitazone, allopurinol, isosorbide-5-mononitrate,
irbesartan, digoxin, ramipril, valsartan, metformin, amlodipine, atorvastatin, cimetidine and
hydrochlorothiazide. No clinically relevant interactions have been identified. As a result no dose
adjustment for aliskiren or these co-administered medicinal products is necessary.
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 aliskiren. Although this
has not been investigated for aliskiren, it is known that P-gp also controls tissue uptake of a variety of
substrates and P-gp inhibitors can increase the tissue-to-plasma concentration ratios. Therefore, P-gp
inhibitors may increase tissue levels more than plasma levels. The potential for drug interactions at the
P-gp site will likely depend on the degree of inhibition of this transporter.
P-gp potent inhibitors
: A single dose drug interaction study in healthy subjects has shown that
ciclosporin (200 and 600 mg) increases C
max
of aliskiren 75 mg approximately 2.5-fold and AUC
approximately 5-fold
.
The increase may be higher with higher aliskiren doses. Therefore, concomitant
use of aliskiren and P-gp potent inhibitors is contraindicated (see section 4.3).
Moderate P-gp inhibitors
: Co-administration of ketoconazole (200 mg) 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 P-gp inhibitors (itraconazol, clarithromycin,
telithromycin, erythromycin, amiodarone).
P-gp substrates or weak inhibitors
: No relevant interactions with atenolol, digoxin, amlodipine or
cimetidine have been observed. When administered with atorvastatin (80 mg), steady-state aliskiren
(300 mg) AUC and C
max
increased by 50%.
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 HCT.
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 to monitor the effects when
initiating and adjusting furosemide therapy to avoid possible underutilisation in clinical situations of
volume overload.
36
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.
Warfarin:
The effects of aliskiren on warfarin pharmacokinetics have not been evaluated.
Food interactions:
Meals with a high fat content have been shown to reduce the absorption of aliskiren
substantially.
Additional information on hydrochlorothiazide interactions
When administered concurrently, the following medicinal products may interact with thiazide
diuretics:
Lithium:
Renal clearance of lithium is reduced by thiazides, therefore the risk of lithium toxicity may
be increased with hydrochlorothiazide. Co-administration of lithium and hydrochlorothiazide is not
recommended. If this combination proves essential, careful monitoring of serum lithium level is
recommended during concomitant use.
Alcohol
: Potentiation of orthostatic hypotension may occur.
Antidiabetic medicinal products (oral agents and insulins)
: Dosage adjustment of the antidiabetic
medicinal product may be required (see section 4.4).
Cholestyramine and colestipol resins:
Absorption of hydrochlorothiazide is impaired in the presence
of anionic exchange resins.
Digitalis glycosides:
Thiazide-induced hypokalaemia or hypomagnesaemia favour the onset of
digitalis-induced cardiac arrhythmias (see section 4.4).
NSAIDs:
The administration of an NSAID may reduce the diuretic, natriuretic and antihypertensive
effects of thiazide diuretics in some patients.
Pressor amines (e.g. noradrenaline):
The effect of pressor amines may be decreased.
Antigout medicine:
Dosage adjustments of antigout medications may be necessary as
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or
sulfinpyrazone may be necessary. Co
-
administration of thiazide diuretics may increase the incidence
of hypersensitivity reactions to allopurinol.
Calcium salts:
Thiazide diuretics may increase serum calcium levels due to decreased excretion. If
calcium supplements or calcium-sparing medicinal products (e.g. vitamin D therapy) must be
prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.
Curare derivatives (e.g. tubocurarine):
The effect of non-depolarising skeletal muscle relaxants may
be potentiated by hydrochlorothiazide.
Other interactions:
The hyperglycaemic effect of beta blockers and diazoxide may be enhanced by
thiazides. Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide-
type diuretics by decreasing gastrointestinal motility and stomach-emptying rate. Thiazides may
increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal excretion of
cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their
myelosuppressive effects.
37
Pregnancy
There are no data on the use of aliskiren in pregnant women. Aliskiren 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 when used during second and third trimesters.
Prolonged exposure to thiazides during the third trimester of pregnancy can reduce maternal plasma
volume as well as uteroplacental blood flow, which may cause a foeto-placental ischaemia and growth
retardation. Moreover, rare cases of hypoglycaemia and thrombocytopenia in neonates have been
reported following exposure near term.
