Rasilamlo

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 



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1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 150 mg/5 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each film-coated tablet contains 150 mg aliskiren (as hemifumarate) and 5 mg amlodipine (as 

besylate). 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Film-coated tablet. 

 

Light yellow, convex, ovaloid tablet with a bevelled edge, with “T2” debossed on one side and 

“NVR” on the other. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Rasilamlo is indicated for the treatment of essential hypertension in adult patients whose blood 

pressure is not adequately controlled with aliskiren or amlodipine used alone. 

 

4.2 Posology and method of administration 

 

Posology 

The recommended dose of Rasilamlo is one tablet per day. 

 

The antihypertensive effect is manifested within 1 week and the effect is near maximal at around 

4 weeks. If blood pressure remains uncontrolled after 4 to 6 weeks of therapy, the dose may be 

titrated up to a maximum of 300 mg aliskiren/10 mg amlodipine. Dose should be individualised and 

adjusted according to the patient’s clinical response. 

 

Rasilamlo may be administered with other antihypertensive medicinal products with the exception of 

use in combination with angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor 

blockers (ARB) in patients with diabetes mellitus or renal impairment (glomerular filtration rate 

(GFR) <60 ml/min/1.73 m2) (see sections 4.3, 4.4 and 5.1). 

 

Posology in patients not adequately controlled with aliskiren or amlodipine monotherapy  

Rasilamlo 150 mg/5 mg may be administered in patients whose blood pressure is not adequately 

controlled with aliskiren 150 mg or amlodipine 5 mg alone. 

 

A patient who experiences dose limiting adverse reactions on either component alone may be 

switched to Rasilamlo containing a lower dose of that component to achieve similar blood pressure 

reductions. 

 

Individual dose titration with each of the two components may be recommended before changing to 

the fixed combination. When clinically appropriate and in line with the above-mentioned posology, 

direct change from monotherapy to the fixed combination may be considered. 

 



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Special populations 

Renal impairment 

No adjustment of the initial dose is required for patients with mild to moderate renal impairment 

(GFR 89-60 ml/min/1.73 m2 and 59-30 ml/min/1.73 m2, respectively, see sections 4.4 and 5.2). 

Rasilamlo is not recommended in patients with severe renal impairment (GFR <30 ml/min/1.73 m2). 

 

Hepatic impairment 

Amlodipine dosage recommendations have not been established in patients with mild to moderate 

hepatic impairment. The pharmacokinetics of amlodipine have not been studied in severe hepatic 

impairment; therefore, caution should be exercised when administering Rasilamlo to patients with 

hepatic impairment. 

 

Elderly people (over 65 years) 

There is limited experience with Rasilamlo, in particular in patients aged 75 years or older. 

Therefore, particular caution should be exercised in these patients. The recommended starting dose of 

aliskiren in elderly patients is 150 mg. No clinically meaningful additional blood pressure reduction 

is observed by increasing the dose to 300 mg in the majority of elderly patients. 

 

Paediatric population 

The safety and efficacy of Rasilamlo in children below age 18 have not been established. No data are 

available. 

 

Rasilamlo is contraindicated in children from birth to less than 2 years and should not be used in 

children aged 2 to less than 6 years because of safety concerns due to potential aliskiren overexposure 

(see sections 4.3, 4.4, 5.2, and 5.3). 

 

Method of administration 

Oral use. The tablets should be swallowed whole with some water. Rasilamlo should be taken with a 

light meal once a day, preferably at the same time each day. Concomitant intake with fruit juice 

and/or drinks containing plant extracts (including herbal teas) should be avoided (see section 4.5). 

 

4.3 Contraindications 

 

 Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or 
other dihydropyridine derivatives. 

 History of angioedema with aliskiren. 

 Hereditary or idiopathic angioedema 

 Second and third trimesters of pregnancy (see section 4.6). 

 The concomitant use of aliskiren with ciclosporin and itraconazole, two highly potent P-
glycoprotein (P-gp) inhibitors, and other potent P-gp inhibitors (e.g. quinidine), is 

contraindicated (see section 4.5). 

 The concomitant use of Rasilamlo with an ACEI or an ARB is contraindicated in patients with 
diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) (see sections 4.5 and 5.1). 

 Severe hypotension. 

 Shock (including cardiogenic shock). 

 Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis). 
- Haemodynamically unstable heart failure after acute myocardial infarction. 
- Children from birth to less than 2 years (see sections 4.2 and 5.3). 
 



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4.4 Special warnings and precautions for use 

 

General 

In the event of severe and persistent diarrhoea, Rasilamlo therapy should be stopped (see section 4.8). 

 

As with any antihypertensive medicinal product, excessive reduction of blood pressure in patients 

with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial 

infarction or stroke. 

 

The safety and efficacy of amlodipine in hypertensive crisis have not been established. 

 

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) 

Hypotension, syncope, stroke, hyperkalaemia, and decreased renal function (including acute renal 

failure) have been reported in susceptible individuals, especially if combining medicinal products that 

affect this system (see section 5.1). Dual blockade of the RAAS by combining aliskiren with an ACEI 

or an ARB is therefore not recommended. If dual blockade therapy is considered absolutely 

necessary, this should only occur under specialist supervision and subject to frequent close monitoring 

of renal function, electrolytes and blood pressure. 

 

Heart failure 

Calcium channel blockers, including amlodipine, should be used with caution in patients with 

congestive heart failure, as they may increase the risk of future cardiovascular events and mortality. 

 

No data on cardiovascular mortality and morbidity are available for aliskiren in patients with heart 

failure (see section 5.1). 

 

Aliskiren should be used with caution in patients with heart failure treated with furosemide or 

torasemide (see section 4.5). 

 

Risk of symptomatic hypotension 

Symptomatic hypotension could occur after initiation of treatment with Rasilamlo in the following 

cases: 

 Patients with marked volume depletion or patients with salt depletion (e.g. those receiving high 
doses of diuretics) or 

 Combined use of aliskiren with other agents acting on the RAAS. 
The volume or salt depletion should be corrected prior to administration of Rasilamlo, or the 

treatment should start under close medical supervision. In patients with uncomplicated hypertension 

treated with Rasilamlo in short-term controlled trials, the incidence of hypotension was low (0.2%). 

 

Renal impairment 

In clinical studies aliskiren has not been investigated in hypertensive patients with severe renal 

impairment (serum creatinine ≥150 μmol/l or 1.70 mg/dl in women and ≥177 μmol/l or 2.00 mg/dl in 

men and/or estimated GFR <30 ml/min/1.73 m2), history of dialysis, nephrotic syndrome or 

renovascular hypertension. Rasilamlo is not recommended in patients with severe renal impairment 

(GFR <30 ml/min/1.73 m2). 

 

As for other medicinal products acting on the renin-angiotensin-aldosterone system, caution should be 

exercised when Rasilamlo 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, diabetes mellitus 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. 

 



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Increases in serum potassium have been observed with aliskiren in post-marketing experience and 

these may be exacerbated by concomitant use of other agents acting on the RAAS or by non-steroidal 

anti-inflammatory drugs (NSAIDs). Consistent with standard medical practice, periodic 

determination of renal function including serum electrolytes is advised if co-administration is 

considered necessary. 

 

Hepatic impairment 

The half life of amlodipine is prolonged and AUC values are higher in patients with impaired liver 

function; dosage recommendations have not been established. Caution should be exercised when 

administering Rasilamlo to patients with hepatic impairment (see sections 4.2 and 5.2). 

 

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy 

As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral 

stenosis, or obstructive hypertrophic cardiomyopathy. 

 

Renal artery stenosis 

No controlled clinical data are available on the use of Rasilamlo in patients with unilateral or 

bilateral renal artery stenosis, or stenosis to a solitary kidney. However, as with other medicinal 

products acting on the renin-angiotensin-aldosterone system, there is an increased risk of renal 

insufficiency, including acute renal failure, when patients with renal artery stenosis are treated with 

aliskiren. Therefore caution should be exercised in these patients. If renal failure occurs, treatment 

should be discontinued. 

 

Anaphylactic reactions and angioedema 

Anaphylactic reactions have been observed during treatment with aliskiren from post-marketing 

experience (see section 4.8). As with other medicinal products acting on the renin-angiotensin-

aldosterone system, angioedema or symptoms suggestive of angioedema (swelling of the face, lips, 

throat and/or tongue) have been reported in patients treated with aliskiren. 

 

A number of these patients had a history of angioedema or symptoms suggestive of angioedema, 

which in some cases followed use of other medicinal products that can cause angioedema, including 

RAAS blockers (angiotensin converting enzyme inhibitors or angiotensin receptor blockers) (see 

section 4.8). 

 

In post-marketing experience, angioedema or angioedema-like reactions have been reported when 

aliskiren was co-administered with ACEIs and/or ARBs (see section 4.8). 

 

Special caution is necessary in patients with a hypersensitivity predisposition. 

 

Patients with history of angioedema may be at increased risk of experiencing angioedema during 

treatment with aliskiren (see sections 4.3 and 4.8). Caution should therefore be exercised when 

prescribing aliskiren to patients with a history of angioedema, and such patients should be closely 

monitored during treatment (see section 4.8) especially at the beginning of the treatment. 

 

If anaphylactic reactions or angioedema occur, Rasilamlo should be promptly discontinued and 

appropriate therapy and monitoring provided until complete and sustained resolution of signs and 

symptoms has occurred. Patients should be informed to report to the physician any signs suggestive of 

allergic reactions, in particular difficulties in breathing or swallowing, swelling of face, extremities, 

eyes, lips or tongue. Where there is involvement of the tongue, glottis or larynx adrenaline should be 

administered. In addition, measures necessary to maintain patent airways should be provided. 

 



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Paediatric population 

Aliskiren is a P-glycoprotein (P-gp) substrate, and there is a potential for aliskiren overexposure in 

children with an immature P-gp drug transporter system. The age at which the transporter system is 

mature cannot be determined (see sections 5.2 and 5.3). Therefore, Rasilamlo is contraindicated in 

children from birth to less than 2 years and should not be used in children aged 2 to less than 6 years. 

 

Limited safety data are available from a pharmacokinetic study of aliskiren treatment in 39 

hypertensive children aged 6 to less than 18 years (see sections 4.8 and 5.2). 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Information on Rasilamlo interactions 

No interaction studies with other medicinal products were performed with Rasilamlo. Therefore, 

information on interactions with other medicinal products that are known for the individual active 

substances is provided in this section. 

 

Co-administration of aliskiren and amlodipine does not cause meaningful changes in the steady-state 

pharmacokinetic exposure (AUC) and the maximum concentration (Cmax) of either component in 

healthy volunteers. 

 

Information on aliskiren interactions 

Contraindicated (see section 4.3) 

- P-gp potent inhibitors 
A single dose drug interaction study in healthy subjects has shown that ciclosporin (200 and 600 mg) 

increases Cmax of aliskiren 75 mg approximately 2.5-fold and AUC approximately 5-fold. The 

increase may be higher with higher aliskiren doses. In healthy subjects, itraconazole (100 mg) 

increases AUC and Cmax of aliskiren (150 mg) by 6.5-fold and 5.8-fold, respectively. Therefore, 

concomitant use of aliskiren and P-gp potent inhibitors is contraindicated (see section 4.3). 

 

Not recommended (see section 4.2) 

- Fruit juice and drinks containing plant extracts 
Administration of fruit juice with aliskiren resulted in a decrease in AUC and Cmax of aliskiren. Co-

administration of grapefruit juice with aliskiren 150 mg resulted in a 61% decrease in aliskiren AUC 

and co-administration with aliskiren 300 mg resulted in a 38% decrease in aliskiren AUC. Co-

administration of orange or apple juice with aliskiren 150 mg resulted in a 62% decrease in aliskiren 

AUC or in a 63% decrease in aliskiren AUC, respectively. This decrease is likely due to an 

inhibition of organic anion transporting polypeptide-mediated uptake of aliskiren by components of 

fruit juice in the gastrointestinal tract. Therefore, because of the risk of therapeutic failure, fruit juice 

should not be taken together with Rasilamlo. The effect of drinks containing plant extracts (including 

herbal teas) on the absorption of aliskiren has not been investigated. However, compounds potentially 

inhibiting organic anion transporting polypeptide-mediated uptake of aliskiren are widely present in 

fruits, vegetables, and many other plant products. Therefore, drinks containing plant extracts, 

including herbal teas, should not be taken together with Rasilamlo. 

 

Dual blockade of the RAAS with aliskiren, ARBs or ACEIs 

Clinical trial data has shown that dual blockade of the RAAS through the combined use of ACEIs, 

ARBs or aliskiren is associated with a higher frequency of adverse events such as hypotension, stroke, 

hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a 

single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). 

 



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Caution required with concomitant use 

- P-gp 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 (see section 5.2). Rifampicin, which is an 

inducer of P-gp, reduced aliskiren bioavailability by approximately 50% in a clinical study. Other 

inducers of P-gp (St. John’s wort) might decrease the bioavailability of 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. 

 

- Moderate P-gp inhibitors 
Co-administration of ketoconazole (200 mg) or verapamil (240 mg) with aliskiren (300 mg) resulted 

in a 76% or 97% increase in aliskiren AUC, respectively. The change in plasma levels of aliskiren in 

the presence of ketoconazole or verapamil is expected to be within the range that would be achieved 

if the dose of aliskiren were doubled; aliskiren doses of up to 600 mg, or twice the highest 

recommended therapeutic dose, have been found to be well tolerated in controlled clinical trials. 

Preclinical studies indicate that aliskiren and ketoconazole co-administration enhances aliskiren 

gastrointestinal absorption and decreases biliary excretion. Therefore, caution should be exercised 

when aliskiren is administered with ketoconazole, verapamil or other moderate P-gp inhibitors 

(clarithromycin, telithromycin, erythromycin, amiodarone). 

 

- Medicinal products affecting serum potassium levels 
Concomitant use of other agents affecting the RAAS, of NSAIDs or of agents that increase serum 

potassium levels (e.g. potassium-sparing diuretics, potassium supplements, salt substitutes containing 

potassium, heparin) may lead to increases in serum potassium. If co-medication with an agent 

affecting the level of serum potassium is considered necessary, caution is advisable. 

 

- Non-steroidal anti-inflammatory drugs (NSAIDs) 
As with other medicinal products acting on the renin-angiotensin-aldosterone 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. 

 

- Furosemide and torasemide 
Oral co-administration of aliskiren and furosemide had no effect on the pharmacokinetics of aliskiren 

but reduced exposure to furosemide by 20-30% (the effect of aliskiren on furosemide administered 

intramuscularly or intravenously has not been investigated). After multiple doses of furosemide 

(60 mg/day) co-administered with aliskiren (300 mg/day) to patients with heart failure the urinary 

sodium excretion and the urine volume were reduced during the first 4 hours by 31% and 24%, 

respectively, as compared to furosemide alone. The mean weight of patients concomitantly treated 

with furosemide and 300 mg aliskiren (84.6 kg) was higher than the weight of patients treated with 

furosemide alone (83.4 kg). Smaller changes in furosemide pharmacokinetics and efficacy were 

observed with aliskiren 150 mg/day. 

 

The available clinical data did not indicate that higher doses of torasemide were used after co-

administration with aliskiren. Torasemide renal excretion is known to be mediated by organic anion 

transporters (OATs). Aliskiren is minimally excreted via the renal route, and only 0.6% of the 

aliskiren dose is recovered in urine following oral administration (see section 5.2). However, since 

aliskiren has been shown to be a substrate for the organic anion-transporting polypeptide 1A2 

(OATP1A2) (see interaction with organic anion transporting polypeptide (OATP) inhibitors), there is 

a potential for aliskiren to reduce plasma torasemide exposure by an interference with the absorption 

process. 



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In patients treated with both aliskiren and oral furosemide or torasemide, it is therefore recommended 

that the effects of furosemide or torasemide be monitored when initiating and adjusting furosemide, 

torasemide or aliskiren therapy to avoid changes in extracellular fluid volume and possible situations 

of volume overload (see section 4.4). 

 

- Warfarin 
The effects of aliskiren on warfarin pharmacokinetics have not been evaluated. 

 

- Food interactions 
Meals (low or high fat content) have been shown to reduce the absorption of aliskiren substantially 

(see section 4.2). The available clinical data do not suggest an additive effect of different types of 
foods and/or drinks, however the potential for decreased aliskiren bioavailability due to this additive 

effect has not been studied and therefore cannot be excluded. Concomitant administration of aliskiren 

with fruit juice or drinks containing plant extracts, including herbal teas, should be avoided. 

 

No interactions 

- Compounds that have been investigated in aliskiren clinical pharmacokinetic studies include 
acenocoumarol, atenolol, celecoxib, pioglitazone, allopurinol, isosorbide-5-mononitrate and 

hydrochlorothiazide. No interactions have been identified. 

 

- Co-administration of aliskiren with either metformin (↓28%), amlodipine (↑29%) or cimetidine 
(↑19%) resulted in between 20% and 30% change in Cmax or AUC of aliskiren. When 

administered with atorvastatin, steady-state aliskiren AUC and Cmax increased by 50%. Co-

administration of aliskiren had no significant impact on atorvastatin, metformin or amlodipine 

pharmacokinetics. As a result no dose adjustment for aliskiren or these co-administered 

medicinal products is necessary. 

 

- Digoxin and verapamil bioavailability may be slightly decreased by aliskiren. 
 

- CYP450 interactions 
Aliskiren does not inhibit the CYP450 isoenzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A). 

Aliskiren does not induce CYP3A4. Therefore aliskiren is not expected to affect the systemic 

exposure of substances that inhibit, induce or are metabolised by these enzymes. Aliskiren is 

metabolised minimally by the cytochrome P450 enzymes. Hence, interactions due to inhibition or 

induction of CYP450 isoenzymes are not expected. However, CYP3A4 inhibitors often also affect P-

gp. Increased aliskiren exposure during co-administration of CYP3A4 inhibitors that also inhibit P-gp 

can therefore be expected (see other P-gp references in section 4.5). 

 

- P-gp substrates or weak inhibitors 
No relevant interactions with atenolol, digoxin, amlodipine or cimetidine have been observed. When 

administered with atorvastatin (80 mg), steady-state aliskiren (300 mg) AUC and Cmax increased by 

50%. In experimental animals, it has been shown that P-gp is a major determinant of aliskiren 

bioavailability. Inducers of P-gp (St. John’s wort, rifampicin) might therefore decrease the 

bioavailability of aliskiren. 

 

- Organic anion transporting polypeptide (OATP) inhibitors 

Preclinical studies indicate that aliskiren might be a substrate of organic anion transporting 

polypeptides. Therefore, the potential exists for interactions between OATP inhibitors and aliskiren 

when administered concomitantly (see interaction with fruit juice). 

 



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Information on amlodipine interactions 

Effects of other medicinal products on amlodipine 

Caution required with concomitant use 

- CYP3A4 inhibitors 
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, 

azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give 

rise to significant increase in amlodipine exposure. The clinical translation of these pharmacokinetic 

variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus 

be required. 

 

- CYP3A4 inducers 
There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant 

use of CYP3A4 inducers (e.g. rifampicin, hypericum perforatum) may give a lower plasma 

concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 

inducers. 

 

- Grapefruit juice 
Administration of amlodipine with grapefruit or grapefruit juice is not recommended as 

bioavailability may be increased in some patients, resulting in increased blood pressure lowering 

effects. 

 

- Dantrolene (infusion) 
In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with 

hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of 

hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as 

amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of 

malignant hyperthermia. 

 

Effects of amlodipine on other medicinal products 

- The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects 
of other antihypertensive medicinal products. 

 

- Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in 
a 77% increase in exposure to simvastatin compared to simvastatin alone. It is recommended to 

limit the dose of simvastatin to 20 mg daily in patients on amlodipine. 

 

No interactions 

- In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, 
digoxin, warfarin or ciclosporin. 

 

4.6 Fertility, pregnancy and lactation 

 

Women of child-bearing potential/contraception in males and females 

Healthcare professionals prescribing Rasilamlo should counsel women of childbearing potential about 

the potential risk during pregnancy. A switch to a suitable alternative antihypertensive treatment 

should be carried out in advance of a planned pregnancy since Rasilamlo should not be used in 

women planning to become pregnant. 

 

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 RAAS have been associated with 

serious foetal malformations and neonatal death. As for any medicine that acts directly on the RAAS, 

aliskiren should not be used during the first trimester of pregnancy and is contraindicated during the 

second and third trimesters (see section 4.3). 

 



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The safety of amlodipine in human pregnancy has not been established. Reproductive studies in rats 

have shown no toxicity except for delayed date of delivery and prolonged duration of labour at 

dosages 50 times greater than the maximum recommended dosage for humans (see section 5.3). Use 

in pregnancy is only recommended when there is no safer alternative and when the disease itself 

carries greater risk for the mother and foetus. 

 

Rasilamlo should not be used during the first trimester of pregnancy. Rasilamlo is contraindicated 

during the second and third trimesters (see section 4.3). 

 

If pregnancy is detected during therapy, Rasilamlo should be discontinued accordingly as soon as 

possible. 

 

Breast-feeding 

It is unknown whether aliskiren and/or amlodipine are excreted in human milk. Aliskiren was 

secreted in the milk of lactating rats. 

 

Since there is insufficient/limited information on the excretion of aliskiren and amlodipine in human 

or animal breast milk, a risk to the newborns/infants cannot be excluded. It is therefore not 

recommended for women who are breast-feeding to use Rasilamlo. 

 

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from 

Rasilamlo therapy taking into account the benefit of breast-feeding for the child and the benefit of 

therapy for the woman. 

 

Fertility 

There are no clinical data on fertility with the use of Rasilamlo. 

 

Reversible biochemical changes in the head of spermatozoa have been reported in some patients 

treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of 

amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3). 

The fertility of rats was unaffected at doses of up to aliskiren 250 mg/kg/day (see section 5.3). 

 

4.7 Effects on ability to drive and use machines 

 

When driving vehicles or using machines it must be borne in mind that dizziness or drowsiness may 

occasionally occur when taking Rasilamlo. 

 

Amlodipine can have minor or moderate influence on the ability to drive and use machines. If 

patients taking amlodipine suffer from dizziness, headache, fatigue or nausea, the ability to react may 

be impaired. 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

The safety profile of Rasilamlo presented below is based on clinical studies performed with 

Rasilamlo and the known safety profile of the individual components aliskiren and amlodipine. 

Safety information for Rasilamlo in patients aged 75 years and older is limited. 

 

The most frequent adverse reactions for Rasilamlo are hypotension and peripheral oedema. The 

adverse reactions previously reported with one of the individual components of Rasilamlo (aliskiren 

and amlodipine) and included in the tabulated list of adverse reactions may occur with Rasilamlo. 

 



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Tabulated list of adverse reactions: 

The adverse reactions are ranked by frequency, the most frequent first, 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, adverse reactions are presented in order of decreasing 

seriousness. The adverse reactions observed with Rasilamlo or with monotherapy with one or both of 

the two components are included in the table below. For adverse reactions observed with more than 

one component of a fixed-dose combination, the highest frequency is listed in the table below. 