No specific clinical studies have been performed with this combination, therefore Rasilez HCT 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). A switch to a suitable
alternative treatment should be carried out in advance of a planned pregnancy. If pregnancy is detected
during therapy, Rasilez HCT should be discontinued as soon as possible.
Lactation
Rasilez HCT is contraindicated during lactation (see section 4.3). It is not known whether aliskiren is
excreted in human milk. Aliskiren was secreted in the milk of lactating rats. Thiazides appear in
human milk and may inhibit lactation. They can produce adverse biological effects including
hypokalaemia, haemolysis (glucose-6-phosphate dehydrogenase (G6PD) defect) and hypersensitivity
due to sulphonamide properties.
No studies on the effect on the ability to drive and use machines have been performed. Rasilez HCT is
unlikely to affect the ability to drive and use machines. However, when driving vehicles or operating
machinery it must be borne in mind that dizziness or drowsiness may occasionally occur when taking
antihypertensive therapy.
Aliskiren/hydrochlorothiazide combination
The safety of Rasilez HCT has been evaluated in 9 clinical trials with more than 3,900 patients,
including over 700 treated for over 6 months, and 190 for over 1 year. The incidence of adverse
reactions showed no association with gender, age, body mass index, race or ethnicity. Treatment with
Rasilez HCT had an overall incidence of adverse experiences at doses up to 300 mg/25 mg similar to
placebo. 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 frequency of adverse reactions listed below is defined using the following convention: very
common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to
< 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within
each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Gastrointestinal disorders
Common:
Diarrhoea
Diarrhoea
: Diarrhoea is a dose-related adverse drug reaction for aliskiren. In controlled clinical trials,
the incidence of diarrhoea in Rasilez HCT-treated patients was 1.3% compared to 1.4% for aliskiren-
or 1.9% for hydrochlorothiazide-treated patients.
38
Serum potassium
: In a large placebo-controlled clinical trial, the opposite effects of aliskiren (150 mg
or 300 mg) and hydrochlorothiazide (12.5 mg or 25 mg) on serum potassium approximately balanced
each other in many patients. In other patients, one or the other effect may be dominant. Periodic
determinations of serum potassium to detect possible electrolyte imbalance should be performed in
patients at risk at appropriate intervals (see sections 4.4 and 4.5).
Additional information on individual components
Adverse reactions previously reported with one of the individual components may occur with Rasilez
HCT even if not observed in clinical trials.
Aliskiren
Treatment with Aliskiren up to 300 mg resulted in an overall incidence of adverse reactions similar to
placebo. 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 known aliskiren adverse drug reactions are presented in the table below using the same
convention as described previously for the fixed combination.
Gastrointestinal disorders
Common: Diarrhoea
Skin and subcutaneous tissue disorders
Rash
Rare:
Angioedema
In controlled clinical trials, angioedema occurred rarely during treatment with aliskiren 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 patients should discontinue treatment and contact the physician (see section 4.4).
The incidence of cough was similar in placebo (0.6%) and aliskiren-treated (0.9%) patients.
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 RAS,
such as ACEIs and angiotensin receptor blockers.
Serum potassium
: Increases in serum potassium were minor and infrequent in patients with essential
hypertension treated with aliskiren alone (0.9% compared to 0.6% with placebo). However, in one
study where aliskiren 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, 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).
39
Uncommon:
Hydrochlorothiazide
Adverse events (regardless of relationship to medicinal product) reported with the use of
hydrochlorothiazide alone include:
Blood and lymphatic system disorders
Aplastic anaemia, bone marrow depression,
neutropenia/agranulocytosis, haemolytic anaemia, leucopenia,
thrombocytopenia
Psychiatric disorders
Not known:
Depression, sleep disturbances
Nervous system disorders
Not known:
Restlessness, light-headedness, vertigo, paraesthesia, dizziness
Eye disorders
Cardiac disorders
Transient blurred vision, xanthopsia
Not known:
Cardiac arrhythmias
Vascular disorders
Not known: Postural hypotension
Respiratory, thoracic and mediastinal disorders
Not known:
Respiratory distress (including pneumonitis and pulmonary oedema)
Gastrointestinal disorders
Not known:
Pancreatitis, anorexia, diarrhoea, constipation, gastric irritation,
sialadenitis, loss of appetite
Hepatobiliary disorders
Not known: Jaundice (intrahepatic cholestatic jaundice)
Skin and subcutaneous tissue disorders
Not known: Anaphylactic reactions, toxic epidermal necrolysis, necrotising angiitis
(vasculitis, cutaneous vasculitis), cutaneous lupus erythematosus-like
reactions, reactivation of cutaneous lupus erythematosus,
photosensitivity reactions, rash, urticaria
Musculoskeletal and connective tissue disorders
Not known: Weakness, muscle spasm
Renal and urinary disorders
Not known: Interstitial nephritis, renal dysfunction
General disorders and administration site conditions
Not known:
Fever
Investigations
Not known:
Electrolyte imbalance, including hypokalaemia and hyponatraemia (see
section 4.4), hyperuricaemia, glycosuria, hyperglycaemia, increases in
cholesterol and triglycerides
No information is available on the treatment of overdose with Rasilez HCT. The most likely
manifestation of overdose would be hypotension, related to the antihypertensive effect of aliskiren.
hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. The most
common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in
muscle spasms and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis
glycosides or certain antiarrhythmic medicinal products. If symptomatic hypotension should occur,
supportive treatment should be initiated.
40
Not known:
Not known:
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Renin inhibitor (aliskiren) combinations with diuretics
(hydrochlorothiazide), ATC code: C09XA52
Rasilez HCT combines two antihypertensive compounds to control blood pressure in patients with
essential hypertension: Aliskiren belongs to the class of direct renin inhibitors and hydrochlorothiazide
to the class of thiazide diuretics. The combination of these substances with complementary
mechanisms of action provides an additive antihypertensive effect, reducing blood pressure to a
greater degree than either component alone.
Aliskiren
Aliskiren is an orally active, non-peptide, potent and selective direct inhibitor of human renin.
By inhibiting the enzyme renin, aliskiren inhibits the renin-angiotensin system (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 (angiotensin converting
enzyme inhibitors (ACEI) and angiotension 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 effects on PRA are not known at the present
time.
In hypertensive patients, once-daily administration of aliskiren 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 (12 months), and was independent of age, gender, body mass
index and ethnicity.
There has been no evidence of first-dose hypotension and no effect on pulse rate in patients treated in
controlled clinical studies. 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 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
aliskiren 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 aliskiren and placebo, respectively. The
clinical relevance of a reduction in UACR is not established in the absence of an effect on blood
pressure. Aliskiren 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.
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 aliskiren 150 mg was well tolerated. B-type natriuretic
peptide (BNP) levels were reduced by 25% in the aliskiren arm compared to placebo. However the
clinical significance of this reduction is unknown.
Combination therapy studies are available for aliskiren added to the diuretic hydrochlorothiazide, the
ACEI ramipril, the calcium channel blocker amlodipine, the ARB valsartan, and the beta blocker
atenolol. These combinations were efficacious and well tolerated.
41
Hydrochlorothiazide
The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been
shown that there is a high-affinity receptor in the renal cortex as the primary binding site for the
thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule. The mode of
action of thiazides is through inhibition of the Na+Cl- symporter by competing for the Cl- site, thereby
affecting electrolyte reabsorption mechanisms: directly increasing sodium and chloride excretion to an
approximately equal extent, and indirectly by this diuretic action reducing plasma volume, with
consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and a
decrease in serum potassium.
Aliskiren/hydrochlorothiazide
Over 3,900 hypertensive patients received Rasilez HCT once daily in clinical trials.
In hypertensive patients, once-daily administration of Rasilez HCT provided dose-dependent
reductions in both systolic and diastolic blood pressure that were maintained over the entire 24-hour
dose interval. The antihypertensive effect is largely manifested within 1 week and the maximum effect
is generally seen within 4 weeks.The blood-pressure-lowering effect was sustained during long-term
treatment, and was independent of age, gender, body mass index and ethnicity. The antihypertensive
effect of a single dose of the combination persisted for 24 hours. Upon withdrawal of the aliskiren
treatment (aliskiren with or without hydrochlorothiazide add-on), the return of blood pressure towards
baseline was gradual (3-4 weeks) with no evidence of the rebound effect.