 

Blood and lymphatic system disorders 

Very rare Leukopeniaam, thrombocytopeniaam 

Immune system disorders 

Rare Anaphylactic reactionsa, hypersensitivity 

reactionsa 

Very rare Allergic reactionsam 

Metabolism and nutrition disorders 

Very rare Hyperglycaemiaam 

Psychiatric disorders 

Uncommon Insomniaam, mood changes (including anxiety)am, 

depressionam 

Rare Confusionam 

Nervous system disorders 

Common Somnolenceam, headache (especially at the 

beginning of treatment)am 

Uncommon Tremoram, dysgeusiaam, syncopeam, hypoesthesiaam, 

paraesthesiaam 

Very rare Hypertoniaam, peripheral neuropathyam 

Eye disorders 

Uncommon Visual disturbance (including diplopia)am 

Ear and labyrinth disorders 

Uncommon Tinnitusam 

Not known Vertigoa 

Cardiac disorders 

Common Dizzinessa,am, palpitationsa,am, peripheral 

oedemac,a,am* 

Very rare Myocardial infarctionam, arrhythmia (including 

bradycardia, ventricular tachycardia, and atrial 

fibrillation)am 

Vascular disorders 

Common Flushingam, hypotensionc,a,am 

Very rare Vasculitisam 

Respiratory, thoracic and mediastinal disorders 

Uncommon Dyspnoeaa, am, rhinitisam, cougha,am 

Gastrointestinal disorders 

Common Diarrhoeaa, abdominal painam, nauseaa,am 

Uncommon Vomitinga,am, dyspepsiaam, altered bowel habits 

(including diarrhoea and constipation)am, dry 

moutham 

Very rare Pancreatitisam, gastritisam, gingival hyperplasiaam 

Hepatobiliary disorders 

Very rare Hepatitisa,am, jaundicea,am, hepatic enzymes 

increased (mostly consistent with cholestasis)am 

Not known Liver disordera,**, liver failurea,*** 



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Skin and subcutaneous tissue disorders 

Uncommon Severe cutaneous adverse reactions (SCARs) 

including Stevens Johnson syndromea, toxic 

epidermal necrolysis (TEN)a, oral mucosal 

reactionsa, rasha,am, pruritusa,am, urticariaa,am, 

alopeciaam, purpuraam, skin decolourationam, 

hyperhidrosisam, exanthemaam 

Rare Angioedemaa, erythemaa 

Very rare Erythema multiformeam, exfoliative dermatitisam, 

Stevens-Johnson syndromeam, Quincke oedemaam, 

photosensitivityam 

Musculoskeletal and connective tissue disorders 

Common Arthralgiaa,am, ankle swellingam 

Uncommon Myalgiaam, muscle crampsam, back painam 

Renal and urinary disorders 

Uncommon Acute renal failurea, renal impairmenta, 

micturition disorderam, nocturiaam, increased 

urinary frequencyam 

Reproductive system and breast disorders 

Uncommon Impotenceam, gynaecomastiaam 

General disorders and administration site conditions 

Common Fatigueam 

Uncommon Chest painam, astheniaam, painam, malaiseam 

Investigations 

Common Hyperkalaemiaa 

Uncommon Liver enzyme increaseda, weight increaseam, 

weight decreaseam 

Rare Haemoglobin decreaseda, haematocrit decreaseda, 

blood creatinine increaseda 

Not known Hyponatraemiaa 
c Adverse reaction observed with Rasilamlo; 
a Adverse reaction observed with monotherapy with aliskiren; 
am Adverse reaction observed with monotherapy with amlodipine; 

* Peripheral oedema is a known, dose-dependent adverse reaction of amlodipine and has also been 

reported with aliskiren therapy in post-marketing experience. The most frequently reported adverse 

reaction for Rasilamlo in clinical trials was peripheral oedema, which occurred at a frequency lower 

than or equal to that of the corresponding amlodipine doses, but higher than with aliskiren; 

** Isolated cases of liver disorder with clinical symptoms and laboratory evidence of more marked 

hepatic dysfunction; 

***Including one case of “liver failure fulminant” reported in the post-marketing experience, for 

which a causal relationship with aliskiren cannot be excluded. 

 

Additional information on individual components 

Adverse reactions previously reported with one of the individual components may occur with 

Rasilamlo even if not observed in clinical trials. 

 

Aliskiren 

Description of selected adverse reactions: 

Hypersensitivity reactions including anaphylactic reactions and angioedema have occurred during 

treatment with aliskiren. 

 

In controlled clinical trials, angioedema and hypersensitivity reactions occurred rarely during 

treatment with aliskiren with rates comparable to treatment with placebo or comparators. 

 



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Cases of angioedema or symptoms suggestive of angioedema (swelling of the face, lips, throat and/or 

tongue) have also been reported in post-marketing experience. A number of these patients had a 

history of angioedema or symptoms suggestive of angioedema which in some cases was associated 

with the administration of other medicinal products known to cause angioedema, including RAAS 

blockers (ACEIs or ARBs). 

 

In post-marketing experience, cases of angioedema or angioedema-like reactions have been reported 

when aliskiren was co-administered with ACEIs and/or ARBs. 

 

Hypersensitivity reactions including anaphylactic reactions have also been reported in post-marketing 

experience (see section 4.4). 

 

In the event of any signs suggesting a hypersensitivity reaction/angioedema (in particular difficulties 

in breathing or swallowing, rash, itching, hives or swelling of the face, extremities, eyes, lips and/or 

tongue, dizziness) patients should discontinue treatment and contact the physician (see section 4.4). 

 

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

hypersensitivity reaction. 

 

In post-marketing experience, renal dysfunction and cases of acute renal failure have been reported in 

patients at risk (see section 4.4). 

 

Investigations 

In controlled clinical trials, clinically relevant changes in standard laboratory parameters were 

uncommonly associated with the administration of aliskiren. In clinical studies in hypertensive 

patients, aliskiren had no clinically important effects on total cholesterol, high density lipoprotein 

cholesterol (HDL-C), fasting triglycerides, fasting glucose or uric acid. 

 

Haemoglobin and haematocrit: Small decreases in haemoglobin and haematocrit (mean decreases of 

approximately 0.05 mmol/l and 0.16 volume percent, respectively) were observed. No patients 

discontinued therapy due to anaemia. This effect is also seen with other medicinal products acting on 

the RAAS, such as ACEIs and ARBs. 

 

Serum potassium: Increases in serum potassium have been observed with aliskiren and these may be 

exacerbated by concomitant use of other agents acting on the RAAS or by NSAIDs. Consistent with 

standard medical practice, periodic determination of renal function including serum electrolytes is 

advised if co-administration is considered necessary. 

 

Paediatric population 

Based on the limited amount of safety data available from a pharmacokinetic study of aliskiren 

treatment in 39 hypertensive children 6-17 years of age, the frequency, type and severity of adverse 

reactions in children are expected to be similar to that seen in hypertensive adults. As for other RAAS 

blockers, headache is a common adverse event in children treated with aliskiren. 

 

Amlodipine 

Exceptional cases of extrapyramidal syndrome have been reported. 

 

Reporting of suspected adverse reactions 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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4.9 Overdose 

 

Symptoms 

There is no experience of overdose with Rasilamlo. The most likely manifestation of overdose for 

Rasilamlo would be hypotension, related to the antihypertensive effect of aliskiren and amlodipine. 

 

With aliskiren, the most likely manifestation of overdose would be hypotension, related to the 

antihypertensive effect of aliskiren. 

 

With amlodipine, available data suggest that gross overdose could result in excessive peripheral 

vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension 

up to and including shock with fatal outcome, have been reported with amlodipine. 

 

Treatment 

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

 

Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular 

support including frequent monitoring of cardiac and respiratory function, elevation of extremities 

and attention to circulating fluid volume and urine output. 

 

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is 

no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the 

effects of calcium channel blockade. 

 

Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 

2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of 

amlodipine. 

 

Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit. 

 

In a study conducted in patients with end stage renal disease (ESRD) receiving haemodialysis, 

dialysis clearance of aliskiren was low (<2% of oral clearance). Therefore dialysis is not adequate to 

treat aliskiren over-exposure. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1 Pharmacodynamic properties 

 

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, renin inhibitors, ATC 

code: C09XA53 

 

Rasilamlo combines two antihypertensive compounds with complementary mechanisms to control 

blood pressure in patients with essential hypertension: aliskiren belongs to the class of direct renin 

inhibitors and amlodipine belongs to the calcium antagonist class. 

 



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Rasilamlo 

The use of combined treatment with aliskiren and amlodipine arises from the actions of these two 

medicinal products on different but complementary systems that regulate blood pressure. Calcium 

channel blockers act to prevent the influx of calcium into the vascular smooth muscle cells in the 

vessel wall, thereby preventing smooth muscle cell contraction and vasoconstriction. Renin inhibitors 

suppress the enzymatic activity of renin, and thereby block the formation of Angiotensin II, the major 

effector molecule of the renin-angiotensin-aldosterone system (RAAS). Angiotensin II causes 

vasoconstriction and sodium and water reabsorption. Thus, amlodipine directly inhibits 

vasoconstriction and reduces vascular resistance, while aliskiren, by controlling Ang II production, 

can also inhibit vasoconstriction but additionally shifts water and sodium balance toward levels 

necessary for normotensive conditions. The combined action of aliskiren and amlodipine on these two 

central blood pressure-regulating factors (vasoconstriction and RAAS-mediated hypertensive effects) 

results in more effective antihypertensive effects than seen with monotherapy. 

 

Rasilamlo was studied in a number of active and placebo-controlled trials and long-term trials which 

included a total of 5,570 hypertensive patients with mild to moderate hypertension (diastolic blood 

pressure between 90 mmHg and 109 mmHg). 

 

In hypertensive patients not controlled by the component monotherapies, once-daily administration of 

Rasilamlo provided dose-dependent clinically meaningful reductions in both systolic and diastolic 

blood pressure. 

 

When given to patients whose blood pressure was not adequately controlled by either aliskiren or 

amlodipine, Rasilamlo results in greater blood pressure reductions after one week of treatment than 

the component monotherapies and a near-maximal effect is achieved after four weeks of therapy. 

 

In a study in 820 randomised patients not adequately responsive to aliskiren 300 mg treatment, the 

combination of aliskiren/amlodipine 300 mg/10 mg produced systolic/diastolic mean blood pressure 

reductions of 18.0/13.1 mmHg, which were statistically significantly greater than aliskiren 300 mg 

monotherapy. The combination at a dose of 300 mg/5 mg also showed statistically significantly 

greater blood pressure reduction than aliskiren 300 mg monotherapy. In a subset of 584 patients, the 

combination of aliskiren/amlodipine produced additional systolic/diastolic mean blood pressure 

reductions of 7.9/4.8 mmHg and 11.7/7.7 mmHg for the 300/5 mg and 300/10 mg strengths 

respectively compared to aliskiren 300 mg (the subset constitutes patients without aberrant readings, 

defined as difference in systolic blood pressure (SBP) ≥10 mmHg at baseline or endpoint). 

 

In a study in 847 randomised patients not adequately responsive to amlodipine 10 mg treatment, the 

combination of aliskiren/amlodipine 150 mg/10 mg and 300 mg/10 mg produced systolic/diastolic 

mean blood pressure reductions of 11.0/9.0 mmHg and 14.4/11.0 mmHg respectively, which were 

statistically greater than for amlodipine 10 mg monotherapy. In a subset of 549 patients, the 

combination of aliskiren/amlodipine produced additional systolic/diastolic mean blood pressure 

reductions of 4.0/2.2 mmHg and 7.6/4.7 mmHg for the 150/10 mg and 300/10 mg strengths 

respectively compared to amlodipine 10 mg (the subset constitutes patients without aberrant readings, 

defined as difference in SBP ≥10 mmHg at baseline or endpoint). 

 

In a study in 545 randomised patients not adequately responsive to 5 mg amlodipine, the combination 

of aliskiren 150 mg/amlodipine 5 mg resulted in greater blood pressure reduction than those patients 

remaining on amlodipine 5 mg. 

 



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In an 8-week randomised, double-blind, placebo-controlled, parallel group factorial study in 

1,688 randomised patients with mild to moderate hypertension, treatment with Rasilamlo at doses 

from 150 mg/5 mg to 300 mg/10 mg produced dose-dependent clinically meaningful mean blood 

pressure reductions (systolic/diastolic) ranging between 20.6/14.0 mmHg and 23.9/16.5 mmHg, 

respectively, compared to 15.4/10.2 mmHg for aliskiren 300 mg, 21.0/13.8 mmHg for amlodipine 

10 mg and 6.8/5.4 mmHg with placebo in a population of patients with mean baseline blood pressure 

of 157.3/99.7 mmHg. These were statistically significant versus placebo and aliskiren for all doses. 

The blood pressure reductions with the combination were maintained throughout the entire 24-hour 

dose interval. In a subset of 1,069 patients, Rasilamlo produced mean blood pressure reductions 

(systolic/diastolic) ranging between 20.6/13.6 mmHg and 24.2/17.3 mmHg (the subset of patients 

without aberrant readings, defined as difference in SBP ≥10 mmHg at baseline or endpoint). 

 

The safety of Rasilamlo has been evaluated in studies of up to one year duration. 

 

The effects of Rasilamlo on all cause and cardiovascular mortality and on cardiovascular morbidity 

and target organ damage are currently unknown. 

 

Rasilamlo has been administered to more than 2,800 patients in completed clinical trials, including 

372 patients for one year or more. Treatment with Rasilamlo at doses up to 300 mg/10 mg had an 

overall incidence of adverse experiences similar to the component monotherapies. The incidence of 

adverse events did not show any association with gender, age, body mass index, race or ethnicity. 

There were no new adverse reactions which occurred specifically with Rasilamlo in addition to those 

known to be associated with the individual monotherapies. In a double-blind, randomised placebo-

controlled study in 1,688 patients with mild or moderate hypertension, discontinuation of therapy due 

to a clinical adverse event occurred in 1.7% of patients treated with Rasilamlo versus 1.5% of 

patients given placebo. 

 

Aliskiren 

Aliskiren is an orally active, non-peptide, potent and selective direct inhibitor of human renin. 

 

By inhibiting the enzyme renin, aliskiren inhibits the RAAS at the point of activation, blocking the 

conversion of angiotensinogen to angiotensin I and decreasing levels of angiotensin I and 

angiotensin II. Whereas other medicinal products that inhibit the RAAS (ACEI and angiotensin II 

receptor blockers (ARB)) cause a compensatory rise in plasma renin activity (PRA), treatment with 

aliskiren decreases PRA in hypertensive patients by approximately 50 to 80%. Similar reductions 

were found when aliskiren was combined with other antihypertensive medicinal products. The 

clinical implications of the differences in effect on PRA are not known at the present time. 

 

Hypertension 

In hypertensive patients, once-daily administration of 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, and was independent of age, gender, body mass 

index and ethnicity. Aliskiren has been studied in 1,864 patients aged 65 years or older, and in 

426 patients aged 75 years or older. 

 

Aliskiren monotherapy studies have shown blood-pressure-lowering effects comparable to other 

classes of antihypertensive medicinal products including selected ACEI and ARB. Compared to a 

diuretic (hydrochlorothiazide, HCTZ), aliskiren 300 mg lowered systolic/diastolic blood pressure by 

17.0/12.3 mmHg, compared to 14.4/10.5 mmHg for HCTZ 25 mg after 12 weeks of treatment. 

 

Combination therapy studies are available for aliskiren added to the diuretic hydrochlorothiazide and 

the beta blocker atenolol. These combinations were well tolerated. Aliskiren induced an additive 

blood-pressure-lowering effect when added to hydrochlorothiazide. 



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The efficacy and safety of aliskiren-based therapy were compared to ramipril-based therapy in a 9-

month non-inferiority study in 901 elderly patients (≥65 years) with essential systolic hypertension. 

Aliskiren 150 mg or 300 mg per day or ramipril 5 mg or 10 mg per day were administered for 

36 weeks with optional add-on therapy of hydrochlorothiazide (12.5 mg or 25 mg) at week 12, and 

amlodipine (5 mg or 10 mg) at week 22. Over the 12 week period, aliskiren monotherapy lowered 

systolic/diastolic blood pressure by 14.0/5.1 mmHg, compared to 11.6/3.6 mmHg for ramipril, 

consistent with aliskiren being non-inferior to ramipril at the dosages chosen and the differences in 

systolic and diastolic blood pressure were statistically significant. Tolerability was comparable in 

both treatment arms, however cough was more often reported with the ramipril regimen than the 

aliskiren regimen (14.2% vs. 4.4%), whilst diarrhoea was more common with the aliskiren regimen 

than for the ramipril regimen (6.6% vs. 5.0%). 

 

In a 8-week study in 754 hypertensive elderly (≥65 years) and very elderly patients (30% ≥75 years) 

aliskiren at doses of 75 mg, 150 mg and 300 mg provided statistically significant superior reduction 

in blood pressure (both systolic and diastolic) when compared to placebo. No additional blood 

pressure lowering effect was detected with 300 mg aliskiren compared to 150 mg aliskiren. All three 

doses were well tolerated in both elderly and very elderly patients. 

 

There has been no evidence of first-dose hypotension and no effect on pulse rate in patients treated in 

controlled clinical studies. Excessive hypotension was uncommonly (0.1%) seen in patients with 

uncomplicated hypertension treated with aliskiren alone. Hypotension was also uncommon (<1%) 

during combination therapy with other antihypertensive medicinal products. With cessation of 

treatment, blood pressure gradually returned towards baseline levels over a period of several weeks, 

with no evidence of a rebound effect for blood pressure or PRA. 

 

In a 36-week study involving 820 patients with ischaemic left ventricular dysfunction, no changes in 

ventricular remodelling as assessed by left ventricular end systolic volume were detected with 

aliskiren compared to placebo on top of background therapy. 

 

The combined rates of cardiovascular death, hospitalisation for heart failure, recurrent heart attack, 

stroke and resuscitated sudden death were similar in the aliskiren group and the placebo group. 

However, in patients receiving aliskiren there was a significantly higher rate of hyperkalaemia, 

hypotension and kidney dysfunction when compared to the placebo group. 

 

Aliskiren was evaluated for cardiovascular and/or renal benefit in a double-blind placebo controlled 

randomised trial in 8,606 patients with type 2 diabetes and chronic kidney disease (evidenced by 

proteinuria and/or GFR <60 ml/min/1.73 m2) with or without cardiovascular disease. In most patients 

arterial blood pressure was well controlled at baseline. The primary endpoint was a composite of 

cardiovascular and renal complications. 

 

In this study, aliskiren 300 mg was compared to placebo when added to standard of care which 

included either an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. The 

study was discontinued prematurely because the participants were unlikely to benefit from aliskiren. 

The final study results indicated a hazard ratio for the primary endpoint of 1.097 in favour of placebo 

(95.4% Confidence Interval: 0.987, 1.218, 2-sided p=0.0787). In addition, an increased incidence of 

adverse events was observed with aliskiren compared to placebo (38.2% versus 30.3%). In particular 

there was an increased incidence of renal dysfunction (14.5% versus 12.4%), hyperkalaemia (39.1% 

versus 29.0%), hypotension-related events (19.9% versus 16.3%) and adjudicated stroke endpoints 

(3.4% versus 2.7%). The increased incidence of stroke was greater in patients with renal 

insufficiency. 

 



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Aliskiren 150 mg (increased to 300 mg if tolerated) added to conventional therapy was evaluated in a 

double-blind placebo-controlled randomised trial in 1,639 patients with reduced ejection fraction 

hospitalised for an episode of acute heart failure (NYHA Class III–IV) who were haemodynamically 

stable at baseline. The primary endpoint was cardiovascular death or heart failure rehospitalisation 

within 6 months; secondary endpoints were assessed within 12 months. 

 

The study showed no benefit of aliskiren when administered on top of standard therapy for acute 

heart failure and an increased risk of cardiovascular events in patients with diabetes mellitus. Study 

results indicated a non-significant effect of aliskiren with a hazard ratio of 0.92 (95% Confidence 

Interval: 0.76-1.12; p=0.41, aliskiren vs. placebo). Different treatment effects of aliskiren were 

reported for overall mortality within 12 months dependent on diabetes mellitus status. In the subgroup 

of patients with diabetes mellitus the hazard ratio was 1.64 in favour of placebo (95% Confidence 

Interval: 1.15-2.33), whereas the hazard ratio in the subgroup of patients without diabetes was 0.69 in 

favour of aliskiren (95% Confidence Interval: 0.50-0.94); p-value for interaction = 0.0003. An 

increased incidence of hyperkalaemia (20.9% versus 17.5%), renal impairment/renal failure (16.6% 

versus 12.1%) and hypotension (17.1% versus 12.6%) was observed in the aliskiren group compared 

with placebo and was greater in patients with diabetes. 

 

Effects of aliskiren on mortality and cardiovascular morbidity are currently unknown. 

 

No long-term efficacy data for aliskiren in patients with heart failure are currently available. 

 

Cardiac electrophysiology 

No effect on QT interval was reported in a randomised, double-blind, placebo, and active-controlled 

study using standard and Holter electrocardiography. 

 

Amlodipine 

The amlodipine component of Rasilamlo inhibits the transmembrane entry of calcium ions into 

cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is 

due to a direct relaxant effect on vascular smooth muscle, causing reductions in peripheral vascular 

resistance and in blood pressure. Experimental data suggest that amlodipine binds to both 

dihydropyridine and non-dihydropyridine binding sites. 

 

The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the 

movement of extracellular calcium ions into these cells through specific ion channels. 

 

Following administration of therapeutic doses to patients with hypertension, amlodipine produces 

vasodilatation resulting in a reduction of supine and standing blood pressures. These decreases in 

blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine 

levels with chronic dosing. 

 

Plasma concentrations correlate with effect in both young and elderly patients. 

 

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a 

decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal 

plasma flow without change in filtration fraction or proteinuria. 

 

As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest and 

during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have 

generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on 

left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been 

associated with a negative inotropic effect when administered in the therapeutic dose range to intact 

animals and humans, even when co-administered with beta blockers to humans. 

 



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Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals 

or humans. In clinical studies in which amlodipine was administered in combination with beta 

blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic 

parameters were observed. 

 

Amlodipine has demonstrated beneficial clinical effects in patients with chronic stable angina, 

vasospastic angina and angiographically documented coronary artery disease. 

 

Use in patients with heart failure 

Calcium channel blockers, including amlodipine, should be used with caution in patients with 

congestive heart failure, as they may increase the risk of future cardiovascular events and mortality. 

 

Use in patients with hypertension 

A randomised double-blind morbidity-mortality study called the Antihypertensive and Lipid-

Lowering treatment to prevent Heart Attack Trial (ALLHAT) was performed to compare newer 

therapies: amlodipine 2.5-10 mg/day (calcium channel blocker) or lisinopril 10-40 mg/day (ACE-

inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/day in mild 

to moderate hypertension. 

 

A total of 33,357 hypertensive patients aged 55 or older were randomised and followed for a mean of 

4.9 years. The patients had at least one additional coronary heart disease risk factor, including: 

previous myocardial infarction or stroke (>6 months prior to enrollment) or documentation of other 

atherosclerotic cardiovascular disease (overall 51.5%), type 2 diabetes (36.1%), high density 

lipoprotein - cholesterol <35 mg/dl or <0.906 mmol/l (11.6%), left ventricular hypertrophy diagnosed 

by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%). 

 

The primary endpoint was a composite of fatal coronary heart disease or non-fatal myocardial 

infarction. There was no significant difference in the primary endpoint between amlodipine-based 

therapy and chlorthalidone-based therapy: risk ratio (RR) 0.98 95% CI (0.90-1.07) p=0.65. Among 

secondary endpoints, the incidence of heart failure (component of a composite combined 

cardiovascular endpoint) was significantly higher in the amlodipine group as compared to the 

chlorthalidone group (10.2% vs 7.7%, RR 1.38, 95% CI [1.25-1.52] p<0.001). However, there was 

no significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-

based therapy RR 0.96 95% CI [0.89-1.02] p=0.20. 

 

Paediatric population 

The European Medicines Agency has waived the obligation to submit the results of studies with 

Rasilamlo in all subsets of the paediatric population in essential hypertension (see section 4.2 for 

information on paediatric use). 

 

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 Cmax 
by 85% and AUC by 70%. At steady state meals with low fat content reduce Cmax by 76% and AUC 

0-tau by 67% in hypertensive patients. 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. 

 

Transporters 

MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption 

and biliary excretion of aliskiren in pre-clinical studies. 

 



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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. 

 

Biotransformation and elimination 

The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as 

unchanged compound in the faeces (78%). Approximately 1.4% of the total oral dose is metabolised. 

The enzyme responsible for this metabolism is CYP3A4. Approximately 0.6% of the dose is 

recovered in urine following oral administration. Following intravenous administration, mean plasma 

clearance is approximately 9 l/h. 

 

Linearity 

Exposure to aliskiren increased more than in proportion to the increase in dose. After single dose 

administration in the dose range of 75 to 600 mg, a 2-fold increase in dose results in a ~2.3 and 2.6-

fold increase in AUC and Cmax, respectively. At steady state the non-linearity may be more 

pronounced. Mechanisms responsible for deviation from linearity have not been identified. A possible 

mechanism is saturation of transporters at the absorption site or at the hepatobiliary clearance route. 

 

Paediatric population 

In a pharmacokinetic study of aliskiren treatment in 39 paediatric hypertensive patients aged 6 to 

17 years given daily doses of 2 mg/kg or 6 mg/kg aliskiren administered as granules 

(3.125 mg/tablet), pharmacokinetic parameters were similar to those in adults. The results of this 

study did not suggest that age, body weight or gender have any significant effect on aliskiren 

systemic exposure (see section 4.2). 

 

Results from an in vitro MDR1 human tissue study suggested an age and tissue dependent pattern of 

MDR1 (P-gp) transporter maturation. A high inter-individual variability of mRNA expression levels 

was observed (up to 600-fold). Hepatic MDR1 mRNA expression was statistically significantly lower 

in samples from foetuses, neonates and infants up to 23 months. 

 

The age at which the transporter system is mature cannot be determined. There is a potential for 

aliskiren overexposure in children with an immature MDR1 (P-gp) system (see “Transporters” above 

and sections 4.2, 4.4 and 5.3). 

 

Amlodipine 

Absorption 

After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations of 

amlodipine are reached in 6-12 hours. Absolute bioavailability has been estimated as between 64% 

and 80%. Amlodipine bioavailability is unaffected by food ingestion. 

 

Distribution 

The volume of distribution is approximately 21 l/kg. In vitro studies with amlodipine have shown that 

approximately 97.5% of circulating amlodipine is bound to plasma proteins. 

 

Biotransformation and elimination 

Amlodipine is extensively (approximately 90%) metabolised in the liver to inactive metabolites, with 

10% of the parent compound and 60% of the metabolites excreted in the urine. 

 

Amlodipine elimination from plasma is biphasic with a terminal elimination half-life of 

approximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration 

for 7-8 days. 

 

Linearity 

Amlodipine exhibits linear pharmacokinetics between the therapeutic dose range of 5 mg and 10 mg. 



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Aliskiren/amlodipine 

Following oral administration of Rasilamlo, the median peak plasma concentration time is within 

3 hours for aliskiren and 8 hours for amlodipine. The rate and extent of absorption of Rasilamlo are 

similar in fasting state to those of aliskiren and amlodipine when administered as individual 

monotherapies. A bioequivalence study under light meal conditions has not been conducted for 

Rasilamlo. 

 

The results from a food effect study using a standard high fat meal with the 300 mg/10 mg fixed 

combination tablet showed that food reduced the rate and extent of absorption of aliskiren in the 

fixed combination tablet with a similar magnitude of effect as for aliskiren monotherapy. Consistent 

with the monotherapy formulation, food had no effect on the pharmacokinetics of amlodipine in the 

fixed combination tablet. 

 

Characteristics in patients 

Aliskiren 

Aliskiren is an effective once-a-day antihypertensive treatment in adult patients, regardless of gender, 

age, body mass index and ethnicity. 

 

The AUC is 50% higher in elderly (>65 years) than in young subjects. Gender, weight and ethnicity 

have no clinically relevant influence on aliskiren pharmacokinetics. 

 

The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renal 

insufficiency. Relative AUC and Cmax of aliskiren in subjects with renal impairment ranged between 

0.8 to 2 times the levels in healthy subjects following single dose administration and at steady state. 

These observed changes, however, did not correlate with the severity of renal impairment. No 

adjustment of the initial dosage of aliskiren is required in patients with mild to moderate renal 

impairment (see sections 4.2 and 4.4). Aliskiren is not recommended in patients with severe renal 

impairment (glomerular filtration rate (GFR) <30 ml/min/1.73 m2). 

 

The pharmacokinetics of aliskiren were evaluated in patients with end stage renal disease receiving 

haemodialysis. Administration of a single oral dose of 300 mg aliskiren was associated with very 

minor changes in the pharmacokinetics of aliskiren (change in Cmax of less than 1.2 fold; increase in 

AUC of up to 1.6 fold) compared to matched healthy subjects. Timing of haemodialysis did not 

significantly alter the pharmacokinetics of aliskiren in ESRD patients. Therefore, if administration of 

aliskiren in ESRD patients receiving haemodialysis is considered necessary, no dose adjustment is 

warranted in these patients. However, the use of aliskiren is not recommended in patients with severe 

renal impairment (see section 4.4). 

 

The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe liver 

disease. Consequently, no adjustment of the initial dose of aliskiren is required in patients with mild 

to severe hepatic impairment. 

 

Amlodipine 

The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger 

subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and 

elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with 

congestive heart failure were as expected for the patient age group in this study (see section 4.4). 

 

A population pharmacokinetic study has been conducted in 74 hypertensive children aged from 1 to 

17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving 

amlodipine between 1.25 and 20 mg given either once or twice daily. In children 6 to 12 years and in 

adolescents 13-17 years of age the typical oral clearance (CL/F) was 22.5 and 27.4 l/hr respectively 

in males and 16.4 and 21.3 l/hr respectively in females. Large variability in exposure between 

individuals was observed. Data reported in children below 6 years are limited. 

 



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The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. 

 

Very limited clinical data are available regarding amlodipine administration in patients with hepatic 

impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine with 

resulting increase in AUC of approximately 40-60%. Therefore caution should be exercised in 

patients with hepatic impairment. 

 

5.3 Preclinical safety data 

 

Aliskiren 

Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic mouse study. No 

carcinogenic potential was detected. One colonic adenoma and one caecal adenocarcinoma recorded 

in rats at the dose of 1,500 mg/kg/day were not statistically significant. Although aliskiren has known 

irritation potential, safety margins obtained in humans at the dose of 300 mg during a study in healthy 

volunteers were considered to be appropriate at 9-11-fold based on faecal concentrations or 6-fold 

based on mucosa concentrations in comparison with 250 mg/kg/day in the rat carcinogenicity study. 

 

Aliskiren was devoid of any mutagenic potential in the in vitro and in vivo mutagenicity studies. The 

assays included in vitro assays in bacterial and mammalian cells and in vivo assessments in rats. 

 

Reproductive toxicity studies with aliskiren did not reveal any evidence of embryofoetal toxicity or 

teratogenicity at doses up to 600 mg/kg/day in rats or 100 mg/kg/day in rabbits. Fertility, pre-natal 

development and post-natal development were unaffected in rats at doses up to 250 mg/kg/day. The 

doses in rats and rabbits provided systemic exposures of 1 to 4 and 5 times higher, respectively, than 

the maximum recommended human dose (300 mg). 

 

Safety pharmacology studies did not reveal any adverse effects on central nervous, respiratory or 

cardiovascular function. Findings during repeat-dose toxicity studies in animals were consistent with 

the known local irritation potential or the expected pharmacological effects of aliskiren. 

 

Juvenile Animal Studies 

A repeat-dose toxicity study was conducted in juvenile rats 8 days post-partum for 4 weeks with 

aliskiren dosing at 30, 100 or 300 mg/kg/day. High acute mortality (within hours) and severe 

morbidity were observed at 100 and 300 mg/kg/day (2.3- and 6.8-fold the maximum recommended 

human dose (MRHD) on mg/m2 basis assuming a 60 kg adult patient) with no cause of death 

established and occurring without signs or prodromal symptoms. The ratio of lethal dose of 

100 mg/kg/day and no-observed-adverse-effect-level (NOAEL) of 30 mg/kg/day is unexpectedly low. 

 

Another repeat-dose toxicity study was conducted in juvenile rats 14 days post-partum for 8 weeks 

with aliskiren dosing at 30, 100 or 300 mg/kg/day. Delayed mortality was observed at 300 mg/kg/day 

(8.5-fold the MRHD on mg/m2 basis assuming a 60 kg adult patient) with no cause of death 

established. 

 

For the surviving juvenile rats, no effects on behavioural or reproductive performance were observed. 

 

Plasma aliskiren exposure (AUC) in rats aged 8 days was nearly 4-fold higher than that in rats aged 

14 days at 100 mg/kg/day. Plasma aliskiren exposure in rats aged 14 days was between 85- and 387-

fold higher than that in adult rats aged 64 days. 

 

A single dose study was conducted in juvenile rats aged 14, 21, 24, 28, 31 or 36 days post-partum. 

No mortality or significant toxicity was observed. The plasma exposure was approximately 100-fold 

higher in rats aged 14 days and 3-fold higher in rats aged 21 days compared to adult rats. 

 



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A mechanistic study was conducted to investigate the relationship between age, aliskiren exposure 

and MDR1 and OATP2 expression maturation in rats. The results showed that developmental 

changes of aliskiren exposure correlated with the ontogeny of transporter maturation in jejunum, liver, 

kidney and brain. 

 

The pharmacokinetics of aliskiren was evaluated in rats aged from 8 to 28 days after intravenous 

administration of aliskiren 3 mg/kg. The clearance of aliskiren increased in an age-dependent 

manner. Clearance in rats aged 8 or 14 days was similar, but at these ages the clearance was only 

about 23% of clearance in rats aged 21 days and 16% of clearance in rats aged 28 days. 

 

These studies indicate that excessive aliskiren exposure (>400-fold higher in 8-day old rats compared 

with adult rats) and high acute toxicity in juvenile rats are caused by immature MDR1, which 

suggests that in paediatric patients with immature MDR1, there is a potential for aliskiren 

overexposure (see sections 4.2, 4.3 and 5.2). 

 

Amlodipine 

Safety data for amlodipine are well established both clinically and non-clinically. 

 

Reproductive toxicology 

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of 

labour and decreased pup survival at dosages approximately 50 times greater than the maximum 

recommended dosage for humans based on mg/kg. 

 

Impairment of fertility 

There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 

14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human 

dose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipine 

besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma 

follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in 

the number of mature spermatids and Sertoli cells. 

 

Carcinogenesis, mutagenesis 

Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to 

provide daily dosage levels of 0.5, 1.25 and 2.5 mg/kg/day showed no evidence of carcinogenicity. 

The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose 

of 10 mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats. 

 

Mutagenicity studies revealed no effects related to the medicinal product at either the gene or 

chromosome levels. 

 

*Based on patient weight of 50 kg 

 

Rasilamlo 

Preclinical safety studies have demonstrated that the combination of aliskiren and amlodipine was 

well tolerated in rats. The findings from the 2- and 13-week oral toxicity studies in rats were 

consistent with those of aliskiren and amlodipine when both active substances are administered alone. 

There were no new toxicities or increased severity of the toxicities which were associated with either 

component. 

 

 



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6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Tablet core 

Cellulose microcrystalline 

Crospovidone 

Povidone 

Magnesium stearate 

Silica colloidal anhydrous 

 

Coating 

Hypromellose 

Titanium dioxide (E171) 

Macrogol 

Talc 

Iron oxide yellow (E172) 

Iron oxide red (E172) 

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

PVC/PCTFE – Alu blisters: 

18 months 

 

PA/Alu/PVC – Alu blisters: 

18 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 

 

PVC/polychlorotrifluoroethylene (PCTFE) - Alu calendar blisters: 

Single pack containing 14, 28, 56, 98 tablets 

Multi-packs containing 280 tablets (20 packs of 14) 

 

PVC/polychlorotrifluoroethylene (PCTFE) - Alu blisters: 

Single pack containing 30, 90 tablets 

Unit dose pack (perforated unit dose blister) containing 56x1 tablet 

Multi-packs of unit dose (perforated unit dose blister) containing 98x1 tablet (2 packs of 49x1) 

 

PA/Alu/PVC – Alu calendar blisters: 

Single pack containing 14, 28, 56 tablets 

Multi-packs containing 98 tablets (2 packs of 49) and 280 tablets (20 packs of 14) 

 

Not all pack sizes or strengths may be marketed. 

 



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6.6 Special precautions for disposal 

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/686/001-014 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 14 April 2011 

Date of latest renewal: 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this medicinal product is available on the website of the European 

Medicines Agency http://www.ema.europa.eu 

 



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1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 150 mg/10 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each film-coated tablet contains 150 mg aliskiren (as hemifumarate) and 10 mg amlodipine (as 

besylate). 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Film-coated tablet. 

 

Yellow, convex, ovaloid tablet with a bevelled edge, with “T7” debossed on one side and “NVR” on 

the other. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Rasilamlo is indicated for the treatment of essential hypertension in adult patients whose blood 

pressure is not adequately controlled with aliskiren or amlodipine used alone. 

 

4.2 Posology and method of administration 

 

Posology 

The recommended dose of Rasilamlo is one tablet per day. 

 

The antihypertensive effect is manifested within 1 week and the effect is near maximal at around 

4 weeks. If blood pressure remains uncontrolled after 4 to 6 weeks of therapy, the dose may be 

titrated up to a maximum of 300 mg aliskiren/10 mg amlodipine. Dose should be individualised and 

adjusted according to the patient’s clinical response. 

 

Rasilamlo may be administered with other antihypertensive medicinal products with the exception of 

use in combination with angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor 

blockers (ARB) in patients with diabetes mellitus or renal impairment (glomerular filtration rate 

(GFR) <60 ml/min/1.73 m2) (see sections 4.3, 4.4 and 5.1). 

 

Posology in patients not adequately controlled with aliskiren or amlodipine monotherapy  

Rasilamlo 150 mg/10 mg may be administered in patients whose blood pressure is not adequately 

controlled with amlodipine 10 mg alone or with Rasilamlo 150 mg/5 mg. 

 

A patient who experiences dose limiting adverse reactions on either component alone may be 

switched to Rasilamlo containing a lower dose of that component to achieve similar blood pressure 

reductions. 

 

Individual dose titration with each of the two components may be recommended before changing to 

the fixed combination. When clinically appropriate and in line with the above-mentioned posology, 

direct change from monotherapy to the fixed combination may be considered. 

 



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Special populations 

Renal impairment 

No adjustment of the initial dose is required for patients with mild to moderate renal impairment 

(GFR 89-60 ml/min/1.73 m2 and 59-30 ml/min/1.73 m2, respectively, see sections 4.4 and 5.2). 

Rasilamlo is not recommended in patients with severe renal impairment (GFR <30 ml/min/1.73 m2). 

 

Hepatic impairment 

Amlodipine dosage recommendations have not been established in patients with mild to moderate 

hepatic impairment. The pharmacokinetics of amlodipine have not been studied in severe hepatic 

impairment; therefore, caution should be exercised when administering Rasilamlo to patients with 

hepatic impairment. 

 

Elderly people (over 65 years) 

There is limited experience with Rasilamlo, in particular in patients aged 75 years or older. 

Therefore, particular caution should be exercised in these patients. The recommended starting dose of 

aliskiren in elderly patients is 150 mg. No clinically meaningful additional blood pressure reduction 

is observed by increasing the dose to 300 mg in the majority of elderly patients. 

 

Paediatric population 

The safety and efficacy of Rasilamlo in children below age 18 have not been established. No data are 

available. 

 

Rasilamlo is contraindicated in children from birth to less than 2 years and should not be used in 

children aged 2 to less than 6 years because of safety concerns due to potential aliskiren overexposure 

(see sections 4.3, 4.4, 5.2, and 5.3). 

 

Method of administration 

Oral use. The tablets should be swallowed whole with some water. Rasilamlo should be taken with a 

light meal once a day, preferably at the same time each day. Concomitant intake with fruit juice 

and/or drinks containing plant extracts (including herbal teas) should be avoided (see section 4.5). 

 

4.3 Contraindications 

 

 Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or 
other dihydropyridine derivatives. 

 History of angioedema with aliskiren. 

 Hereditary or idiopathic angioedema 

 Second and third trimesters of pregnancy (see section 4.6). 

 The concomitant use of aliskiren with ciclosporin and itraconazole, two highly potent P-
glycoprotein (P-gp) inhibitors, and other potent P-gp inhibitors (e.g. quinidine), is 

contraindicated (see section 4.5). 

 The concomitant use of Rasilamlo with an ACEI or an ARB is contraindicated in patients with 
diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) (see sections  4.5 and 5.1). 

 Severe hypotension. 

 Shock (including cardiogenic shock). 

 Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis). 

 Haemodynamically unstable heart failure after acute myocardial infarction. 

 Children from birth to less than 2 years (see sections 4.2 and 5.3). 
 



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4.4 Special warnings and precautions for use 

 

General 

In the event of severe and persistent diarrhoea, Rasilamlo therapy should be stopped (see section 4.8). 

 

As with any antihypertensive medicinal product, excessive reduction of blood pressure in patients 

with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial 

infarction or stroke. 

 

The safety and efficacy of amlodipine in hypertensive crisis have not been established. 

 

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) 

Hypotension, syncope, stroke, hyperkalaemia, and decreased renal function (including acute renal 

failure) have been reported in susceptible individuals, especially if combining medicinal products that  

affect this system (see section 5.1). Dual blockade of the RAAS by combining aliskiren with an ACEI 

or an ARB is therefore not recommended. If dual blockade therapy is considered absolutely 

necessary, this should only occur under specialist supervision and subject to frequent close monitoring 

of renal function, electrolytes and blood pressure. 

 

Heart failure 

Calcium channel blockers, including amlodipine, should be used with caution in patients with 

congestive heart failure, as they may increase the risk of future cardiovascular events and mortality. 

 

No data on cardiovascular mortality and morbidity are available for aliskiren in patients with heart 

failure (see section 5.1). 

 

Aliskiren should be used with caution in patients with heart failure treated with furosemide or 

torasemide (see section 4.5). 

 

Risk of symptomatic hypotension 

Symptomatic hypotension could occur after initiation of treatment with Rasilamloin the following 

cases: 

 Patients with marked volume depletion or patients with salt depletion (e.g. those receiving high 
doses of diuretics) or 

 Combined use of aliskiren with other agents acting on the RAAS. 
The volume or salt depletion should be corrected prior to administration of Rasilamlo, or the 

treatment should start under close medical supervision. In patients with uncomplicated hypertension 

treated with Rasilamlo in short-term controlled trials, the incidence of hypotension was low (0.2%). 

 

Renal impairment 

In clinical studies aliskiren has not been investigated in hypertensive patients with severe renal 

impairment (serum creatinine ≥150 μmol/l or 1.70 mg/dl in women and ≥177 μmol/l or 2.00 mg/dl in 

men and/or estimated GFR <30 ml/min/1.73 m2), history of dialysis, nephrotic syndrome or 

renovascular hypertension. Rasilamlo is not recommended in patients with severe renal impairment 

(GFR <30 ml/min/1.73 m2). 

 

As for other medicinal products acting on the renin-angiotensin-aldosterone system, caution should be 

exercised when Rasilamlo 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, diabetes mellitus 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. 

 



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Increases in serum potassium have been observed with aliskiren in post-marketing experience and 

these may be exacerbated by concomitant use of other agents acting on the RAAS or by non-steroidal 

anti-inflammatory drugs (NSAIDs). Consistent with standard medical practice, periodic 

determination of renal function including serum electrolytes is advised if co-administration is 

considered necessary. 

 

Hepatic impairment 

The half life of amlodipine is prolonged and AUC values are higher in patients with impaired liver 

function; dosage recommendations have not been established. Caution should be exercised when 

administering Rasilamlo to patients with hepatic impairment (see sections 4.2 and 5.2). 

 

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy 

As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral 

stenosis, or obstructive hypertrophic cardiomyopathy. 

 

Renal artery stenosis 

No controlled clinical data are available on the use of Rasilamlo in patients with unilateral or 

bilateral renal artery stenosis, or stenosis to a solitary kidney. However, as with other medicinal 

products acting on the renin-angiotensin-aldosterone system, there is an increased risk of renal 

insufficiency, including acute renal failure, when patients with renal artery stenosis are treated with 

aliskiren. Therefore caution should be exercised in these patients. If renal failure occurs, treatment 

should be discontinued. 

 

Anaphylactic reactions and angioedema 

Anaphylactic reactions have been observed during treatment with aliskiren from post-marketing 

experience (see section 4.8). As with other medicinal products acting on the renin-angiotensin-

aldosterone system, angioedema or symptoms suggestive of angioedema (swelling of the face, lips, 

throat and/or tongue) have been reported in patients treated with aliskiren. 

 

A number of these patients had a history of angioedema or symptoms suggestive of angioedema, 

which in some cases followed use of other medicinal products that can cause angioedema, including 

RAAS blockers (angiotensin converting enzyme inhibitors or angiotensin receptor blockers) (see 

section 4.8). 

 

In post-marketing experience, angioedema or angioedema-like reactions have been reported when 

aliskiren was co-administered with ACEIs and/or ARBs (see section 4.8). 

 

Special caution is necessary in patients with a hypersensitivity predisposition. 

 

Patients with history of angioedema may be at increased risk of experiencing angioedema during 

treatment with aliskiren (see sections 4.3 and 4.8). Caution should therefore be exercised when 

prescribing aliskiren to patients with a history of angioedema, and such patients should be closely 

monitored during treatment (see section 4.8) especially at the beginning of the treatment. 

 

If anaphylactic reactions or angioedema occur, Rasilamlo should be promptly discontinued and 

appropriate therapy and monitoring provided until complete and sustained resolution of signs and 

symptoms has occurred. Patients should be informed to report to the physician any signs suggestive of 

allergic reactions, in particular difficulties in breathing or swallowing, swelling of face, extremities, 

eyes, lips or tongue. Where there is involvement of the tongue, glottis or larynx adrenaline should be 

administered. In addition, measures necessary to maintain patent airways should be provided. 