Rasilez HCT was studied in a placebo-controlled trial including 2,762 hypertensive patients with
diastolic blood pressure ≥ 95 mmHg and < 110 mmHg (mean baseline blood pressure of
153.6/99.2 mmHg). In this study, Rasilez HCT in doses from 150 mg/12.5 mg to 300 mg/25 mg
produced dose-dependent blood pressure reductions (systolic/diastolic) from 17.6/11.9 mmHg to
21.2/14.3 mmHg, respectively, compared to 7.5/6.9 mmHg with placebo. The greater blood pressure
reductions with these combination doses were also significantly greater than the respective doses of
aliskiren and hydrochlorothiazide when used alone. The combination of aliskiren and
hydrochlorothiazide neutralised the reactive increase of PRA caused by hydrochlorothiazide.
When administered in hypertensive patients with markedly elevated blood pressure (systolic blood
pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg), Rasilez HCT in doses from
150 mg/12.5 mg to 300 mg/25 mg administered without up-titration from monotherapy demonstrated
significantly greater systolic/diastolic blood pressure control rates (< 140/90 mmHg) as compared to
the respective monotherapies. In this population, Rasilez HCT 150 mg/12.5 mg to 300 mg/25 mg
provided dose-dependent systolic/diastolic blood pressure reduction from 20.6/12.4 mmHg to
24.8/14.5 mmHg, which were significantly superior to the respective monotherapies. The safety of the
combination therapy was similar to the respective monotherapies regardless of severity of
hypertension or of the presence or absence of additional cardiovascular risk. Hypotension and related
adverse events were uncommon with the combination treatment, with no increased incidence in
elderly patients.
In a study in 880 randomised patients not adequately responsive to aliskiren 300 mg treatment, the
combination of aliskiren/hydrochlorothiazide 300 mg/25 mg produced systolic/diastolic blood
pressure reductions of 15.8/11.0 mmHg, which were significantly greater than aliskiren 300 mg
monotherapy. In a study in 722 randomised patients not adequately responsive to hydrochlorothiazide
25 mg treatment, the combination of aliskiren/hydrochlorothiazide 300 mg/25 mg produced
systolic/diastolic blood pressure reductions of 16.78/10.7 mmHg, which were significantly greater
than hydrochlorothiazide 25 mg monotherapy.
In another clinical trial, the efficacy and safety of Rasilez HCT were also assessed in 489 obese
hypertensive patients who did not respond to hydrochlorothiazide 25 mg (baseline systolic/diastolic
blood pressure 149.4/96.8 mmHg). In this difficult-to-treat population, Rasilez HCT provided a blood
pressure reduction (systolic/diastolic) of 15.8/11.9 mmHg compared to 15.4/11.3 mmHg for
irbesartan/hydrochlorothiazide, 13.6/10.3 mmHg for amlodipine/hydrochlorothiazide and
42
8.6/7.9 mmHg for hydrochlorothiazide monotherapy, with similar safety to hydrochlorothiazide
monotherapy.
In a study in 183 randomised patients with severe hypertension (mean sitting diastolic blood pressure
≥ 105 and < 120 mmHg), aliskiren treatment regimen with optional addition of hydrochlorothiazide
25 mg was shown to be safe and efficacious in reducing blood pressure.
5.2 Pharmacokinetic properties
Aliskiren
Absorption
Following oral absorption, peak plasma concentrations of aliskiren are reached after 1-3 hours. The
absolute bioavailability of aliskiren is approximately 2-3%. Meals with a high fat content reduce C
max
by 85% and AUC by 70%. Steady-state-plasma concentrations are reached within 5-7 days following
once-daily administration and steady-state levels are approximately 2-fold greater than with the initial
dose.
Distribution
Following intravenous administration, the mean volume of distribution at steady state is approximately
135 litres, indicating that aliskiren distributes extensively into the extravascular space. Aliskiren
plasma protein binding is moderate (47-51%) and independent of the concentration.