 



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Paediatric population 

Aliskiren is a P-glycoprotein (P-gp) substrate, and there is a potential for aliskiren overexposure in 

children with an immature P-gp drug transporter system. The age at which the transporter system is 

mature cannot be determined (see sections 5.2 and 5.3). Therefore, Rasilamlo is contraindicated in 

children from birth to less than 2 years and should not be used in children aged 2 to less than 6 years. 

 

Limited safety data are available from a pharmacokinetic study of aliskiren treatment in 39 

hypertensive children aged 6 to less than 18 years (see sections 4.8 and 5.2). 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Information on Rasilamlo interactions 

No interaction studies with other medicinal products were performed with Rasilamlo. Therefore, 

information on interactions with other medicinal products that are known for the individual active 

substances is provided in this section. 

 

Co-administration of aliskiren and amlodipine does not cause meaningful changes in the steady-state 

pharmacokinetic exposure (AUC) and the maximum concentration (Cmax) of either component in 

healthy volunteers. 

 

Information on aliskiren interactions 

Contraindicated (see section 4.3) 

- P-gp potent inhibitors 
A single dose drug interaction study in healthy subjects has shown that ciclosporin (200 and 600 mg) 

increases Cmax of aliskiren 75 mg approximately 2.5-fold and AUC approximately 5-fold. The 

increase may be higher with higher aliskiren doses. In healthy subjects, itraconazole (100 mg) 

increases AUC and Cmax of aliskiren (150 mg) by 6.5-fold and 5.8-fold, respectively. Therefore, 

concomitant use of aliskiren and P-gp potent inhibitors is contraindicated (see section 4.3). 

 

Not recommended (see section 4.2) 

- Fruit juice and drinks containing plant extracts 
Administration of fruit juice with aliskiren resulted in a decrease in AUC and Cmax of aliskiren. Co-

administration of grapefruit juice with aliskiren 150 mg resulted in a 61% decrease in aliskiren AUC 

and co-administration with aliskiren 300 mg resulted in a 38% decrease in aliskiren AUC. Co-

administration of orange or apple juice with aliskiren 150 mg resulted in a 62% decrease in aliskiren 

AUC or in a 63% decrease in aliskiren AUC, respectively. This decrease is likely due to an 

inhibition of organic anion transporting polypeptide-mediated uptake of aliskiren by components of 

fruit juice in the gastrointestinal tract. Therefore, because of the risk of therapeutic failure, fruit juice 

should not be taken together with Rasilamlo. The effect of drinks containing plant extracts (including 

herbal teas) on the absorption of aliskiren has not been investigated. However, compounds potentially 

inhibiting organic anion transporting polypeptide-mediated uptake of aliskiren are widely present in 

fruits, vegetables, and many other plant products. Therefore, drinks containing plant extracts, 

including herbal teas, should not be taken together with Rasilamlo. 

 

Dual blockade of the RAAS with aliskiren, ARBs or ACEIs 

Clinical trial data has shown that dual blockade of the RAAS through the combined use of ACEIs, 

ARBs or aliskiren is associated with a higher frequency of adverse events such as hypotension, stroke, 

hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a 

single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). 

 



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Caution required with concomitant use 

- P-gp 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 (see section 5.2). Rifampicin, which is an 

inducer of P-gp, reduced aliskiren bioavailability by approximately 50% in a clinical study. Other 

inducers of P-gp (St. John’s wort) might decrease the bioavailability of 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. 

 

- Moderate P-gp inhibitors 
Co-administration of ketoconazole (200 mg) or verapamil (240 mg) with aliskiren (300 mg) resulted 

in a 76% or 97% increase in aliskiren AUC, respectively. The change in plasma levels of aliskiren in 

the presence of ketoconazole or verapamil is expected to be within the range that would be achieved 

if the dose of aliskiren were doubled; aliskiren doses of up to 600 mg, or twice the highest 

recommended therapeutic dose, have been found to be well tolerated in controlled clinical trials. 

Preclinical studies indicate that aliskiren and ketoconazole co-administration enhances aliskiren 

gastrointestinal absorption and decreases biliary excretion. Therefore, caution should be exercised 

when aliskiren is administered with ketoconazole, verapamil or other moderate P-gp inhibitors 

(clarithromycin, telithromycin, erythromycin, amiodarone). 

 

- Medicinal products affecting serum potassium levels 
Concomitant use of other agents affecting the RAAS, of NSAIDs or of agents that increase serum 

potassium levels (e.g. potassium-sparing diuretics, potassium supplements, salt substitutes containing 

potassium, heparin) may lead to increases in serum potassium. If co-medication with an agent 

affecting the level of serum potassium is considered necessary, caution is advisable. 

 

- Non-steroidal anti-inflammatory drugs (NSAIDs) 
As with other medicinal products acting on the renin-angiotensin-aldosterone 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. 

 

- Furosemide and torasemide 
Oral co-administration of aliskiren and furosemide had no effect on the pharmacokinetics of aliskiren 

but reduced exposure to furosemide by 20-30% (the effect of aliskiren on furosemide administered 

intramuscularly or intravenously has not been investigated). After multiple doses of furosemide 

(60 mg/day) co-administered with aliskiren (300 mg/day) to patients with heart failure the urinary 

sodium excretion and the urine volume were reduced during the first 4 hours by 31% and 24%, 

respectively, as compared to furosemide alone. The mean weight of patients concomitantly treated 

with furosemide and 300 mg aliskiren (84.6 kg) was higher than the weight of patients treated with 

furosemide alone (83.4 kg). Smaller changes in furosemide pharmacokinetics and efficacy were 

observed with aliskiren 150 mg/day.  

 

The available clinical data did not indicate that higher doses of torasemide were used after co-

administration with aliskiren. Torasemide renal excretion is known to be mediated by organic anion 

transporters (OATs). Aliskiren is minimally excreted via the renal route, and only 0.6% of the 

aliskiren dose is recovered in urine following oral administration (see section 5.2). However, since 

aliskiren has been shown to be a substrate for the organic anion-transporting polypeptide 1A2 

(OATP1A2) (see interaction with organic anion transporting polypeptide (OATP) inhibitors), there is 

a potential for aliskiren to reduce plasma torasemide exposure by an interference with the absorption 

process. 



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In patients treated with both aliskiren and oral furosemide or torasemide, it is therefore recommended 

that the effects of furosemide or torasemide be monitored when initiating and adjusting furosemide, 

torasemide or aliskiren therapy to avoid changes in extracellular fluid volume and possible situations 

of volume overload (see section 4.4). 

 

- Warfarin 
The effects of aliskiren on warfarin pharmacokinetics have not been evaluated. 

 

- Food interactions 
Meals (low or high fat content) have been shown to reduce the absorption of aliskiren substantially 

(see section 4.2). The available clinical data do not suggest an additive effect of different types of 
foods and/or drinks, however the potential for decreased aliskiren bioavailability due to this additive 

effect has not been studied and therefore cannot be excluded. Concomitant administration of aliskiren 

with fruit juice or drinks containing plant extracts, including herbal teas, should be avoided. 

 

No interactions 

- Compounds that have been investigated in aliskiren clinical pharmacokinetic studies include 
acenocoumarol, atenolol, celecoxib, pioglitazone, allopurinol, isosorbide-5-mononitrate and 

hydrochlorothiazide. No interactions have been identified. 

 

- Co-administration of aliskiren with either metformin (↓28%), amlodipine (↑29%) or cimetidine 
(↑19%) resulted in between 20% and 30% change in Cmax or AUC of aliskiren. When 

administered with atorvastatin, steady-state aliskiren AUC and Cmax increased by 50%. Co-

administration of aliskiren had no significant impact on atorvastatin, metformin or amlodipine 

pharmacokinetics. As a result no dose adjustment for aliskiren or these co-administered 

medicinal products is necessary. 

 

- Digoxin and verapamil bioavailability may be slightly decreased by aliskiren. 
 

- CYP450 interactions 
Aliskiren does not inhibit the CYP450 isoenzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A). 

Aliskiren does not induce CYP3A4. Therefore aliskiren is not expected to affect the systemic 

exposure of substances that inhibit, induce or are metabolised by these enzymes. Aliskiren is 

metabolised minimally by the cytochrome P450 enzymes. Hence, interactions due to inhibition or 

induction of CYP450 isoenzymes are not expected. However, CYP3A4 inhibitors often also affect P-

gp. Increased aliskiren exposure during co-administration of CYP3A4 inhibitors that also inhibit P-gp 

can therefore be expected (see other P-gp references in section 4.5). 

 

- P-gp substrates or weak inhibitors 
No relevant interactions with atenolol, digoxin, amlodipine or cimetidine have been observed. When 

administered with atorvastatin (80 mg), steady-state aliskiren (300 mg) AUC and Cmax increased by 

50%. In experimental animals, it has been shown that P-gp is a major determinant of aliskiren 

bioavailability. Inducers of P-gp (St. John’s wort, rifampicin) might therefore decrease the 

bioavailability of aliskiren. 

 

- Organic anion transporting polypeptide (OATP) inhibitors 

Preclinical studies indicate that aliskiren might be a substrate of organic anion transporting 

polypeptides. Therefore, the potential exists for interactions between OATP inhibitors and aliskiren 

when administered concomitantly (see interaction with fruit juice). 

 



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Information on amlodipine interactions 

Effects of other medicinal products on amlodipine 

Caution required with concomitant use 

- CYP3A4 inhibitors 
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, 

azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give 

rise to significant increase in amlodipine exposure. The clinical translation of these pharmacokinetic 

variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus 

be required. 

 

- CYP3A4 inducers 
There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant 

use of CYP3A4 inducers (e.g. rifampicin, hypericum perforatum) may give a lower plasma 

concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 

inducers. 

 

- Grapefruit juice 
Administration of amlodipine with grapefruit or grapefruit juice is not recommended as 

bioavailability may be increased in some patients, resulting in increased blood pressure lowering 

effects. 

 

- Dantrolene (infusion) 
In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with 

hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of 

hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as 

amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of 

malignant hyperthermia. 

 

Effects of amlodipine on other medicinal products 

- The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects 
of other antihypertensive medicinal products. 

 

- Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in 
a 77% increase in exposure to simvastatin compared to simvastatin alone. It is recommended to 

limit the dose of simvastatin to 20 mg daily in patients on amlodipine. 

 

No interactions 

- In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, 
digoxin, warfarin or ciclosporin. 

 

4.6 Fertility, pregnancy and lactation 

 

Women of child-bearing potential/contraception in males and females 

Healthcare professionals prescribing Rasilamlo should counsel women of childbearing potential about 

the potential risk during pregnancy. A switch to a suitable alternative antihypertensive treatment 

should be carried out in advance of a planned pregnancy since Rasilamlo should not be used in 

women planning to become pregnant. 

 

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 RAAS have been associated with 

serious foetal malformations and neonatal death. As for any medicine that acts directly on the RAAS, 

aliskiren should not be used during the first trimester of pregnancy and is contraindicated during the 

second and third trimesters (see section 4.3). 

 



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The safety of amlodipine in human pregnancy has not been established. Reproductive studies in rats 

have shown no toxicity except for delayed date of delivery and prolonged duration of labour at 

dosages 50 times greater than the maximum recommended dosage for humans (see section 5.3). Use 

in pregnancy is only recommended when there is no safer alternative and when the disease itself 

carries greater risk for the mother and foetus. 

 

Rasilamlo should not be used during the first trimester of pregnancy. Rasilamlo is contraindicated 

during the second and third trimesters (see section 4.3). 

 

If pregnancy is detected during therapy, Rasilamlo should be discontinued accordingly as soon as 

possible. 

 

Breast-feeding 

It is unknown whether aliskiren and/or amlodipine are excreted in human milk. Aliskiren was 

secreted in the milk of lactating rats. 

 

Since there is insufficient/limited information on the excretion of aliskiren and amlodipine in human 

or animal breast milk, a risk to the newborns/infants cannot be excluded. It is therefore not 

recommended for women who are breast-feeding to use Rasilamlo. 

 

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from 

Rasilamlo therapy taking into account the benefit of breast-feeding for the child and the benefit of 

therapy for the woman. 

 

Fertility 

There are no clinical data on fertility with the use of Rasilamlo. 

 

Reversible biochemical changes in the head of spermatozoa have been reported in some patients 

treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of 

amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3). 

The fertility of rats was unaffected at doses of up to aliskiren 250 mg/kg/day (see section 5.3). 

 

4.7 Effects on ability to drive and use machines 

 

When driving vehicles or using machines it must be borne in mind that dizziness or drowsiness may 

occasionally occur when taking Rasilamlo. 

 

Amlodipine can have minor or moderate influence on the ability to drive and use machines. If 

patients taking amlodipine suffer from dizziness, headache, fatigue or nausea, the ability to react may 

be impaired. 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

The safety profile of Rasilamlo presented below is based on clinical studies performed with 

Rasilamlo and the known safety profile of the individual components aliskiren and amlodipine. 

Safety information for Rasilamlo in patients aged 75 years and older is limited. 

 

The most frequent adverse reactions for Rasilamlo are hypotension and peripheral oedema. The 

adverse reactions previously reported with one of the individual components of Rasilamlo (aliskiren 

and amlodipine) and included in the tabulated list of adverse reactions may occur with Rasilamlo. 

 



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Tabulated list of adverse reactions: 

The adverse reactions are ranked by frequency, the most frequent first, 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, adverse reactions are presented in order of decreasing 

seriousness. The adverse reactions observed with Rasilamlo or with monotherapy with one or both of 

the two components are included in the table below. For adverse reactions observed with more than 
one component of a fixed-dose combination, the highest frequency is listed in the table below. 

 

Blood and lymphatic system disorders 

Very rare Leukopeniaam, thrombocytopeniaam 

Immune system disorders 

Rare Anaphylactic reactionsa, hypersensitivity 

reactionsa 

Very rare Allergic reactionsam 

Metabolism and nutrition disorders 

Very rare Hyperglycaemiaam 

Psychiatric disorders 

Uncommon Insomniaam, mood changes (including anxiety)am, 

depressionam 

Rare Confusionam 

Nervous system disorders 

Common Somnolenceam, headache (especially at the 

beginning of treatment)am 

Uncommon Tremoram, dysgeusiaam, syncopeam, hypoesthesiaam, 

paraesthesiaam 

Very rare Hypertoniaam, peripheral neuropathyam 

Eye disorders 

Uncommon Visual disturbance (including diplopia)am 

Ear and labyrinth disorders 

Uncommon Tinnitusam 

Not known Vertigoa 

Cardiac disorders 

Common Dizzinessa,am, palpitationsa,am, peripheral 

oedemac,a,am* 

Very rare Myocardial infarctionam, arrhythmia (including 

bradycardia, ventricular tachycardia, and atrial 

fibrillation)am 

Vascular disorders 

Common Flushingam, hypotensionc,a,am 

Very rare Vasculitisam 

Respiratory, thoracic and mediastinal disorders 

Uncommon Dyspnoeaa, am, rhinitisam, cougha,am 

Gastrointestinal disorders 

Common Diarrhoeaa, abdominal painam, nauseaa,am 

Uncommon Vomitinga,am, dyspepsiaam, altered bowel habits 

(including diarrhoea and constipation)am, dry 

moutham 

Very rare Pancreatitisam, gastritisam, gingival hyperplasiaam 

Hepatobiliary disorders 

Very rare Hepatitisa,am, jaundicea,am, hepatic enzymes 

increased (mostly consistent with cholestasis)am 

Not known Liver disordera,**, liver failurea,*** 



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Skin and subcutaneous tissue disorders 

Uncommon Severe cutaneous adverse reactions (SCARs) 

including Stevens Johnson syndromea, toxic 

epidermal necrolysis (TEN)a, oral mucosal 

reactionsa, rasha,am, pruritusa,am, urticariaa,am, 

alopeciaam, purpuraam, skin decolourationam, 

hyperhidrosisam, exanthemaam 

Rare Angioedemaa, erythemaa 

Very rare Erythema multiformeam, exfoliative dermatitisam, 

Stevens-Johnson syndromeam, Quincke oedemaam, 

photosensitivityam 

Musculoskeletal and connective tissue disorders 

Common Arthralgiaa,am, ankle swellingam 

Uncommon Myalgiaam, muscle crampsam, back painam 

Renal and urinary disorders 

Uncommon Acute renal failurea, renal impairmenta, 

micturition disorderam, nocturiaam, increased 

urinary frequencyam 

Reproductive system and breast disorders 

Uncommon Impotenceam, gynaecomastiaam 

General disorders and administration site conditions 

Common Fatigueam 

Uncommon Chest painam, astheniaam, painam, malaiseam 

Investigations 

Common Hyperkalaemiaa 

Uncommon Liver enzyme increaseda, weight increaseam, 

weight decreaseam 

Rare Haemoglobin decreaseda, haematocrit decreaseda, 

blood creatinine increaseda 

Not known Hyponatraemiaa 
c Adverse reaction observed with Rasilamlo; 
a Adverse reaction observed with monotherapy with aliskiren; 
am Adverse reaction observed with monotherapy with amlodipine; 

* Peripheral oedema is a known, dose-dependent adverse reaction of amlodipine and has also been 

reported with aliskiren therapy in post-marketing experience. The most frequently reported adverse 

reaction for Rasilamlo in clinical trials was peripheral oedema, which occurred at a frequency lower 

than or equal to that of the corresponding amlodipine doses, but higher than with aliskiren; 

** Isolated cases of liver disorder with clinical symptoms and laboratory evidence of more marked 

hepatic dysfunction; 

***Including one case of “liver failure fulminant” reported in the post-marketing experience, for 

which a causal relationship with aliskiren cannot be excluded. 

 

Additional information on individual components 

Adverse reactions previously reported with one of the individual components may occur with 

Rasilamlo even if not observed in clinical trials. 

 

Aliskiren 

Description of selected adverse reactions: 

Hypersensitivity reactions including anaphylactic reactions and angioedema have occurred during 

treatment with aliskiren. 

 

In controlled clinical trials, angioedema and hypersensitivity reactions occurred rarely during 

treatment with aliskiren with rates comparable to treatment with placebo or comparators. 

 



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Cases of angioedema or symptoms suggestive of angioedema (swelling of the face, lips, throat and/or 

tongue) have also been reported in post-marketing experience. A number of these patients had a 

history of angioedema or symptoms suggestive of angioedema which in some cases was associated 

with the administration of other medicinal products known to cause angioedema, including RAAS 

blockers (ACEIs or ARBs). 

 

In post-marketing experience, cases of angioedema or angioedema-like reactions have been reported 

when aliskiren was co-administered with ACEIs and/or ARBs. 

 

Hypersensitivity reactions including anaphylactic reactions have also been reported in post-marketing 

experience (see section 4.4). 

 

In the event of any signs suggesting a hypersensitivity reaction/angioedema (in particular difficulties 

in breathing or swallowing, rash, itching, hives or swelling of the face, extremities, eyes, lips and/or 

tongue, dizziness) patients should discontinue treatment and contact the physician (see section 4.4). 

 

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

hypersensitivity reaction. 

 

In post-marketing experience, renal dysfunction and cases of acute renal failure have been reported in 

patients at risk (see section 4.4). 

 

Investigations 

In controlled clinical trials, clinically relevant changes in standard laboratory parameters were 

uncommonly associated with the administration of aliskiren. In clinical studies in hypertensive 

patients, aliskiren had no clinically important effects on total cholesterol, high density lipoprotein 

cholesterol (HDL-C), fasting triglycerides, fasting glucose or uric acid. 

 

Haemoglobin and haematocrit: Small decreases in haemoglobin and haematocrit (mean decreases of 

approximately 0.05 mmol/l and 0.16 volume percent, respectively) were observed. No patients 

discontinued therapy due to anaemia. This effect is also seen with other medicinal products acting on 

the RAAS, such as ACEIs and ARBs. 

 

Serum potassium: Increases in serum potassium have been observed with aliskiren and these may be 

exacerbated by concomitant use of other agents acting on the RAAS or by NSAIDs. Consistent with 

standard medical practice, periodic determination of renal function including serum electrolytes is 

advised if co-administration is considered necessary. 

 

Paediatric population 

Based on the limited amount of safety data available from a pharmacokinetic study of aliskiren 

treatment in 39 hypertensive children 6-17 years of age, the frequency, type and severity of adverse 

reactions in children are expected to be similar to that seen in hypertensive adults. As for other RAAS 

blockers, headache is a common adverse event in children treated with aliskiren. 

 

Amlodipine 

Exceptional cases of extrapyramidal syndrome have been reported. 

 

Reporting of suspected adverse reactions 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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4.9 Overdose 

 

Symptoms 

There is no experience of overdose with Rasilamlo. The most likely manifestation of overdose for 

Rasilamlo would be hypotension, related to the antihypertensive effect of aliskiren and amlodipine. 

 

With aliskiren, the most likely manifestation of overdose would be hypotension, related to the 

antihypertensive effect of aliskiren. 

 

With amlodipine, available data suggest that gross overdose could result in excessive peripheral 

vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension 

up to and including shock with fatal outcome, have been reported with amlodipine. 

 

Treatment 

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

 

Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular 

support including frequent monitoring of cardiac and respiratory function, elevation of extremities 

and attention to circulating fluid volume and urine output. 

 

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is 

no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the 

effects of calcium channel blockade. 

 

Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 

2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of 

amlodipine. 

 

Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit. 

 

In a study conducted in patients with end stage renal disease (ESRD) receiving haemodialysis, 

dialysis clearance of aliskiren was low (<2% of oral clearance). Therefore dialysis is not adequate to 

treat aliskiren over-exposure. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1 Pharmacodynamic properties 

 

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, renin inhibitors, ATC 

code: C09XA53 

 

Rasilamlo combines two antihypertensive compounds with complementary mechanisms to control 

blood pressure in patients with essential hypertension: aliskiren belongs to the class of direct renin 

inhibitors and amlodipine belongs to the calcium antagonist class. 

 



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Rasilamlo 

The use of combined treatment with aliskiren and amlodipine arises from the actions of these two 

medicinal products on different but complementary systems that regulate blood pressure. Calcium 

channel blockers act to prevent the influx of calcium into the vascular smooth muscle cells in the 

vessel wall, thereby preventing smooth muscle cell contraction and vasoconstriction. Renin inhibitors 

suppress the enzymatic activity of renin, and thereby block the formation of Angiotensin II, the major 

effector molecule of the renin-angiotensin-aldosterone system (RAAS). Angiotensin II causes 

vasoconstriction and sodium and water reabsorption. Thus, amlodipine directly inhibits 

vasoconstriction and reduces vascular resistance, while aliskiren, by controlling Ang II production, 

can also inhibit vasoconstriction but additionally shifts water and sodium balance toward levels 

necessary for normotensive conditions. The combined action of aliskiren and amlodipine on these two 

central blood pressure-regulating factors (vasoconstriction and RAAS-mediated hypertensive effects) 

results in more effective antihypertensive effects than seen with monotherapy. 

 

Rasilamlo was studied in a number of active and placebo-controlled trials and long-term trials which 

included a total of 5,570 hypertensive patients with mild to moderate hypertension (diastolic blood 

pressure between 90 mmHg and 109 mmHg). 

 

In hypertensive patients not controlled by the component monotherapies, once-daily administration of 

Rasilamlo provided dose-dependent clinically meaningful reductions in both systolic and diastolic 

blood pressure. 