Metabolism and elimination
The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as unchanged
compound in the faeces (oral radioactive dose recovery = 91%). Approximately 1.4% of the total oral
dose is metabolised. The enzyme responsible for this metabolism is CYP3A4. Approximately 0.6% of
the dose is recovered in urine following oral administration. Following intravenous administration, the
mean plasma clearance is approximately 9 l/h.
Linearity
Exposure to aliskiren increased slightly 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. Mechanisms responsible for the deviation from dose
proportionality have not been identified. A possible mechanism is saturation of transporters at the
absorption site or at the hepatobiliary clearance route.
Hydrochlorothiazide
Absorption
The absorption of hydrochlorothiazide, after an oral dose, is rapid (T
max
about 2 h), with similar
absorption characteristics for both suspension and tablet formulations. Absolute bioavailability of
hydrochlorothiazide is 60-80% after oral administration.
Concomitant administration with food has been reported to both increase and decrease the systemic
availability of hydrochlorothiazide compared with the fasted state. The magnitude of these effects is
small and has little clinical importance.
Distribution
The apparent volume of distribution is 4-8 l/kg. Circulating hydrochlorothiazide is bound to serum
proteins (40-70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at
approximately 3 times the level in plasma.
Metabolism and elimination
After oral administration, > 95% of the absorbed dose being excreted as unchanged compound in the
urine. The distribution and elimination kinetics have generally been described by a bi-exponential
decay function, with a terminal half-life of 6-15 h.
43
Linearity
The increase in mean AUC is linear and dose proportional in the therapeutic range. There is no change
in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed
once daily.
Aliskiren/hydrochlorothiazide
Following oral administration of Rasilez HCT tablets, the median peak plasma concentration time is
within 1 hour for aliskiren and 2.5 hours for hydrochlorothiazide.
The rate and extent of absorption of Rasilez HCT are equivalent to the bioavailability of aliskiren and
hydrochlorothiazide when administered as individual monotherapies. Similar food effect was observed
for Rasilez HCT as for the individual monotherapies.
Characteristics in patients
Rasilez HCT has been shown to be effective as a once-a-day antihypertensive treatment in adult
patients, regardless of gender, age, body mass index and ethnicity.
The pharmacokinetics of aliskiren and hydrochlorothiazide are not significantly affected in patients
with mild to moderate liver disease. Consequently, no initial dose adjustment of Rasilez HCT is
required in patients with mild to moderate hepatic impairment. No data are available on patients with
severe hepatic impairment treated by Rasilez HCT. However, due to its hydrochlorothiazide
component, Rasilez HCT is contraindicated in patients with severe hepatic impairment (see section
4.3).
No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see
sections 4.4 and 4.2). No data are available for Rasilez HCT in patients with severe renal impairment
(GFR < 30 ml/min/1.73 m
2
). However, as expected for a compound which is cleared almost
exclusively via the kidneys, renal function has a marked effect on the kinetics of hydrochlorothiazide.
Therefore, Rasilez HCT is contraindicated in patients with severe renal impairment (GFR
< 30 ml/min/1.73 m
2
) (see section 4.3).
No initial dose adjustment of Rasilez HCT is required in elderly patients.
No pharmacokinetic data are available in the paediatric population.
5.3 Preclinical safety data
Safety pharmacology studies with aliskiren 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. No carcinogenic potential for aliskiren was detected in a 2-year rat study and a 6-month
transgenic mouse study. One colonic adenoma and one caecal adenocarcinoma recorded in rats at the
dose of 1,500 mg/kg/day were not statistically significant. Aliskiren was devoid of any mutagenic
potential, embryo-foetal toxicity or teratogenicity. Fertility, prenatal development and postnatal
development were unaffected in rats.
Preclinical evaluations to support the administration of hydrochlorothiazide in humans included
in
vitro
genotoxicity assays and reproductive toxicity and carcinogenicity studies in rodents. Extensive
clinical data are available for hydrochlorothiazide and these are reflected in the relevant sections.
The findings observed in the 2-week and 13-week toxicity studies were consistent with those observed
previously with aliskiren or hydrochlorothiazide monotherapies. There were no new or unexpected
findings observed of relevance to human use. Increased cellular vacuolation of the adrenal gland zona
glomerulosa was observed during the 13-week toxicity study in rats. The finding was observed in
animals treated with hydrochlorothiazide but not in those animals receiving aliskiren alone or vehicle.