 

When given to patients whose blood pressure was not adequately controlled by either aliskiren or 

amlodipine, Rasilamlo results in greater blood pressure reductions after one week of treatment than 

the component monotherapies and a near-maximal effect is achieved after four weeks of therapy. 

 

In a study in 820 randomised patients not adequately responsive to aliskiren 300 mg treatment, the 

combination of aliskiren/amlodipine 300 mg/10 mg produced systolic/diastolic mean blood pressure 

reductions of 18.0/13.1 mmHg, which were statistically significantly greater than aliskiren 300 mg 

monotherapy. The combination at a dose of 300 mg/5 mg also showed statistically significantly 

greater blood pressure reduction than aliskiren 300 mg monotherapy. In a subset of 584 patients, the 

combination of aliskiren/amlodipine produced additional systolic/diastolic mean blood pressure 

reductions of 7.9/4.8 mmHg and 11.7/7.7 mmHg for the 300/5 mg and 300/10 mg strengths 

respectively compared to aliskiren 300 mg (the subset constitutes patients without aberrant readings, 

defined as difference in systolic blood pressure (SBP) ≥10 mmHg at baseline or endpoint). 

 

In a study in 847 randomised patients not adequately responsive to amlodipine 10 mg treatment, the 

combination of aliskiren/amlodipine 150 mg/10 mg and 300 mg/10 mg produced systolic/diastolic 

mean blood pressure reductions of 11.0/9.0 mmHg and 14.4/11.0 mmHg respectively, which were 

statistically greater than for amlodipine 10 mg monotherapy. In a subset of 549 patients, the 

combination of aliskiren/amlodipine produced additional systolic/diastolic mean blood pressure 

reductions of 4.0/2.2 mmHg and 7.6/4.7 mmHg for the 150/10 mg and 300/10 mg strengths 

respectively compared to amlodipine 10 mg (the subset constitutes patients without aberrant readings, 

defined as difference in SBP ≥10 mmHg at baseline or endpoint). 

 

In a study in 545 randomised patients not adequately responsive to 5 mg amlodipine, the combination 

of aliskiren 150 mg/amlodipine 5 mg resulted in greater blood pressure reduction than those patients 

remaining on amlodipine 5 mg. 

 



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In an 8-week randomised, double-blind, placebo-controlled, parallel group factorial study in 

1,688 randomised patients with mild to moderate hypertension, treatment with Rasilamlo at doses 

from 150 mg/5 mg to 300 mg/10 mg produced dose-dependent clinically meaningful mean blood 

pressure reductions (systolic/diastolic) ranging between 20.6/14.0 mmHg and 23.9/16.5 mmHg, 

respectively, compared to 15.4/10.2 mmHg for aliskiren 300 mg, 21.0/13.8 mmHg for amlodipine 

10 mg and 6.8/5.4 mmHg with placebo in a population of patients with mean baseline blood pressure 

of 157.3/99.7 mmHg. These were statistically significant versus placebo and aliskiren for all doses. 

The blood pressure reductions with the combination were maintained throughout the entire 24-hour 

dose interval. In a subset of 1,069 patients, Rasilamlo produced mean blood pressure reductions 

(systolic/diastolic) ranging between 20.6/13.6 mmHg and 24.2/17.3 mmHg (the subset of patients 

without aberrant readings, defined as difference in SBP ≥10 mmHg at baseline or endpoint). 

 

The safety of Rasilamlo has been evaluated in studies of up to one year duration. 

 

The effects of Rasilamlo on all cause and cardiovascular mortality and on cardiovascular morbidity 

and target organ damage are currently unknown. 

 

Rasilamlo has been administered to more than 2,800 patients in completed clinical trials, including 

372 patients for one year or more. Treatment with Rasilamlo at doses up to 300 mg/10 mg had an 

overall incidence of adverse experiences similar to the component monotherapies. The incidence of 

adverse events did not show any association with gender, age, body mass index, race or ethnicity. 

There were no new adverse reactions which occurred specifically with Rasilamlo in addition to those 

known to be associated with the individual monotherapies. In a double-blind, randomised placebo-

controlled study in 1,688 patients with mild or moderate hypertension, discontinuation of therapy due 

to a clinical adverse event occurred in 1.7% of patients treated with Rasilamlo versus 1.5% of 

patients given placebo. 

 

Aliskiren 

Aliskiren is an orally active, non-peptide, potent and selective direct inhibitor of human renin. 

 

By inhibiting the enzyme renin, aliskiren inhibits the RAAS at the point of activation, blocking the 

conversion of angiotensinogen to angiotensin I and decreasing levels of angiotensin I and 

angiotensin II. Whereas other medicinal products that inhibit the RAAS (ACEI and angiotensin II 

receptor blockers (ARB)) cause a compensatory rise in plasma renin activity (PRA), treatment with 

aliskiren decreases PRA in hypertensive patients by approximately 50 to 80%. Similar reductions 

were found when aliskiren was combined with other antihypertensive medicinal products. The 

clinical implications of the differences in effect on PRA are not known at the present time. 

 

Hypertension 

In hypertensive patients, once-daily administration of 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, and was independent of age, gender, body mass 

index and ethnicity. Aliskiren has been studied in 1,864 patients aged 65 years or older, and in 

426 patients aged 75 years or older. 

 

Aliskiren monotherapy studies have shown blood-pressure-lowering effects comparable to other 

classes of antihypertensive medicinal products including selected ACEI and ARB. Compared to a 

diuretic (hydrochlorothiazide, HCTZ), aliskiren 300 mg lowered systolic/diastolic blood pressure by 

17.0/12.3 mmHg, compared to 14.4/10.5 mmHg for HCTZ 25 mg after 12 weeks of treatment. 

 

Combination therapy studies are available for aliskiren added to the diuretic hydrochlorothiazide and 

the beta blocker atenolol. These combinations were well tolerated. Aliskiren induced an additive 

blood-pressure-lowering effect when added to hydrochlorothiazide. 



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The efficacy and safety of aliskiren-based therapy were compared to ramipril-based therapy in a 9-

month non-inferiority study in 901 elderly patients (≥65 years) with essential systolic hypertension. 

Aliskiren 150 mg or 300 mg per day or ramipril 5 mg or 10 mg per day were administered for 

36 weeks with optional add-on therapy of hydrochlorothiazide (12.5 mg or 25 mg) at week 12, and 

amlodipine (5 mg or 10 mg) at week 22. Over the 12 week period, aliskiren monotherapy lowered 

systolic/diastolic blood pressure by 14.0/5.1 mmHg, compared to 11.6/3.6 mmHg for ramipril, 

consistent with aliskiren being non-inferior to ramipril at the dosages chosen and the differences in 

systolic and diastolic blood pressure were statistically significant. Tolerability was comparable in 

both treatment arms, however cough was more often reported with the ramipril regimen than the 

aliskiren regimen (14.2% vs. 4.4%), whilst diarrhoea was more common with the aliskiren regimen 

than for the ramipril regimen (6.6% vs. 5.0%). 

 

In a 8-week study in 754 hypertensive elderly (≥65 years) and very elderly patients (30% ≥75 years) 

aliskiren at doses of 75 mg, 150 mg and 300 mg provided statistically significant superior reduction 

in blood pressure (both systolic and diastolic) when compared to placebo. No additional blood 

pressure lowering effect was detected with 300 mg aliskiren compared to 150 mg aliskiren. All three 

doses were well tolerated in both elderly and very elderly patients. 

 

There has been no evidence of first-dose hypotension and no effect on pulse rate in patients treated in 

controlled clinical studies. Excessive hypotension was uncommonly (0.1%) seen in patients with 

uncomplicated hypertension treated with aliskiren alone. Hypotension was also uncommon (<1%) 

during combination therapy with other antihypertensive medicinal products. With cessation of 

treatment, blood pressure gradually returned towards baseline levels over a period of several weeks, 

with no evidence of a rebound effect for blood pressure or PRA. 

 

In a 36-week study involving 820 patients with ischaemic left ventricular dysfunction, no changes in 

ventricular remodelling as assessed by left ventricular end systolic volume were detected with 

aliskiren compared to placebo on top of background therapy. 

 

The combined rates of cardiovascular death, hospitalisation for heart failure, recurrent heart attack, 

stroke and resuscitated sudden death were similar in the aliskiren group and the placebo group. 

However, in patients receiving aliskiren there was a significantly higher rate of hyperkalaemia, 

hypotension and kidney dysfunction when compared to the placebo group. 

 

Aliskiren was evaluated for cardiovascular and/or renal benefit in a double-blind placebo controlled 

randomised trial in 8,606 patients with type 2 diabetes and chronic kidney disease (evidenced by 

proteinuria and/or GFR <60 ml/min/1.73 m2) with or without cardiovascular disease. In most patients 

arterial blood pressure was well controlled at baseline. The primary endpoint was a composite of 

cardiovascular and renal complications. 

 

In this study, aliskiren 300 mg was compared to placebo when added to standard of care which 

included either an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. The 

study was discontinued prematurely because the participants were unlikely to benefit from aliskiren. 

The final study results indicated a hazard ratio for the primary endpoint of 1.097 in favour of placebo 

(95.4% Confidence Interval: 0.987, 1.218, 2-sided p=0.0787). In addition, an increased incidence of 

adverse events was observed with aliskiren compared to placebo (38.2% versus 30.3%). In particular 

there was an increased incidence of renal dysfunction (14.5% versus 12.4%), hyperkalaemia (39.1% 

versus 29.0%), hypotension-related events (19.9% versus 16.3%) and adjudicated stroke endpoints 

(3.4% versus 2.7%). The increased incidence of stroke was greater in patients with renal 

insufficiency. 

 



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Aliskiren 150 mg (increased to 300 mg if tolerated) added to conventional therapy was evaluated in a 

double-blind placebo-controlled randomised trial in 1,639 patients with reduced ejection fraction 

hospitalised for an episode of acute heart failure (NYHA Class III–IV) who were haemodynamically 

stable at baseline. The primary endpoint was cardiovascular death or heart failure rehospitalisation 

within 6 months; secondary endpoints were assessed within 12 months. 

 

The study showed no benefit of aliskiren when administered on top of standard therapy for acute 

heart failure and an increased risk of cardiovascular events in patients with diabetes mellitus. Study 

results indicated a non-significant effect of aliskiren with a hazard ratio of 0.92 (95% Confidence 

Interval: 0.76-1.12; p=0.41, aliskiren vs. placebo). Different treatment effects of aliskiren were 

reported for overall mortality within 12 months dependent on diabetes mellitus status. In the subgroup 

of patients with diabetes mellitus the hazard ratio was 1.64 in favour of placebo (95% Confidence 

Interval: 1.15-2.33), whereas the hazard ratio in the subgroup of patients without diabetes was 0.69 in 

favour of aliskiren (95% Confidence Interval: 0.50-0.94); p-value for interaction = 0.0003. An 

increased incidence of hyperkalaemia (20.9% versus 17.5%), renal impairment/renal failure (16.6% 

versus 12.1%) and hypotension (17.1% versus 12.6%) was observed in the aliskiren group compared 

with placebo and was greater in patients with diabetes. 

 

Effects of aliskiren on mortality and cardiovascular morbidity are currently unknown. 

 

No long-term efficacy data for aliskiren in patients with heart failure are currently available. 

 

Cardiac electrophysiology 

No effect on QT interval was reported in a randomised, double-blind, placebo, and active-controlled 

study using standard and Holter electrocardiography. 

 

Amlodipine 

The amlodipine component of Rasilamlo inhibits the transmembrane entry of calcium ions into 

cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is 

due to a direct relaxant effect on vascular smooth muscle, causing reductions in peripheral vascular 

resistance and in blood pressure. Experimental data suggest that amlodipine binds to both 

dihydropyridine and non-dihydropyridine binding sites. 

 

The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the 

movement of extracellular calcium ions into these cells through specific ion channels. 

 

Following administration of therapeutic doses to patients with hypertension, amlodipine produces 

vasodilatation resulting in a reduction of supine and standing blood pressures. These decreases in 

blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine 

levels with chronic dosing. 

 

Plasma concentrations correlate with effect in both young and elderly patients. 

 

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a 

decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal 

plasma flow without change in filtration fraction or proteinuria. 

 

As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest and 

during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have 

generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on 

left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been 

associated with a negative inotropic effect when administered in the therapeutic dose range to intact 

animals and humans, even when co-administered with beta blockers to humans. 

 



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Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals 

or humans. In clinical studies in which amlodipine was administered in combination with beta 

blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic 

parameters were observed. 

 

Amlodipine has demonstrated beneficial clinical effects in patients with chronic stable angina, 

vasospastic angina and angiographically documented coronary artery disease. 

 

Use in patients with heart failure 

Calcium channel blockers, including amlodipine, should be used with caution in patients with 

congestive heart failure, as they may increase the risk of future cardiovascular events and mortality. 

 

Use in patients with hypertension 

A randomised double-blind morbidity-mortality study called the Antihypertensive and Lipid-

Lowering treatment to prevent Heart Attack Trial (ALLHAT) was performed to compare newer 

therapies: amlodipine 2.5-10 mg/day (calcium channel blocker) or lisinopril 10-40 mg/day (ACE-

inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/day in mild 

to moderate hypertension. 

 

A total of 33,357 hypertensive patients aged 55 or older were randomised and followed for a mean of 

4.9 years. The patients had at least one additional coronary heart disease risk factor, including: 

previous myocardial infarction or stroke (>6 months prior to enrollment) or documentation of other 

atherosclerotic cardiovascular disease (overall 51.5%), type 2 diabetes (36.1%), high density 

lipoprotein - cholesterol <35 mg/dl or <0.906 mmol/l (11.6%), left ventricular hypertrophy diagnosed 

by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%). 

 

The primary endpoint was a composite of fatal coronary heart disease or non-fatal myocardial 

infarction. There was no significant difference in the primary endpoint between amlodipine-based 

therapy and chlorthalidone-based therapy: risk ratio (RR) 0.98 95% CI (0.90-1.07) p=0.65. Among 

secondary endpoints, the incidence of heart failure (component of a composite combined 

cardiovascular endpoint) was significantly higher in the amlodipine group as compared to the 

chlorthalidone group (10.2% vs 7.7%, RR 1.38, 95% CI [1.25-1.52] p<0.001). However, there was 

no significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-

based therapy RR 0.96 95% CI [0.89-1.02] p=0.20. 

 

Paediatric population 

The European Medicines Agency has waived the obligation to submit the results of studies with 

Rasilamlo in all subsets of the paediatric population in essential hypertension (see section 4.2 for 

information on paediatric use). 

 

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 Cmax 
by 85% and AUC by 70%. At steady state meals with low fat content reduce Cmax by 76% and AUC 

0-tau by 67% in hypertensive patients. 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. 

 

Transporters 

MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption 

and biliary excretion of aliskiren in pre-clinical studies. 

 



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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. 

 

Biotransformation and elimination 

The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as 

unchanged compound in the faeces (78%). Approximately 1.4% of the total oral dose is metabolised. 

The enzyme responsible for this metabolism is CYP3A4. Approximately 0.6% of the dose is 

recovered in urine following oral administration. Following intravenous administration, mean plasma 

clearance is approximately 9 l/h. 

 

Linearity 

Exposure to aliskiren increased more than in proportion to the increase in dose. After single dose 

administration in the dose range of 75 to 600 mg, a 2-fold increase in dose results in a ~2.3 and 2.6-

fold increase in AUC and Cmax, respectively. At steady state the non-linearity may be more 

pronounced. Mechanisms responsible for deviation from linearity have not been identified. A possible 

mechanism is saturation of transporters at the absorption site or at the hepatobiliary clearance route. 

 

Paediatric population 

In a pharmacokinetic study of aliskiren treatment in 39 paediatric hypertensive patients aged 6 to 

17 years given daily doses of 2 mg/kg or 6 mg/kg aliskiren administered as granules 

(3.125 mg/tablet), pharmacokinetic parameters were similar to those in adults. The results of this 

study did not suggest that age, body weight or gender have any significant effect on aliskiren 

systemic exposure (see section 4.2). 

 

Results from an in vitro MDR1 human tissue study suggested an age and tissue dependent pattern of 

MDR1 (P-gp) transporter maturation. A high inter-individual variability of mRNA expression levels 

was observed (up to 600-fold). Hepatic MDR1 mRNA expression was statistically significantly lower 

in samples from foetuses, neonates and infants up to 23 months. 

 

The age at which the transporter system is mature cannot be determined. There is a potential for 

aliskiren overexposure in children with an immature MDR1 (P-gp) system (see “Transporters” above 

and sections 4.2, 4.4 and 5.3). 

 

Amlodipine 

Absorption 

After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations of 

amlodipine are reached in 6-12 hours. Absolute bioavailability has been estimated as between 64% 

and 80%. Amlodipine bioavailability is unaffected by food ingestion. 

 

Distribution 

The volume of distribution is approximately 21 l/kg. In vitro studies with amlodipine have shown that 

approximately 97.5% of circulating amlodipine is bound to plasma proteins. 

 

Biotransformation and elimination 

Amlodipine is extensively (approximately 90%) metabolised in the liver to inactive metabolites, with 

10% of the parent compound and 60% of the metabolites excreted in the urine. 

 

Amlodipine elimination from plasma is biphasic with a terminal elimination half-life of 

approximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration 

for 7-8 days. 

 

Linearity 

Amlodipine exhibits linear pharmacokinetics between the therapeutic dose range of 5 mg and 10 mg. 



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Aliskiren/amlodipine 

Following oral administration of Rasilamlo, the median peak plasma concentration time is within 

3 hours for aliskiren and 8 hours for amlodipine. The rate and extent of absorption of Rasilamlo are 

similar in fasting state to those of aliskiren and amlodipine when administered as individual 

monotherapies. A bioequivalence study under light meal conditions has not been conducted for 

Rasilamlo. 

 

The results from a food effect study using a standard high fat meal with the 300 mg/10 mg fixed 

combination tablet showed that food reduced the rate and extent of absorption of aliskiren in the 

fixed combination tablet with a similar magnitude of effect as for aliskiren monotherapy. Consistent 

with the monotherapy formulation, food had no effect on the pharmacokinetics of amlodipine in the 

fixed combination tablet. 

 

Characteristics in patients 

Aliskiren 

Aliskiren is an effective once-a-day antihypertensive treatment in adult patients, regardless of gender, 

age, body mass index and ethnicity. 

 

The AUC is 50% higher in elderly (>65 years) than in young subjects. Gender, weight and ethnicity 

have no clinically relevant influence on aliskiren pharmacokinetics. 

 

The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renal 

insufficiency. Relative AUC and Cmax of aliskiren in subjects with renal impairment ranged between 

0.8 to 2 times the levels in healthy subjects following single dose administration and at steady state. 

These observed changes, however, did not correlate with the severity of renal impairment. No 

adjustment of the initial dosage of aliskiren is required in patients with mild to moderate renal 

impairment (see sections 4.2 and 4.4). Aliskiren is not recommended in patients with severe renal 

impairment (glomerular filtration rate (GFR) <30 ml/min/1.73 m2). 

 

The pharmacokinetics of aliskiren were evaluated in patients with end stage renal disease receiving 

haemodialysis. Administration of a single oral dose of 300 mg aliskiren was associated with very 

minor changes in the pharmacokinetics of aliskiren (change in Cmax of less than 1.2 fold; increase in 

AUC of up to 1.6 fold) compared to matched healthy subjects. Timing of haemodialysis did not 

significantly alter the pharmacokinetics of aliskiren in ESRD patients. Therefore, if administration of 

aliskiren in ESRD patients receiving haemodialysis is considered necessary, no dose adjustment is 

warranted in these patients. However, the use of aliskiren is not recommended in patients with severe 

renal impairment (see section 4.4). 

 

The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe liver 

disease. Consequently, no adjustment of the initial dose of aliskiren is required in patients with mild 

to severe hepatic impairment. 

 

Amlodipine 

The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger 

subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and 

elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with 

congestive heart failure were as expected for the patient age group in this study (see section 4.4). 

 

A population pharmacokinetic study has been conducted in 74 hypertensive children aged from 1 to 

17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving 

amlodipine between 1.25 and 20 mg given either once or twice daily. In children 6 to 12 years and in 

adolescents 13-17 years of age the typical oral clearance (CL/F) was 22.5 and 27.4 l/hr respectively 

in males and 16.4 and 21.3 l/hr respectively in females. Large variability in exposure between 

individuals was observed. Data reported in children below 6 years are limited. 

 



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The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. 

 

Very limited clinical data are available regarding amlodipine administration in patients with hepatic 

impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine with 

resulting increase in AUC of approximately 40-60%. Therefore caution should be exercised in 

patients with hepatic impairment. 

 

5.3 Preclinical safety data 

 

Aliskiren 

Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic mouse study. No 

carcinogenic potential was detected. One colonic adenoma and one caecal adenocarcinoma recorded 

in rats at the dose of 1,500 mg/kg/day were not statistically significant. Although aliskiren has known 

irritation potential, safety margins obtained in humans at the dose of 300 mg during a study in healthy 

volunteers were considered to be appropriate at 9-11-fold based on faecal concentrations or 6-fold 

based on mucosa concentrations in comparison with 250 mg/kg/day in the rat carcinogenicity study. 

 

Aliskiren was devoid of any mutagenic potential in the in vitro and in vivo mutagenicity studies. The 

assays included in vitro assays in bacterial and mammalian cells and in vivo assessments in rats. 

 

Reproductive toxicity studies with aliskiren did not reveal any evidence of embryofoetal toxicity or 

teratogenicity at doses up to 600 mg/kg/day in rats or 100 mg/kg/day in rabbits. Fertility, pre-natal 

development and post-natal development were unaffected in rats at doses up to 250 mg/kg/day. The 

doses in rats and rabbits provided systemic exposures of 1 to 4 and 5 times higher, respectively, than 

the maximum recommended human dose (300 mg). 

 

Safety pharmacology studies did not reveal any adverse effects on central nervous, respiratory or 

cardiovascular function. Findings during repeat-dose toxicity studies in animals were consistent with 

the known local irritation potential or the expected pharmacological effects of aliskiren. 

 

Juvenile Animal Studies 

A repeat-dose toxicity study was conducted in juvenile rats 8 days post-partum for 4 weeks with 

aliskiren dosing at 30, 100 or 300 mg/kg/day. High acute mortality (within hours) and severe 

morbidity were observed at 100 and 300 mg/kg/day (2.3- and 6.8-fold the maximum recommended 

human dose (MRHD) on mg/m2 basis assuming a 60 kg adult patient) with no cause of death 

established and occurring without signs or prodromal symptoms. The ratio of lethal dose of 

100 mg/kg/day and no-observed-adverse-effect-level (NOAEL) of 30 mg/kg/day is unexpectedly low. 

 

Another repeat-dose toxicity study was conducted in juvenile rats 14 days post-partum for 8 weeks 

with aliskiren dosing at 30, 100 or 300 mg/kg/day. Delayed mortality was observed at 300 mg/kg/day 

(8.5-fold the MRHD on mg/m2 basis assuming a 60 kg adult patient) with no cause of death 

established. 

 

For the surviving juvenile rats, no effects on behavioural or reproductive performance were observed. 

 

Plasma aliskiren exposure (AUC) in rats aged 8 days was nearly 4-fold higher than that in rats aged 

14 days at 100 mg/kg/day. Plasma aliskiren exposure in rats aged 14 days was between 85- and 387-

fold higher than that in adult rats aged 64 days. 

 

A single dose study was conducted in juvenile rats aged 14, 21, 24, 28, 31 or 36 days post-partum. 

No mortality or significant toxicity was observed. The plasma exposure was approximately 100-fold 

higher in rats aged 14 days and 3-fold higher in rats aged 21 days compared to adult rats. 

 



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A mechanistic study was conducted to investigate the relationship between age, aliskiren exposure 

and MDR1 and OATP2 expression maturation in rats. The results showed that developmental 

changes of aliskiren exposure correlated with the ontogeny of transporter maturation in jejunum, liver, 

kidney and brain. 

 

The pharmacokinetics of aliskiren was evaluated in rats aged from 8 to 28 days after intravenous 

administration of aliskiren 3 mg/kg. The clearance of aliskiren increased in an age-dependent 

manner. Clearance in rats aged 8 or 14 days was similar, but at these ages the clearance was only 

about 23% of clearance in rats aged 21 days and 16% of clearance in rats aged 28 days. 

 

These studies indicate that excessive aliskiren exposure (>400-fold higher in 8-day old rats compared 

with adult rats) and high acute toxicity in juvenile rats are caused by immature MDR1, which 

suggests that in paediatric patients with immature MDR1, there is a potential for aliskiren 

overexposure (see sections 4.2, 4.3 and 5.2). 

 

Amlodipine 

Safety data for amlodipine are well established both clinically and non-clinically. 

 

Reproductive toxicology 

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of 

labour and decreased pup survival at dosages approximately 50 times greater than the maximum 

recommended dosage for humans based on mg/kg. 

 

Impairment of fertility 

There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 

14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human 

dose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipine 

besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma 

follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in 

the number of mature spermatids and Sertoli cells. 

 

Carcinogenesis, mutagenesis 

Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to 

provide daily dosage levels of 0.5, 1.25 and 2.5 mg/kg/day showed no evidence of carcinogenicity. 

The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose 

of 10 mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats. 

 

Mutagenicity studies revealed no effects related to the medicinal product at either the gene or 

chromosome levels. 

 

*Based on patient weight of 50 kg 

 

Rasilamlo 

Preclinical safety studies have demonstrated that the combination of aliskiren and amlodipine was 

well tolerated in rats. The findings from the 2- and 13-week oral toxicity studies in rats were 

consistent with those of aliskiren and amlodipine when both active substances are administered alone. 

There were no new toxicities or increased severity of the toxicities which were associated with either 

component. 

 

 



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48 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Tablet core 

Cellulose microcrystalline 

Crospovidone 

Povidone 

Magnesium stearate 

Silica colloidal anhydrous 

 

Coating 

Hypromellose 

Titanium dioxide (E171) 

Macrogol 

Talc 

Iron oxide yellow (E172) 

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

PVC/PCTFE – Alu blisters: 

18 months 

 

PA/Alu/PVC – Alu blisters: 

18 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 

 

PVC/polychlorotrifluoroethylene (PCTFE) - Alu calendar blisters: 

Single pack containing 14, 28, 56, 98 tablets 

Multi-packs containing 280 tablets (20 packs of 14) 

 

PVC/polychlorotrifluoroethylene (PCTFE) - Alu blisters: 

Single pack containing 30, 90 tablets 

Unit dose pack (perforated unit dose blister) containing 56x1 tablet 

Multi-packs of unit dose (perforated unit dose blister) containing 98x1 tablet (2 packs of 49x1) 

 

PA/Alu/PVC – Alu calendar blisters: 

Single pack containing 14, 28, 56 tablets 

Multi-packs containing 98 tablets (2 packs of 49) and 280 tablets (20 packs of 14) 

 

Not all pack sizes or strengths may be marketed. 

 

6.6 Special precautions for disposal 

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 

 



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49 

 

7. MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/686/015-028 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 14 April 2011 

Date of latest renewal: 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this medicinal product is available on the website of the European 

Medicines Agency http://www.ema.europa.eu 

 



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1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 300 mg/5 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each film-coated tablet contains 300 mg aliskiren (as hemifumarate) and 5 mg amlodipine (as 

besylate). 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Film-coated tablet. 

 

Dark yellow, convex, ovaloid tablet with a bevelled edge, with “T11” debossed on one side and 

“NVR” on the other. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Rasilamlo is indicated for the treatment of essential hypertension in adult patients whose blood 

pressure is not adequately controlled with aliskiren or amlodipine used alone. 

 

4.2 Posology and method of administration 

 

Posology 

The recommended dose of Rasilamlo is one tablet per day. 

 

The antihypertensive effect is manifested within 1 week and the effect is near maximal at around 

4 weeks. If blood pressure remains uncontrolled after 4 to 6 weeks of therapy, the dose may be 

titrated up to a maximum of 300 mg aliskiren/10 mg amlodipine. Dose should be individualised and 

adjusted according to the patient’s clinical response. 

 

Rasilamlo may be administered with other antihypertensive medicinal products with the exception of 

use in combination with angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor 

blockers (ARB) in patients with diabetes mellitus or renal impairment (glomerular filtration rate 

(GFR) <60 ml/min/1.73 m2) (see sections 4.3, 4.4 and 5.1). 

 

Posology in patients not adequately controlled with aliskiren or amlodipine monotherapy  

Rasilamlo 300 mg/5 mg may be administered in patients whose blood pressure is not adequately 

controlled with aliskiren 300 mg alone or with Rasilamlo 150 mg/5 mg. 

 

A patient who experiences dose limiting adverse reactions on either component alone may be 

switched to Rasilamlo containing a lower dose of that component to achieve similar blood pressure 

reductions. 

 

Individual dose titration with each of the two components may be recommended before changing to 

the fixed combination. When clinically appropriate and in line with the above-mentioned posology, 

direct change from monotherapy to the fixed combination may be considered. 

 



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Special populations 

Renal impairment 

No adjustment of the initial dose is required for patients with mild to moderate renal impairment 

(GFR 89-60 ml/min/1.73 m2 and 59-30 ml/min/1.73 m2, respectively, see sections 4.4 and 5.2). 

Rasilamlo is not recommended in patients with severe renal impairment (GFR <30 ml/min/1.73 m2). 

 

Hepatic impairment 

Amlodipine dosage recommendations have not been established in patients with mild to moderate 

hepatic impairment. The pharmacokinetics of amlodipine have not been studied in severe hepatic 

impairment; therefore, caution should be exercised when administering Rasilamlo to patients with 

hepatic impairment. 

 

Elderly people (over 65 years) 

There is limited experience with Rasilamlo, in particular in patients aged 75 years or older. 

Therefore, particular caution should be exercised in these patients. The recommended starting dose of 

aliskiren in elderly patients is 150 mg. No clinically meaningful additional blood pressure reduction 

is observed by increasing the dose to 300 mg in the majority of elderly patients. 

 

Paediatric population 

The safety and efficacy of Rasilamlo in children below age 18 have not been established. No data are 

available. 

 

Rasilamlo is contraindicated in children from birth to less than 2 years and should not be used in 

children aged 2 to less than 6 years because of safety concerns due to potential aliskiren overexposure 

(see sections 4.3, 4.4, 5.2, and 5.3). 

 

Method of administration 

Oral use. The tablets should be swallowed whole with some water. Rasilamlo should be taken with a 

light meal once a day, preferably at the same time each day. Concomitant intake with fruit juice 

and/or drinks containing plant extracts (including herbal teas) should be avoided (see section 4.5). 

 

4.3 Contraindications 

 

 Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or 
other dihydropyridine derivatives. 

 History of angioedema with aliskiren. 

 Hereditary or idiopathic angioedema 

 Second and third trimesters of pregnancy (see section 4.6). 

 The concomitant use of aliskiren with ciclosporin and itraconazole, two highly potent P-
glycoprotein (P-gp) inhibitors, and other potent P-gp inhibitors (e.g. quinidine), is 

contraindicated (see section 4.5). 

 The concomitant use of Rasilamlo with an ACEI or an ARB is contraindicated in patients with 
diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) (see sections  4.5 and 5.1). 

 Severe hypotension. 

 Shock (including cardiogenic shock). 

 Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis). 

 Haemodynamically unstable heart failure after acute myocardial infarction. 

 Children from birth to less than 2 years (see sections 4.2 and 5.3). 
 



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4.4 Special warnings and precautions for use 

 

General 

In the event of severe and persistent diarrhoea, Rasilamlo therapy should be stopped (see section 4.8). 

 

As with any antihypertensive medicinal product, excessive reduction of blood pressure in patients 

with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial 

infarction or stroke. 

 

The safety and efficacy of amlodipine in hypertensive crisis have not been established. 

 

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) 

Hypotension, syncope, stroke, hyperkalaemia, and decreased renal function (including acute renal 

failure) have been reported in susceptible individuals, especially if combining medicinal products that  

affect this system (see section 5.1). Dual blockade of the RAAS by combining aliskiren with an ACEI 

or an ARB is therefore not recommended. If dual blockade therapy is considered absolutely 

necessary, this should only occur under specialist supervision and subject to frequent close monitoring 

of renal function, electrolytes and blood pressure. 

 

Heart failure 

Calcium channel blockers, including amlodipine, should be used with caution in patients with 

congestive heart failure, as they may increase the risk of future cardiovascular events and mortality. 

 

No data on cardiovascular mortality and morbidity are available for aliskiren in patients with heart 

failure (see section 5.1). 

 

Aliskiren should be used with caution in patients with heart failure treated with furosemide or 

torasemide (see section 4.5). 

 

Risk of symptomatic hypotension 

Symptomatic hypotension could occur after initiation of treatment with Rasilamloin the following 

cases: 

 Patients with marked volume depletion or patients with salt depletion (e.g. those receiving high 
doses of diuretics) or 

 Combined use of aliskiren with other agents acting on the RAAS. 
The volume or salt depletion should be corrected prior to the administration of Rasilamlo, or the 

treatment should start under close medical supervision. In patients with uncomplicated hypertension 

treated with Rasilamlo in short-term controlled trials, the incidence of hypotension was low (0.2%). 

 

Renal impairment 

In clinical studies aliskiren has not been investigated in hypertensive patients with severe renal 

impairment (serum creatinine ≥150 μmol/l or 1.70 mg/dl in women and ≥177 μmol/l or 2.00 mg/dl in 

men and/or estimated GFR <30 ml/min/1.73 m2), history of dialysis, nephrotic syndrome or 

renovascular hypertension. Rasilamlo is not recommended in patients with severe renal impairment 

(GFR <30 ml/min/1.73 m2). 

 

As for other medicinal products acting on the renin-angiotensin-aldosterone system, caution should be 

exercised when Rasilamlo 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, diabetes mellitus 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. 

 



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Increases in serum potassium have been observed with aliskiren in post-marketing experience and 

these may be exacerbated by concomitant use of other agents acting on the RAAS or by non-steroidal 

anti-inflammatory drugs (NSAIDs). Consistent with standard medical practice, periodic 

determination of renal function including serum electrolytes is advised if co-administration is 

considered necessary. 

 

Hepatic impairment 

The half life of amlodipine is prolonged and AUC values are higher in patients with impaired liver 

function; dosage recommendations have not been established. Caution should be exercised when 

administering Rasilamlo to patients with hepatic impairment (see sections 4.2 and 5.2). 

 

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy 

As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral 

stenosis, or obstructive hypertrophic cardiomyopathy. 

 

Renal artery stenosis 

No controlled clinical data are available on the use of Rasilamlo in patients with unilateral or 

bilateral renal artery stenosis, or stenosis to a solitary kidney. However, as with other medicinal 

products acting on the renin-angiotensin-aldosterone system, there is an increased risk of renal 

insufficiency, including acute renal failure, when patients with renal artery stenosis are treated with 

aliskiren. Therefore caution should be exercised in these patients. If renal failure occurs, treatment 

should be discontinued. 

 

Anaphylactic reactions and angioedema 

Anaphylactic reactions have been observed during treatment with aliskiren from post-marketing 

experience (see section 4.8). As with other medicinal products acting on the renin-angiotensin-

aldosterone system, angioedema or symptoms suggestive of angioedema (swelling of the face, lips, 

throat and/or tongue) have been reported in patients treated with aliskiren. 

 

A number of these patients had a history of angioedema or symptoms suggestive of angioedema, 

which in some cases followed use of other medicinal products that can cause angioedema, including 

RAAS blockers (angiotensin converting enzyme inhibitors or angiotensin receptor blockers) (see 

section 4.8). 

 

In post-marketing experience, angioedema or angioedema-like reactions have been reported when 

aliskiren was co-administered with ACEIs and/or ARBs (see section 4.8). 

 

Special caution is necessary in patients with a hypersensitivity predisposition. 

 

Patients with history of angioedema may be at increased risk of experiencing angioedema during 

treatment with aliskiren (see sections 4.3 and 4.8). Caution should therefore be exercised when 

prescribing aliskiren to patients with a history of angioedema, and such patients should be closely 

monitored during treatment (see section 4.8) especially at the beginning of the treatment. 

 

If anaphylactic reactions or angioedema occur, Rasilamlo should be promptly discontinued and 

appropriate therapy and monitoring provided until complete and sustained resolution of signs and 

symptoms has occurred. Patients should be informed to report to the physician any signs suggestive of 

allergic reactions, in particular difficulties in breathing or swallowing, swelling of face, extremities, 

eyes, lips or tongue. Where there is involvement of the tongue, glottis or larynx adrenaline should be 

administered. In addition, measures necessary to maintain patent airways should be provided. 

 



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Paediatric population 

Aliskiren is a P-glycoprotein (P-gp) substrate, and there is a potential for aliskiren overexposure in 

children with an immature P-gp drug transporter system. The age at which the transporter system is 

mature cannot be determined (see sections 5.2 and 5.3). Therefore, Rasilamlo is contraindicated in 

children from birth to less than 2 years and should not be used in children aged 2 to less than 6 years. 

 

Limited safety data are available from a pharmacokinetic study of aliskiren treatment in 39 

hypertensive children aged 6 to less than 18 years (see sections 4.8 and 5.2). 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Information on Rasilamlo interactions 

No interaction studies with other medicinal products were performed with Rasilamlo. Therefore, 

information on interactions with other medicinal products that are known for the individual active 

substances is provided in this section. 

 

Co-administration of aliskiren and amlodipine does not cause meaningful changes in the steady-state 

pharmacokinetic exposure (AUC) and the maximum concentration (Cmax) of either component in 

healthy volunteers. 

 

Information on aliskiren interactions 

Contraindicated (see section 4.3) 

- P-gp potent inhibitors 
A single dose drug interaction study in healthy subjects has shown that ciclosporin (200 and 600 mg) 

increases Cmax of aliskiren 75 mg approximately 2.5-fold and AUC approximately 5-fold. The 

increase may be higher with higher aliskiren doses. In healthy subjects, itraconazole (100 mg) 

increases AUC and Cmax of aliskiren (150 mg) by 6.5-fold and 5.8-fold, respectively. Therefore, 

concomitant use of aliskiren and P-gp potent inhibitors is contraindicated (see section 4.3). 

 

Not recommended (see section 4.2) 

- Fruit juice and drinks containing plant extracts 
Administration of fruit juice with aliskiren resulted in a decrease in AUC and Cmax of aliskiren. Co-

administration of grapefruit juice with aliskiren 150 mg resulted in a 61% decrease in aliskiren AUC 

and co-administration with aliskiren 300 mg resulted in a 38% decrease in aliskiren AUC. Co-

administration of orange or apple juice with aliskiren 150 mg resulted in a 62% decrease in aliskiren 

AUC or in a 63% decrease in aliskiren AUC, respectively. This decrease is likely due to an 

inhibition of organic anion transporting polypeptide-mediated uptake of aliskiren by components of 

fruit juice in the gastrointestinal tract. Therefore, because of the risk of therapeutic failure, fruit juice 

should not be taken together with Rasilamlo. The effect of drinks containing plant extracts (including 

herbal teas) on the absorption of aliskiren has not been investigated. However, compounds potentially 

inhibiting organic anion transporting polypeptide-mediated uptake of aliskiren are widely present in 

fruits, vegetables, and many other plant products. Therefore, drinks containing plant extracts, 

including herbal teas, should not be taken together with Rasilamlo. 

 

Dual blockade of the RAAS with aliskiren, ARBs or ACEIs 

Clinical trial data has shown that dual blockade of the RAAS through the combined use of ACEIs, 

ARBs or aliskiren is associated with a higher frequency of adverse events such as hypotension, stroke, 

hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a 

single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). 

 



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Caution required with concomitant use 

- P-gp 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 (see section 5.2). Rifampicin, which is an 

inducer of P-gp, reduced aliskiren bioavailability by approximately 50% in a clinical study. Other 

inducers of P-gp (St. John’s wort) might decrease the bioavailability of 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. 

 

- Moderate P-gp inhibitors 
Co-administration of ketoconazole (200 mg) or verapamil (240 mg) with aliskiren (300 mg) resulted 

in a 76% or 97% increase in aliskiren AUC, respectively. The change in plasma levels of aliskiren in 

the presence of ketoconazole or verapamil is expected to be within the range that would be achieved 

if the dose of aliskiren were doubled; aliskiren doses of up to 600 mg, or twice the highest 

recommended therapeutic dose, have been found to be well tolerated in controlled clinical trials. 

Preclinical studies indicate that aliskiren and ketoconazole co-administration enhances aliskiren 

gastrointestinal absorption and decreases biliary excretion. Therefore, caution should be exercised 

when aliskiren is administered with ketoconazole, verapamil or other moderate P-gp inhibitors 

(clarithromycin, telithromycin, erythromycin, amiodarone). 

 

- Medicinal products affecting serum potassium levels 
Concomitant use of other agents affecting the RAAS, of NSAIDs or of agents that increase serum 

potassium levels (e.g. potassium-sparing diuretics, potassium supplements, salt substitutes containing 

potassium, heparin) may lead to increases in serum potassium. If co-medication with an agent 

affecting the level of serum potassium is considered necessary, caution is advisable. 

 

- Non-steroidal anti-inflammatory drugs (NSAIDs) 
As with other medicinal products acting on the renin-angiotensin-aldosterone 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. 

 

- Furosemide and torasemide 
Oral co-administration of aliskiren and furosemide had no effect on the pharmacokinetics of aliskiren 

but reduced exposure to furosemide by 20-30% (the effect of aliskiren on furosemide administered 

intramuscularly or intravenously has not been investigated). After multiple doses of furosemide 

(60 mg/day) co-administered with aliskiren (300 mg/day) to patients with heart failure the urinary 

sodium excretion and the urine volume were reduced during the first 4 hours by 31% and 24%, 

respectively, as compared to furosemide alone. The mean weight of patients concomitantly treated 

with furosemide and 300 mg aliskiren (84.6 kg) was higher than the weight of patients treated with 

furosemide alone (83.4 kg). Smaller changes in furosemide pharmacokinetics and efficacy were 

observed with aliskiren 150 mg/day. 

 

The available clinical data did not indicate that higher doses of torasemide were used after co-

administration with aliskiren. Torasemide renal excretion is known to be mediated by organic anion 

transporters (OATs). Aliskiren is minimally excreted via the renal route, and only 0.6% of the 

aliskiren dose is recovered in urine following oral administration (see section 5.2). However, since 

aliskiren has been shown to be a substrate for the organic anion-transporting polypeptide 1A2 

(OATP1A2) (see interaction with organic anion transporting polypeptide (OATP) inhibitors), there is 

a potential for aliskiren to reduce plasma torasemide exposure by an interference with the absorption 

process. 



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In patients treated with both aliskiren and oral furosemide or torasemide, it is therefore recommended 

that the effects of furosemide or torasemide be monitored when initiating and adjusting furosemide, 

torasemide or aliskiren therapy to avoid changes in extracellular fluid volume and possible situations 

of volume overload (see section 4.4). 

 

- Warfarin 
The effects of aliskiren on warfarin pharmacokinetics have not been evaluated. 

 

- Food interactions 
Meals (low or high fat content) have been shown to reduce the absorption of aliskiren substantially 

(see section 4.2). The available clinical data do not suggest an additive effect of different types of 
foods and/or drinks, however the potential for decreased aliskiren bioavailability due to this additive 

effect has not been studied and therefore cannot be excluded. Concomitant administration of aliskiren 

with fruit juice or drinks containing plant extracts, including herbal teas, should be avoided. 

 

No interactions 

- Compounds that have been investigated in aliskiren clinical pharmacokinetic studies include 
acenocoumarol, atenolol, celecoxib, pioglitazone, allopurinol, isosorbide-5-mononitrate and 

hydrochlorothiazide. No interactions have been identified. 

 

- Co-administration of aliskiren with either metformin (↓28%), amlodipine (↑29%) or cimetidine 
(↑19%) resulted in between 20% and 30% change in Cmax or AUC of aliskiren. When 

administered with atorvastatin, steady-state aliskiren AUC and Cmax increased by 50%. Co-

administration of aliskiren had no significant impact on atorvastatin, metformin or amlodipine 

pharmacokinetics. As a result no dose adjustment for aliskiren or these co-administered 

medicinal products is necessary. 

 

- Digoxin and verapamil bioavailability may be slightly decreased by aliskiren. 
 

- CYP450 interactions 
Aliskiren does not inhibit the CYP450 isoenzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A). 

Aliskiren does not induce CYP3A4. Therefore aliskiren is not expected to affect the systemic 

exposure of substances that inhibit, induce or are metabolised by these enzymes. Aliskiren is 

metabolised minimally by the cytochrome P450 enzymes. Hence, interactions due to inhibition or 

induction of CYP450 isoenzymes are not expected. However, CYP3A4 inhibitors often also affect P-

gp. Increased aliskiren exposure during co-administration of CYP3A4 inhibitors that also inhibit P-gp 

can therefore be expected (see other P-gp references in section 4.5). 

 

- P-gp substrates or weak inhibitors 
No relevant interactions with atenolol, digoxin, amlodipine or cimetidine have been observed. When 

administered with atorvastatin (80 mg), steady-state aliskiren (300 mg) AUC and Cmax increased by 

50%. In experimental animals, it has been shown that P-gp is a major determinant of aliskiren 

bioavailability. Inducers of P-gp (St. John’s wort, rifampicin) might therefore decrease the 

bioavailability of aliskiren. 

 

- Organic anion transporting polypeptide (OATP) inhibitors 

Preclinical studies indicate that aliskiren might be a substrate of organic anion transporting 

polypeptides. Therefore, the potential exists for interactions between OATP inhibitors and aliskiren 

when administered concomitantly (see interaction with fruit juice). 

 



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Information on amlodipine interactions 

Effects of other medicinal products on amlodipine 

Caution required with concomitant use 

- CYP3A4 inhibitors 
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, 

azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give 

rise to significant increase in amlodipine exposure. The clinical translation of these pharmacokinetic 

variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus 

be required. 

 

- CYP3A4 inducers 
There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant 

use of CYP3A4 inducers (e.g. rifampicin, hypericum perforatum) may give a lower plasma 

concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 

inducers. 