There was no evidence that this finding was enhanced in the aliskiren/hydrochlorothiazide
combination as it was only apparent at a minimal severity in all animals.
44
6.
6.1 List of excipients
Tablet core
:
Cellulose microcrystalline
Crospovidone
Lactose monohydrate
Wheat starch
Povidone
Magnesium stearate
Silica colloidal anhydrous
Talc
Coating
:
Talc
Hypromellose
Macrogol
Titanium dioxide (E171)
Red iron oxide (E172)
Black iron oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
24 months
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
PA/Alu/PVC – Alu blisters:
Single-packs containing 7, 14, 28, 30, 50 or 56 tablets.
Multi-packs containing 90, 98 or 280 tablets.
PVC/polychlorotrifluoroethylene (PCTFE) – Alu blisters:
Single-packs containing 7, 14, 28, 30, 50, 56, 90 or 98 tablets.
Single-packs (perforated unit dose blister) containing 56 x 1 tablets.
Multi-packs containing 280 tablets.
Multi-packs (perforated unit dose blister) containing 98 x 1 tablets.
Not all pack sizes or strengths may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
45
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/08/491/041-060
9.
16.01.2009
46
1.
FURTHER INFORMATION
What Rasilez HCT contains
-
Each Rasilez HCT 150 mg/12.5 mg film-coated tablet contains 150 mg aliskiren (as
hemifumarate) and 12.5 mg hydrocholorothiazide. The other ingredients are: cellulose
microcrystalline, crospovidone, lactose monohydrate, wheat starch, povidone, magnesium
stearate, silica colloidal anhydrous, talc, hypromellose, macrogol, titanium dioxide (E171).
-
Each Rasilez HCT 150 mg/25 mg film-coated tablet contains 150 mg aliskiren (as
hemifumarate) and 25 mg hydrocholorothiazide. The other ingredients are: cellulose
microcrystalline, crospovidone, lactose monohydrate, wheat starch, povidone, magnesium
stearate, silica colloidal anhydrous, talc, hypromellose, macrogol, titanium dioxide (E171), red
iron oxide (E172), yellow iron oxide (E172).
122
-
Each Rasilez HCT 300 mg/12.5 mg film-coated tablet contains 300 mg aliskiren (as
hemifumarate) and 12.5 mg hydrocholorothiazide. The other ingredients are: cellulose
microcrystalline, crospovidone, lactose monohydrate, wheat starch, povidone, magnesium
stearate, silica colloidal anhydrous, talc, hypromellose, macrogol, titanium dioxide (E171), red
iron oxide (E172), black iron oxide (E172).
-
Each Rasilez HCT 300 mg/25 mg film-coated tablet contains 300 mg aliskiren (as
hemifumarate) and 25 mg hydrocholorothiazide. The other ingredients are: cellulose
microcrystalline, crospovidone, lactose monohydrate, wheat starch, povidone, magnesium
stearate, silica colloidal anhydrous, talc, hypromellose, macrogol, titanium dioxide (E171), red
iron oxide (E172), yellow iron oxide (E172).
What Rasilez HCT looks like and contents of the pack
Rasilez HCT 150 mg/12.5 mg film-coated tablets are white, oval film-coated tablets imprinted with
“LCI” on one side and “NVR” on the other.
Rasilez HCT 150 mg/25 mg film-coated tablets are pale yellow, oval film-coated tablets imprinted
with “CLL” on one side and “NVR” on the other.
Rasilez HCT 300 mg/12.5 mg film-coated tablets are violet white, oval film-coated tablets imprinted
with “CVI” on one side and “NVR” on the other.
Rasilez HCT 300 mg/25 mg film-coated tablets are light yellow, oval film-coated tablets imprinted
with “CVV” on one side and “NVR” on the other.
Rasilez HCT is available in packs containing 7, 14, 28, 30, 50, 56, 90,or 98 tablets.
Packs containing 90 (3x30), 98 (2x49) or 280 (20x14) tablets are multi-packs.
Not all pack sizes or strengths may be available in your country.
Marketing Authorisation Holder
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
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
123
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
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
124
Source: European Medicines Agency
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