 

- Grapefruit juice 
Administration of amlodipine with grapefruit or grapefruit juice is not recommended as 

bioavailability may be increased in some patients, resulting in increased blood pressure lowering 

effects. 

 

- Dantrolene (infusion) 
In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with 

hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of 

hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as 

amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of 

malignant hyperthermia. 

 

Effects of amlodipine on other medicinal products 

- The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects 
of other antihypertensive medicinal products. 

 

- Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in 
a 77% increase in exposure to simvastatin compared to simvastatin alone. It is recommended to 

limit the dose of simvastatin to 20 mg daily in patients on amlodipine. 

 

No interactions 

- In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, 
digoxin, warfarin or ciclosporin. 

 

4.6 Fertility, pregnancy and lactation 

 

Women of child-bearing potential/contraception in males and females 

Healthcare professionals prescribing Rasilamlo should counsel women of childbearing potential about 

the potential risk during pregnancy. A switch to a suitable alternative antihypertensive treatment 

should be carried out in advance of a planned pregnancy since Rasilamlo should not be used in 

women planning to become pregnant. 

 

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 RAAS have been associated with 

serious foetal malformations and neonatal death. As for any medicine that acts directly on the RAAS, 

aliskiren should not be used during the first trimester of pregnancy and is contraindicated during the 

second and third trimesters (see section 4.3). 

 



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The safety of amlodipine in human pregnancy has not been established. Reproductive studies in rats 

have shown no toxicity except for delayed date of delivery and prolonged duration of labour at 

dosages 50 times greater than the maximum recommended dosage for humans (see section 5.3). Use 

in pregnancy is only recommended when there is no safer alternative and when the disease itself 

carries greater risk for the mother and foetus. 

 

Rasilamlo should not be used during the first trimester of pregnancy. Rasilamlo is contraindicated 

during the second and third trimesters (see section 4.3). 

 

If pregnancy is detected during therapy, Rasilamlo should be discontinued accordingly as soon as 

possible. 

 

Breast-feeding 

It is unknown whether aliskiren and/or amlodipine are excreted in human milk. Aliskiren was 

secreted in the milk of lactating rats. 

 

Since there is insufficient/limited information on the excretion of aliskiren and amlodipine in human 

or animal breast milk, a risk to the newborns/infants cannot be excluded. It is therefore not 

recommended for women who are breast-feeding to use Rasilamlo. 

 

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from 

Rasilamlo therapy taking into account the benefit of breast-feeding for the child and the benefit of 

therapy for the woman. 

 

Fertility 

There are no clinical data on fertility with the use of Rasilamlo. 

 

Reversible biochemical changes in the head of spermatozoa have been reported in some patients 

treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of 

amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3). 

The fertility of rats was unaffected at doses of up to aliskiren 250 mg/kg/day (see section 5.3). 

 

4.7 Effects on ability to drive and use machines 

 

When driving vehicles or using machines it must be borne in mind that dizziness or drowsiness may 

occasionally occur when taking Rasilamlo. 

 

Amlodipine can have minor or moderate influence on the ability to drive and use machines. If 

patients taking amlodipine suffer from dizziness, headache, fatigue or nausea, the ability to react may 

be impaired. 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

The safety profile of Rasilamlo presented below is based on clinical studies performed with 

Rasilamlo and the known safety profile of the individual components aliskiren and amlodipine. 

Safety information for Rasilamlo in patients aged 75 years and older is limited. 

 

The most frequent adverse reactions for Rasilamlo are hypotension and peripheral oedema. The 

adverse reactions previously reported with one of the individual components of Rasilamlo (aliskiren 

and amlodipine) and included in the tabulated list of adverse reactions may occur with Rasilamlo. 

 



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Tabulated list of adverse reactions: 

The adverse reactions are ranked by frequency, the most frequent first, 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, adverse reactions are presented in order of decreasing 

seriousness. The adverse reactions observed with Rasilamlo or with monotherapy with one or both of 

the two components are included in the table below. For adverse reactions observed with more than 
one component of a fixed-dose combination, the highest frequency is listed in the table below. 

 

Blood and lymphatic system disorders 

Very rare Leukopeniaam, thrombocytopeniaam 

Immune system disorders 

Rare Anaphylactic reactionsa, hypersensitivity 

reactionsa 

Very rare Allergic reactionsam 

Metabolism and nutrition disorders 

Very rare Hyperglycaemiaam 

Psychiatric disorders 

Uncommon Insomniaam, mood changes (including anxiety)am, 

depressionam 

Rare Confusionam 

Nervous system disorders 

Common Somnolenceam, headache (especially at the 

beginning of treatment)am 

Uncommon Tremoram, dysgeusiaam, syncopeam, hypoesthesiaam, 

paraesthesiaam 

Very rare Hypertoniaam, peripheral neuropathyam 

Eye disorders 

Uncommon Visual disturbance (including diplopia)am 

Ear and labyrinth disorders 

Uncommon Tinnitusam 

Not known Vertigoa 

Cardiac disorders 

Common Dizzinessa,am, palpitationsa,am, peripheral 

oedemac,a,am* 

Very rare Myocardial infarctionam, arrhythmia (including 

bradycardia, ventricular tachycardia, and atrial 

fibrillation)am 

Vascular disorders 

Common Flushingam, hypotensionc,a,am 

Very rare Vasculitisam 

Respiratory, thoracic and mediastinal disorders 

Uncommon Dyspnoeaa, am, rhinitisam, cougha,am 

Gastrointestinal disorders 

Common Diarrhoeaa, abdominal painam, nauseaa,am 

Uncommon Vomitinga,am, dyspepsiaam, altered bowel habits 

(including diarrhoea and constipation)am, dry 

moutham 

Very rare Pancreatitisam, gastritisam, gingival hyperplasiaam 

Hepatobiliary disorders 

Very rare Hepatitisa,am, jaundicea,am, hepatic enzymes 

increased (mostly consistent with cholestasis)am 

Not known Liver disordera,**, liver failurea,*** 



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Skin and subcutaneous tissue disorders 

Uncommon Severe cutaneous adverse reactions (SCARs) 

including Stevens Johnson syndromea, toxic 

epidermal necrolysis (TEN)a, oral mucosal 

reactionsa, rasha,am, pruritusa,am, urticariaa,am, 

alopeciaam, purpuraam, skin decolourationam, 

hyperhidrosisam, exanthemaam 

Rare Angioedemaa, erythemaa 

Very rare Erythema multiformeam, exfoliative dermatitisam, 

Stevens-Johnson syndromeam, Quincke oedemaam, 

photosensitivityam 

Musculoskeletal and connective tissue disorders 

Common Arthralgiaa,am, ankle swellingam 

Uncommon Myalgiaam, muscle crampsam, back painam 

Renal and urinary disorders 

Uncommon Acute renal failurea, renal impairmenta, 

micturition disorderam, nocturiaam, increased 

urinary frequencyam 

Reproductive system and breast disorders 

Uncommon Impotenceam, gynaecomastiaam 

General disorders and administration site conditions 

Common Fatigueam 

Uncommon Chest painam, astheniaam, painam, malaiseam 

Investigations 

Common Hyperkalaemiaa 

Uncommon Liver enzyme increaseda, weight increaseam, 

weight decreaseam 

Rare Haemoglobin decreaseda, haematocrit decreaseda, 

blood creatinine increaseda 

Not known Hyponatraemiaa 
c Adverse reaction observed with Rasilamlo; 
a Adverse reaction observed with monotherapy with aliskiren; 
am Adverse reaction observed with monotherapy with amlodipine; 

* Peripheral oedema is a known, dose-dependent adverse reaction of amlodipine and has also been 

reported with aliskiren therapy in post-marketing experience. The most frequently reported adverse 

reaction for Rasilamlo in clinical trials was peripheral oedema, which occurred at a frequency lower 

than or equal to that of the corresponding amlodipine doses, but higher than with aliskiren; 

** Isolated cases of liver disorder with clinical symptoms and laboratory evidence of more marked 

hepatic dysfunction; 

***Including one case of “liver failure fulminant” reported in the post-marketing experience, for 

which a causal relationship with aliskiren cannot be excluded. 

 

Additional information on individual components 

Adverse reactions previously reported with one of the individual components may occur with 

Rasilamlo even if not observed in clinical trials. 

 

Aliskiren 

Description of selected adverse reactions: 

Hypersensitivity reactions including anaphylactic reactions and angioedema have occurred during 

treatment with aliskiren. 

 

In controlled clinical trials, angioedema and hypersensitivity reactions occurred rarely during 

treatment with aliskiren with rates comparable to treatment with placebo or comparators. 

 



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Cases of angioedema or symptoms suggestive of angioedema (swelling of the face, lips, throat and/or 

tongue) have also been reported in post-marketing experience. A number of these patients had a 

history of angioedema or symptoms suggestive of angioedema which in some cases was associated 

with the administration of other medicinal products known to cause angioedema, including RAAS 

blockers (ACEIs or ARBs). 

 

In post-marketing experience, cases of angioedema or angioedema-like reactions have been reported 

when aliskiren was co-administered with ACEIs and/or ARBs. 

 

Hypersensitivity reactions including anaphylactic reactions have also been reported in post-marketing 

experience (see section 4.4). 

 

In the event of any signs suggesting a hypersensitivity reaction/angioedema (in particular difficulties 

in breathing or swallowing, rash, itching, hives or swelling of the face, extremities, eyes, lips and/or 

tongue, dizziness) patients should discontinue treatment and contact the physician (see section 4.4). 

 

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

hypersensitivity reaction. 

 

In post-marketing experience, renal dysfunction and cases of acute renal failure have been reported in 

patients at risk (see section 4.4). 

 

Investigations 

In controlled clinical trials, clinically relevant changes in standard laboratory parameters were 

uncommonly associated with the administration of aliskiren. In clinical studies in hypertensive 

patients, aliskiren had no clinically important effects on total cholesterol, high density lipoprotein 

cholesterol (HDL-C), fasting triglycerides, fasting glucose or uric acid. 

 

Haemoglobin and haematocrit: Small decreases in haemoglobin and haematocrit (mean decreases of 

approximately 0.05 mmol/l and 0.16 volume percent, respectively) were observed. No patients 

discontinued therapy due to anaemia. This effect is also seen with other medicinal products acting on 

the RAAS, such as ACEIs and ARBs. 

 

Serum potassium: Increases in serum potassium have been observed with aliskiren and these may be 

exacerbated by concomitant use of other agents acting on the RAAS or by NSAIDs. Consistent with 

standard medical practice, periodic determination of renal function including serum electrolytes is 

advised if co-administration is considered necessary. 

 

Paediatric population 

Based on the limited amount of safety data available from a pharmacokinetic study of aliskiren 

treatment in 39 hypertensive children 6-17 years of age, the frequency, type and severity of adverse 

reactions in children are expected to be similar to that seen in hypertensive adults. As for other RAAS 

blockers, headache is a common adverse event in children treated with aliskiren. 

 

Amlodipine 

Exceptional cases of extrapyramidal syndrome have been reported. 

 

Reporting of suspected adverse reactions 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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4.9 Overdose 

 

Symptoms 

There is no experience of overdose with Rasilamlo. The most likely manifestation of overdose for 

Rasilamlo would be hypotension, related to the antihypertensive effect of aliskiren and amlodipine. 

 

With aliskiren, the most likely manifestation of overdose would be hypotension, related to the 

antihypertensive effect of aliskiren. 

 

With amlodipine, available data suggest that gross overdose could result in excessive peripheral 

vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension 

up to and including shock with fatal outcome, have been reported with amlodipine. 

 

Treatment 

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

 

Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular 

support including frequent monitoring of cardiac and respiratory function, elevation of extremities 

and attention to circulating fluid volume and urine output. 

 

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is 

no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the 

effects of calcium channel blockade. 

 

Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 

2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of 

amlodipine. 

 

Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit. 

 

In a study conducted in patients with end stage renal disease (ESRD) receiving haemodialysis, 

dialysis clearance of aliskiren was low (<2% of oral clearance). Therefore dialysis is not adequate to 

treat aliskiren over-exposure. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1 Pharmacodynamic properties 

 

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, renin inhibitors, ATC 

code: C09XA53 

 

Rasilamlo combines two antihypertensive compounds with complementary mechanisms to control 

blood pressure in patients with essential hypertension: aliskiren belongs to the class of direct renin 

inhibitors and amlodipine belongs to the calcium antagonist class. 

 



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Rasilamlo 

The use of combined treatment with aliskiren and amlodipine arises from the actions of these two 

medicinal products on different but complementary systems that regulate blood pressure. Calcium 

channel blockers act to prevent the influx of calcium into the vascular smooth muscle cells in the 

vessel wall, thereby preventing smooth muscle cell contraction and vasoconstriction. Renin inhibitors 

suppress the enzymatic activity of renin, and thereby block the formation of Angiotensin II, the major 

effector molecule of the renin-angiotensin-aldosterone system (RAAS). Angiotensin II causes 

vasoconstriction and sodium and water reabsorption. Thus, amlodipine directly inhibits 

vasoconstriction and reduces vascular resistance, while aliskiren, by controlling Ang II production, 

can also inhibit vasoconstriction but additionally shifts water and sodium balance toward levels 

necessary for normotensive conditions. The combined action of aliskiren and amlodipine on these two 

central blood pressure-regulating factors (vasoconstriction and RAAS-mediated hypertensive effects) 

results in more effective antihypertensive effects than seen with monotherapy. 

 

Rasilamlo was studied in a number of active and placebo-controlled trials and long-term trials which 

included a total of 5,570 hypertensive patients with mild to moderate hypertension (diastolic blood 

pressure between 90 mmHg and 109 mmHg). 

 

In hypertensive patients not controlled by the component monotherapies, once-daily administration of 

Rasilamlo provided dose-dependent clinically meaningful reductions in both systolic and diastolic 

blood pressure. 

 

When given to patients whose blood pressure was not adequately controlled by either aliskiren or 

amlodipine, Rasilamlo results in greater blood pressure reductions after one week of treatment than 

the component monotherapies and a near-maximal effect is achieved after four weeks of therapy. 

 

In a study in 820 randomised patients not adequately responsive to aliskiren 300 mg treatment, the 

combination of aliskiren/amlodipine 300 mg/10 mg produced systolic/diastolic mean blood pressure 

reductions of 18.0/13.1 mmHg, which were statistically significantly greater than aliskiren 300 mg 

monotherapy. The combination at a dose of 300 mg/5 mg also showed statistically significantly 

greater blood pressure reduction than aliskiren 300 mg monotherapy. In a subset of 584 patients, the 

combination of aliskiren/amlodipine produced additional systolic/diastolic mean blood pressure 

reductions of 7.9/4.8 mmHg and 11.7/7.7 mmHg for the 300/5 mg and 300/10 mg strengths 

respectively compared to aliskiren 300 mg (the subset constitutes patients without aberrant readings, 

defined as difference in systolic blood pressure (SBP) ≥10 mmHg at baseline or endpoint). 

 

In a study in 847 randomised patients not adequately responsive to amlodipine 10 mg treatment, the 

combination of aliskiren/amlodipine 150 mg/10 mg and 300 mg/10 mg produced systolic/diastolic 

mean blood pressure reductions of 11.0/9.0 mmHg and 14.4/11.0 mmHg respectively, which were 

statistically greater than for amlodipine 10 mg monotherapy. In a subset of 549 patients, the 

combination of aliskiren/amlodipine produced additional systolic/diastolic mean blood pressure 

reductions of 4.0/2.2 mmHg and 7.6/4.7 mmHg for the 150/10 mg and 300/10 mg strengths 

respectively compared to amlodipine 10 mg (the subset constitutes patients without aberrant readings, 

defined as difference in SBP ≥10 mmHg at baseline or endpoint). 

 

In a study in 545 randomised patients not adequately responsive to 5 mg amlodipine, the combination 

of aliskiren 150 mg/amlodipine 5 mg resulted in greater blood pressure reduction than those patients 

remaining on amlodipine 5 mg. 

 



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In an 8-week randomised, double-blind, placebo-controlled, parallel group factorial study in 

1,688 randomised patients with mild to moderate hypertension, treatment with Rasilamlo at doses 

from 150 mg/5 mg to 300 mg/10 mg produced dose-dependent clinically meaningful mean blood 

pressure reductions (systolic/diastolic) ranging between 20.6/14.0 mmHg and 23.9/16.5 mmHg, 

respectively, compared to 15.4/10.2 mmHg for aliskiren 300 mg, 21.0/13.8 mmHg for amlodipine 

10 mg and 6.8/5.4 mmHg with placebo in a population of patients with mean baseline blood pressure 

of 157.3/99.7 mmHg. These were statistically significant versus placebo and aliskiren for all doses. 

The blood pressure reductions with the combination were maintained throughout the entire 24-hour 

dose interval. In a subset of 1,069 patients, Rasilamlo produced mean blood pressure reductions 

(systolic/diastolic) ranging between 20.6/13.6 mmHg and 24.2/17.3 mmHg (the subset of patients 

without aberrant readings, defined as difference in SBP ≥10 mmHg at baseline or endpoint). 

 

The safety of Rasilamlo has been evaluated in studies of up to one year duration. 

 

The effects of Rasilamlo on all cause and cardiovascular mortality and on cardiovascular morbidity 

and target organ damage are currently unknown. 

 

Rasilamlo has been administered to more than 2,800 patients in completed clinical trials, including 

372 patients for one year or more. Treatment with Rasilamlo at doses up to 300 mg/10 mg had an 

overall incidence of adverse experiences similar to the component monotherapies. The incidence of 

adverse events did not show any association with gender, age, body mass index, race or ethnicity. 

There were no new adverse reactions which occurred specifically with Rasilamlo in addition to those 

known to be associated with the individual monotherapies. In a double-blind, randomised placebo-

controlled study in 1,688 patients with mild or moderate hypertension, discontinuation of therapy due 

to a clinical adverse event occurred in 1.7% of patients treated with Rasilamlo versus 1.5% of 

patients given placebo. 

 

Aliskiren 

Aliskiren is an orally active, non-peptide, potent and selective direct inhibitor of human renin. 

 

By inhibiting the enzyme renin, aliskiren inhibits the RAAS at the point of activation, blocking the 

conversion of angiotensinogen to angiotensin I and decreasing levels of angiotensin I and 

angiotensin II. Whereas other medicinal products that inhibit the RAAS (ACEI and angiotensin II 

receptor blockers (ARB)) cause a compensatory rise in plasma renin activity (PRA), treatment with 

aliskiren decreases PRA in hypertensive patients by approximately 50 to 80%. Similar reductions 

were found when aliskiren was combined with other antihypertensive medicinal products. The 

clinical implications of the differences in effect on PRA are not known at the present time. 

 

Hypertension 

In hypertensive patients, once-daily administration of 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, and was independent of age, gender, body mass 

index and ethnicity. Aliskiren has been studied in 1,864 patients aged 65 years or older, and in 

426 patients aged 75 years or older. 

 

Aliskiren monotherapy studies have shown blood-pressure-lowering effects comparable to other 

classes of antihypertensive medicinal products including selected ACEI and ARB. Compared to a 

diuretic (hydrochlorothiazide, HCTZ), aliskiren 300 mg lowered systolic/diastolic blood pressure by 

17.0/12.3 mmHg, compared to 14.4/10.5 mmHg for HCTZ 25 mg after 12 weeks of treatment. 

 

Combination therapy studies are available for aliskiren added to the diuretic hydrochlorothiazide and 

the beta blocker atenolol. These combinations were well tolerated. Aliskiren induced an additive 

blood-pressure-lowering effect when added to hydrochlorothiazide. 



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The efficacy and safety of aliskiren-based therapy were compared to ramipril-based therapy in a 9-

month non-inferiority study in 901 elderly patients (≥65 years) with essential systolic hypertension. 

Aliskiren 150 mg or 300 mg per day or ramipril 5 mg or 10 mg per day were administered for 

36 weeks with optional add-on therapy of hydrochlorothiazide (12.5 mg or 25 mg) at week 12, and 

amlodipine (5 mg or 10 mg) at week 22. Over the 12 week period, aliskiren monotherapy lowered 

systolic/diastolic blood pressure by 14.0/5.1 mmHg, compared to 11.6/3.6 mmHg for ramipril, 

consistent with aliskiren being non-inferior to ramipril at the dosages chosen and the differences in 

systolic and diastolic blood pressure were statistically significant. Tolerability was comparable in 

both treatment arms, however cough was more often reported with the ramipril regimen than the 

aliskiren regimen (14.2% vs. 4.4%), whilst diarrhoea was more common with the aliskiren regimen 

than for the ramipril regimen (6.6% vs. 5.0%). 

 

In a 8-week study in 754 hypertensive elderly (≥65 years) and very elderly patients (30% ≥75 years) 

aliskiren at doses of 75 mg, 150 mg and 300 mg provided statistically significant superior reduction 

in blood pressure (both systolic and diastolic) when compared to placebo. No additional blood 

pressure lowering effect was detected with 300 mg aliskiren compared to 150 mg aliskiren. All three 

doses were well tolerated in both elderly and very elderly patients. 

 

There has been no evidence of first-dose hypotension and no effect on pulse rate in patients treated in 

controlled clinical studies. Excessive hypotension was uncommonly (0.1%) seen in patients with 

uncomplicated hypertension treated with aliskiren alone. Hypotension was also uncommon (<1%) 

during combination therapy with other antihypertensive medicinal products. With cessation of 

treatment, blood pressure gradually returned towards baseline levels over a period of several weeks, 

with no evidence of a rebound effect for blood pressure or PRA. 

 

In a 36-week study involving 820 patients with ischaemic left ventricular dysfunction, no changes in 

ventricular remodelling as assessed by left ventricular end systolic volume were detected with 

aliskiren compared to placebo on top of background therapy. 

 

The combined rates of cardiovascular death, hospitalisation for heart failure, recurrent heart attack, 

stroke and resuscitated sudden death were similar in the aliskiren group and the placebo group. 

However, in patients receiving aliskiren there was a significantly higher rate of hyperkalaemia, 

hypotension and kidney dysfunction when compared to the placebo group. 

 

Aliskiren was evaluated for cardiovascular and/or renal benefit in a double-blind placebo controlled 

randomised trial in 8,606 patients with type 2 diabetes and chronic kidney disease (evidenced by 

proteinuria and/or GFR <60 ml/min/1.73 m2) with or without cardiovascular disease. In most patients 

arterial blood pressure was well controlled at baseline. The primary endpoint was a composite of 

cardiovascular and renal complications. 

 

In this study, aliskiren 300 mg was compared to placebo when added to standard of care which 

included either an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. The 

study was discontinued prematurely because the participants were unlikely to benefit from aliskiren. 

The final study results indicated a hazard ratio for the primary endpoint of 1.097 in favour of placebo 

(95.4% Confidence Interval: 0.987, 1.218, 2-sided p=0.0787). In addition, an increased incidence of 

adverse events was observed with aliskiren compared to placebo (38.2% versus 30.3%). In particular 

there was an increased incidence of renal dysfunction (14.5% versus 12.4%), hyperkalaemia (39.1% 

versus 29.0%), hypotension-related events (19.9% versus 16.3%) and adjudicated stroke endpoints 

(3.4% versus 2.7%). The increased incidence of stroke was greater in patients with renal 

insufficiency. 

 



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Aliskiren 150 mg (increased to 300 mg if tolerated) added to conventional therapy was evaluated in a 

double-blind placebo-controlled randomised trial in 1,639 patients with reduced ejection fraction 

hospitalised for an episode of acute heart failure (NYHA Class III–IV) who were haemodynamically 

stable at baseline. The primary endpoint was cardiovascular death or heart failure rehospitalisation 

within 6 months; secondary endpoints were assessed within 12 months. 

 

The study showed no benefit of aliskiren when administered on top of standard therapy for acute 

heart failure and an increased risk of cardiovascular events in patients with diabetes mellitus. Study 

results indicated a non-significant effect of aliskiren with a hazard ratio of 0.92 (95% Confidence 

Interval: 0.76-1.12; p=0.41, aliskiren vs. placebo). Different treatment effects of aliskiren were 

reported for overall mortality within 12 months dependent on diabetes mellitus status. In the subgroup 

of patients with diabetes mellitus the hazard ratio was 1.64 in favour of placebo (95% Confidence 

Interval: 1.15-2.33), whereas the hazard ratio in the subgroup of patients without diabetes was 0.69 in 

favour of aliskiren (95% Confidence Interval: 0.50-0.94); p-value for interaction = 0.0003. An 

increased incidence of hyperkalaemia (20.9% versus 17.5%), renal impairment/renal failure (16.6% 

versus 12.1%) and hypotension (17.1% versus 12.6%) was observed in the aliskiren group compared 

with placebo and was greater in patients with diabetes. 

 

Effects of aliskiren on mortality and cardiovascular morbidity are currently unknown. 

 

No long-term efficacy data for aliskiren in patients with heart failure are currently available. 

 

Cardiac electrophysiology 

No effect on QT interval was reported in a randomised, double-blind, placebo, and active-controlled 

study using standard and Holter electrocardiography. 

 

Amlodipine 

The amlodipine component of Rasilamlo inhibits the transmembrane entry of calcium ions into 

cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is 

due to a direct relaxant effect on vascular smooth muscle, causing reductions in peripheral vascular 

resistance and in blood pressure. Experimental data suggest that amlodipine binds to both 

dihydropyridine and non-dihydropyridine binding sites. 

 

The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the 

movement of extracellular calcium ions into these cells through specific ion channels. 

 

Following administration of therapeutic doses to patients with hypertension, amlodipine produces 

vasodilatation resulting in a reduction of supine and standing blood pressures. These decreases in 

blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine 

levels with chronic dosing. 

 

Plasma concentrations correlate with effect in both young and elderly patients. 

 

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a 

decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal 

plasma flow without change in filtration fraction or proteinuria. 

 

As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest and 

during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have 

generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on 

left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been 

associated with a negative inotropic effect when administered in the therapeutic dose range to intact 

animals and humans, even when co-administered with beta blockers to humans. 

 



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Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals 

or humans. In clinical studies in which amlodipine was administered in combination with beta 

blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic 

parameters were observed. 

 

Amlodipine has demonstrated beneficial clinical effects in patients with chronic stable angina, 

vasospastic angina and angiographically documented coronary artery disease. 

 

Use in patients with heart failure 

Calcium channel blockers, including amlodipine, should be used with caution in patients with 

congestive heart failure, as they may increase the risk of future cardiovascular events and mortality. 

 

Use in patients with hypertension 

A randomised double-blind morbidity-mortality study called the Antihypertensive and Lipid-

Lowering treatment to prevent Heart Attack Trial (ALLHAT) was performed to compare newer 

therapies: amlodipine 2.5-10 mg/day (calcium channel blocker) or lisinopril 10-40 mg/day (ACE-

inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/day in mild 

to moderate hypertension. 

 

A total of 33,357 hypertensive patients aged 55 or older were randomised and followed for a mean of 

4.9 years. The patients had at least one additional coronary heart disease risk factor, including: 

previous myocardial infarction or stroke (>6 months prior to enrollment) or documentation of other 

atherosclerotic cardiovascular disease (overall 51.5%), type 2 diabetes (36.1%), high density 

lipoprotein - cholesterol <35 mg/dl or <0.906 mmol/l (11.6%), left ventricular hypertrophy diagnosed 

by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%). 

 

The primary endpoint was a composite of fatal coronary heart disease or non-fatal myocardial 

infarction. There was no significant difference in the primary endpoint between amlodipine-based 

therapy and chlorthalidone-based therapy: risk ratio (RR) 0.98 95% CI (0.90-1.07) p=0.65. Among 

secondary endpoints, the incidence of heart failure (component of a composite combined 

cardiovascular endpoint) was significantly higher in the amlodipine group as compared to the 

chlorthalidone group (10.2% vs 7.7%, RR 1.38, 95% CI [1.25-1.52] p<0.001). However, there was 

no significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-

based therapy RR 0.96 95% CI [0.89-1.02] p=0.20. 

 

Paediatric population 

The European Medicines Agency has waived the obligation to submit the results of studies with 

Rasilamlo in all subsets of the paediatric population in essential hypertension (see section 4.2 for 

information on paediatric use). 

 

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 Cmax 
by 85% and AUC by 70%. At steady state meals with low fat content reduce Cmax by 76% and AUC 

0-tau by 67% in hypertensive patients. 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. 

 

Transporters 

MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption 

and biliary excretion of aliskiren in pre-clinical studies. 

 



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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. 

 

Biotransformation and elimination 

The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as 

unchanged compound in the faeces (78%). Approximately 1.4% of the total oral dose is metabolised. 

The enzyme responsible for this metabolism is CYP3A4. Approximately 0.6% of the dose is 

recovered in urine following oral administration. Following intravenous administration, mean plasma 

clearance is approximately 9 l/h. 

 

Linearity 

Exposure to aliskiren increased more than in proportion to the increase in dose. After single dose 

administration in the dose range of 75 to 600 mg, a 2-fold increase in dose results in a ~2.3 and 2.6-

fold increase in AUC and Cmax, respectively. At steady state the non-linearity may be more 

pronounced. Mechanisms responsible for deviation from linearity have not been identified. A possible 

mechanism is saturation of transporters at the absorption site or at the hepatobiliary clearance route. 

 

Paediatric population 

In a pharmacokinetic study of aliskiren treatment in 39 paediatric hypertensive patients aged 6 to 

17 years given daily doses of 2 mg/kg or 6 mg/kg aliskiren administered as granules 

(3.125 mg/tablet), pharmacokinetic parameters were similar to those in adults. The results of this 

study did not suggest that age, body weight or gender have any significant effect on aliskiren 

systemic exposure (see section 4.2). 

 

Results from an in vitro MDR1 human tissue study suggested an age and tissue dependent pattern of 

MDR1 (P-gp) transporter maturation. A high inter-individual variability of mRNA expression levels 

was observed (up to 600-fold). Hepatic MDR1 mRNA expression was statistically significantly lower 

in samples from foetuses, neonates and infants up to 23 months. 

 

The age at which the transporter system is mature cannot be determined. There is a potential for 

aliskiren overexposure in children with an immature MDR1 (P-gp) system (see “Transporters” above 

and sections 4.2, 4.4 and 5.3). 

 

Amlodipine 

Absorption 

After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations of 

amlodipine are reached in 6-12 hours. Absolute bioavailability has been estimated as between 64% 

and 80%. Amlodipine bioavailability is unaffected by food ingestion. 

 

Distribution 

The volume of distribution is approximately 21 l/kg. In vitro studies with amlodipine have shown that 

approximately 97.5% of circulating amlodipine is bound to plasma proteins. 

 

Biotransformation and elimination 

Amlodipine is extensively (approximately 90%) metabolised in the liver to inactive metabolites, with 

10% of the parent compound and 60% of the metabolites excreted in the urine. 

 

Amlodipine elimination from plasma is biphasic with a terminal elimination half-life of 

approximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration 

for 7-8 days. 

 

Linearity 

Amlodipine exhibits linear pharmacokinetics between the therapeutic dose range of 5 mg and 10 mg. 



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Aliskiren/amlodipine 

Following oral administration of Rasilamlo, the median peak plasma concentration time is within 

3 hours for aliskiren and 8 hours for amlodipine. The rate and extent of absorption of Rasilamlo are 

similar in fasting state to those of aliskiren and amlodipine when administered as individual 

monotherapies. A bioequivalence study under light meal conditions has not been conducted for 

Rasilamlo. 

 

The results from a food effect study using a standard high fat meal with the 300 mg/10 mg fixed 

combination tablet showed that food reduced the rate and extent of absorption of aliskiren in the 

fixed combination tablet with a similar magnitude of effect as for aliskiren monotherapy. Consistent 

with the monotherapy formulation, food had no effect on the pharmacokinetics of amlodipine in the 

fixed combination tablet. 

 

Characteristics in patients 

Aliskiren 

Aliskiren is an effective once-a-day antihypertensive treatment in adult patients, regardless of gender, 

age, body mass index and ethnicity. 

 

The AUC is 50% higher in elderly (>65 years) than in young subjects. Gender, weight and ethnicity 

have no clinically relevant influence on aliskiren pharmacokinetics. 

 

The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renal 

insufficiency. Relative AUC and Cmax of aliskiren in subjects with renal impairment ranged between 

0.8 to 2 times the levels in healthy subjects following single dose administration and at steady state. 

These observed changes, however, did not correlate with the severity of renal impairment. No 

adjustment of the initial dosage of aliskiren is required in patients with mild to moderate renal 

impairment (see sections 4.2 and 4.4). Aliskiren is not recommended in patients with severe renal 

impairment (glomerular filtration rate (GFR) <30 ml/min/1.73 m2). 

 

The pharmacokinetics of aliskiren were evaluated in patients with end stage renal disease receiving 

haemodialysis. Administration of a single oral dose of 300 mg aliskiren was associated with very 

minor changes in the pharmacokinetics of aliskiren (change in Cmax of less than 1.2 fold; increase in 

AUC of up to 1.6 fold) compared to matched healthy subjects. Timing of haemodialysis did not 

significantly alter the pharmacokinetics of aliskiren in ESRD patients. Therefore, if administration of 

aliskiren in ESRD patients receiving haemodialysis is considered necessary, no dose adjustment is 

warranted in these patients. However, the use of aliskiren is not recommended in patients with severe 

renal impairment (see section 4.4). 

 

The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe liver 

disease. Consequently, no adjustment of the initial dose of aliskiren is required in patients with mild 

to severe hepatic impairment. 

 

Amlodipine 

The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger 

subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and 

elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with 

congestive heart failure were as expected for the patient age group in this study (see section 4.4). 

 

A population pharmacokinetic study has been conducted in 74 hypertensive children aged from 1 to 

17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving 

amlodipine between 1.25 and 20 mg given either once or twice daily. In children 6 to 12 years and in 

adolescents 13-17 years of age the typical oral clearance (CL/F) was 22.5 and 27.4 l/hr respectively 

in males and 16.4 and 21.3 l/hr respectively in females. Large variability in exposure between 

individuals was observed. Data reported in children below 6 years are limited. 

 



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The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. 

 

Very limited clinical data are available regarding amlodipine administration in patients with hepatic 

impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine with 

resulting increase in AUC of approximately 40-60%. Therefore caution should be exercised in 

patients with hepatic impairment. 

 

5.3 Preclinical safety data 

 

Aliskiren 

Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic mouse study. No 

carcinogenic potential was detected. One colonic adenoma and one caecal adenocarcinoma recorded 

in rats at the dose of 1,500 mg/kg/day were not statistically significant. Although aliskiren has known 

irritation potential, safety margins obtained in humans at the dose of 300 mg during a study in healthy 

volunteers were considered to be appropriate at 9-11-fold based on faecal concentrations or 6-fold 

based on mucosa concentrations in comparison with 250 mg/kg/day in the rat carcinogenicity study. 

 

Aliskiren was devoid of any mutagenic potential in the in vitro and in vivo mutagenicity studies. The 

assays included in vitro assays in bacterial and mammalian cells and in vivo assessments in rats. 

 

Reproductive toxicity studies with aliskiren did not reveal any evidence of embryofoetal toxicity or 

teratogenicity at doses up to 600 mg/kg/day in rats or 100 mg/kg/day in rabbits. Fertility, pre-natal 

development and post-natal development were unaffected in rats at doses up to 250 mg/kg/day. The 

doses in rats and rabbits provided systemic exposures of 1 to 4 and 5 times higher, respectively, than 

the maximum recommended human dose (300 mg). 

 

Safety pharmacology studies did not reveal any adverse effects on central nervous, respiratory or 

cardiovascular function. Findings during repeat-dose toxicity studies in animals were consistent with 

the known local irritation potential or the expected pharmacological effects of aliskiren. 

 

Juvenile Animal Studies 

A repeat-dose toxicity study was conducted in juvenile rats 8 days post-partum for 4 weeks with 

aliskiren dosing at 30, 100 or 300 mg/kg/day. High acute mortality (within hours) and severe 

morbidity were observed at 100 and 300 mg/kg/day (2.3- and 6.8-fold the maximum recommended 

human dose (MRHD) on mg/m2 basis assuming a 60 kg adult patient) with no cause of death 

established and occurring without signs or prodromal symptoms. The ratio of lethal dose of 

100 mg/kg/day and no-observed-adverse-effect-level (NOAEL) of 30 mg/kg/day is unexpectedly low. 

 

Another repeat-dose toxicity study was conducted in juvenile rats 14 days post-partum for 8 weeks 

with aliskiren dosing at 30, 100 or 300 mg/kg/day. Delayed mortality was observed at 300 mg/kg/day 

(8.5-fold the MRHD on mg/m2 basis assuming a 60 kg adult patient) with no cause of death 

established. 

 

For the surviving juvenile rats, no effects on behavioural or reproductive performance were observed. 

 

Plasma aliskiren exposure (AUC) in rats aged 8 days was nearly 4-fold higher than that in rats aged 

14 days at 100 mg/kg/day. Plasma aliskiren exposure in rats aged 14 days was between 85- and 387-

fold higher than that in adult rats aged 64 days. 

 

A single dose study was conducted in juvenile rats aged 14, 21, 24, 28, 31 or 36 days post-partum. 

No mortality or significant toxicity was observed. The plasma exposure was approximately 100-fold 

higher in rats aged 14 days and 3-fold higher in rats aged 21 days compared to adult rats. 

 



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A mechanistic study was conducted to investigate the relationship between age, aliskiren exposure 

and MDR1 and OATP2 expression maturation in rats. The results showed that developmental 

changes of aliskiren exposure correlated with the ontogeny of transporter maturation in jejunum, liver, 

kidney and brain. 

 

The pharmacokinetics of aliskiren was evaluated in rats aged from 8 to 28 days after intravenous 

administration of aliskiren 3 mg/kg. The clearance of aliskiren increased in an age-dependent 

manner. Clearance in rats aged 8 or 14 days was similar, but at these ages the clearance was only 

about 23% of clearance in rats aged 21 days and 16% of clearance in rats aged 28 days. 

 

These studies indicate that excessive aliskiren exposure (>400-fold higher in 8-day old rats compared 

with adult rats) and high acute toxicity in juvenile rats are caused by immature MDR1, which 

suggests that in paediatric patients with immature MDR1, there is a potential for aliskiren 

overexposure (see sections 4.2, 4.3 and 5.2). 

 

Amlodipine 

Safety data for amlodipine are well established both clinically and non-clinically. 

 

Reproductive toxicology 

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of 

labour and decreased pup survival at dosages approximately 50 times greater than the maximum 

recommended dosage for humans based on mg/kg. 

 

Impairment of fertility 

There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 

14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human 

dose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipine 

besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma 

follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in 

the number of mature spermatids and Sertoli cells. 

 

Carcinogenesis, mutagenesis 

Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to 

provide daily dosage levels of 0.5, 1.25 and 2.5 mg/kg/day showed no evidence of carcinogenicity. 

The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose 

of 10 mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats. 

 

Mutagenicity studies revealed no effects related to the medicinal product at either the gene or 

chromosome levels. 

 

*Based on patient weight of 50 kg 

 

Rasilamlo 

Preclinical safety studies have demonstrated that the combination of aliskiren and amlodipine was 

well tolerated in rats. The findings from the 2- and 13-week oral toxicity studies in rats were 

consistent with those of aliskiren and amlodipine when both active substances are administered alone. 

There were no new toxicities or increased severity of the toxicities which were associated with either 

component. 

 

 



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6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Tablet core 

Cellulose microcrystalline 

Crospovidone 

Povidone 

Magnesium stearate 

Silica colloidal anhydrous 

 

Coating 

Hypromellose 

Titanium dioxide (E171) 

Macrogol 

Talc 

Iron oxide yellow (E172) 

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

PVC/PCTFE – Alu blisters: 

18 months 

 

PA/Alu/PVC – Alu blisters: 

18 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 

 

PVC/polychlorotrifluoroethylene (PCTFE) - Alu calendar blisters: 

Single pack containing 14, 28, 56, 98 tablets 

Multi-packs containing 280 tablets (20 packs of 14) 

 

PVC/polychlorotrifluoroethylene (PCTFE) - Alu blisters: 

Single pack containing 30, 90 tablets 

Unit dose pack (perforated unit dose blister) containing 56x1 tablet 

Multi-packs of unit dose (perforated unit dose blister) containing 98x1 tablet (2 packs of 49x1) 

 

PA/Alu/PVC – Alu calendar blisters: 

Single pack containing 14, 28, 56 tablets 

Multi-packs containing 98 tablets (2 packs of 49) and 280 tablets (20 packs of 14) 

 

Not all pack sizes or strengths may be marketed. 

 



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6.6 Special precautions for disposal 

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/686/029-042 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 14 April 2011 

Date of latest renewal: 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this medicinal product is available on the website of the European 

Medicines Agency http://www.ema.europa.eu 

 



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1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 300 mg/10 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each film-coated tablet contains 300 mg aliskiren (as hemifumarate) and 10 mg amlodipine (as 

besylate). 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Film-coated tablet. 

 

Brown-yellow, convex, ovaloid tablet with a bevelled edge, with “T12” debossed on one side and  

“NVR” on the other. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Rasilamlo is indicated for the treatment of essential hypertension in adult patients whose blood 

pressure is not adequately controlled with aliskiren or amlodipine used alone. 

 

4.2 Posology and method of administration 

 

Posology 

The recommended dose of Rasilamlo is one tablet per day. 

 

The antihypertensive effect is manifested within 1 week and the effect is near maximal at around 

4 weeks. If blood pressure remains uncontrolled after 4 to 6 weeks of therapy, the dose may be 

titrated up to a maximum of 300 mg aliskiren/10 mg amlodipine. Dose should be individualised and 

adjusted according to the patient’s clinical response. 

 

Rasilamlo may be administered with other antihypertensive medicinal products with the exception of 

use in combination with angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor 

blockers (ARB) in patients with diabetes mellitus or renal impairment (glomerular filtration rate 

(GFR) <60 ml/min/1.73 m2) (see sections 4.3, 4.4 and 5.1). 

 

Posology in patients not adequately controlled with aliskiren or amlodipine monotherapy  

Rasilamlo 300 mg/10 mg may be administered in patients whose blood pressure is not adequately 

controlled with aliskiren 300 mg or amlodipine 10 mg alone or Rasilamlo 150 mg/10 mg or 

Rasilamlo 300 mg/5 mg. 

 

A patient who experiences dose limiting adverse reactions on either component alone may be 

switched to Rasilamlo containing a lower dose of that component to achieve similar blood pressure 

reductions. 

 

Individual dose titration with each of the two components may be recommended before changing to 

the fixed combination. When clinically appropriate and in line with the above-mentioned posology, 

direct change from monotherapy to the fixed combination may be considered. 

 



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Special populations 

Renal impairment 

No adjustment of the initial dose is required for patients with mild to moderate renal impairment 

(GFR 89-60 ml/min/1.73 m2 and 59-30 ml/min/1.73 m2, respectively, see sections 4.4 and 5.2). 

Rasilamlo is not recommended in patients with severe renal impairment (GFR <30 ml/min/1.73 m2). 

 

Hepatic impairment 

Amlodipine dosage recommendations have not been established in patients with mild to moderate 

hepatic impairment. The pharmacokinetics of amlodipine have not been studied in severe hepatic 

impairment; therefore, caution should be exercised when administering Rasilamlo to patients with 

hepatic impairment. 

 

Elderly people (over 65 years) 

There is limited experience with Rasilamlo, in particular in patients aged 75 years or older. 

Therefore, particular caution should be exercised in these patients. The recommended starting dose of 

aliskiren in elderly patients is 150 mg. No clinically meaningful additional blood pressure reduction 

is observed by increasing the dose to 300 mg in the majority of elderly patients. 

 

Paediatric population 

The safety and efficacy of Rasilamlo in children below age 18 have not been established. No data are 

available. 

 

Rasilamlo is contraindicated in children from birth to less than 2 years and should not be used in 

children aged 2 to less than 6 years because of safety concerns due to potential aliskiren overexposure 

(see sections 4.3, 4.4, 5.2, and 5.3). 

 

Method of administration 

Oral use. The tablets should be swallowed whole with some water. Rasilamlo should be taken with a 

light meal once a day, preferably at the same time each day. Concomitant intake with fruit juice 

and/or drinks containing plant extracts (including herbal teas) should be avoided (see section 4.5). 

 

4.3 Contraindications 

 

 Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or 
other dihydropyridine derivatives. 

 History of angioedema with aliskiren. 

 Hereditary or idiopathic angioedema 

 Second and third trimesters of pregnancy (see section 4.6). 

 The concomitant use of aliskiren with ciclosporin and itraconazole, two highly potent P-
glycoprotein (P-gp) inhibitors, and other potent P-gp inhibitors (e.g. quinidine), is 

contraindicated (see section 4.5). 

 The concomitant use of Rasilamlo with an ACEI or an ARB is contraindicated in patients with 
diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) (see sections 4.5 and 5.1). 

 Severe hypotension. 

 Shock (including cardiogenic shock). 

 Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis). 

 Haemodynamically unstable heart failure after acute myocardial infarction. 

 Children from birth to less than 2 years (see sections 4.2 and 5.3). 
 



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4.4 Special warnings and precautions for use 

 

General 

In the event of severe and persistent diarrhoea, Rasilamlo therapy should be stopped (see section 4.8). 

 

As with any antihypertensive medicinal product, excessive reduction of blood pressure in patients 

with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial 

infarction or stroke. 

 

The safety and efficacy of amlodipine in hypertensive crisis have not been established. 

 

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) 

Hypotension, syncope, stroke, hyperkalaemia, and decreased renal function (including acute renal 

failure) have been reported in susceptible individuals, especially if combining medicinal products that  

affect this system (see section 5.1). Dual blockade of the RAAS by combining aliskiren with an ACEI 

or an ARB is therefore not recommended. If dual blockade therapy is considered absolutely 

necessary, this should only occur under specialist supervision and subject to frequent close monitoring 

of renal function, electrolytes and blood pressure. 

 

Heart failure 

Calcium channel blockers, including amlodipine, should be used with caution in patients with 

congestive heart failure, as they may increase the risk of future cardiovascular events and mortality. 

 

No data on cardiovascular mortality and morbidity are available for aliskiren in patients with heart 

failure (see section 5.1). 

 

Aliskiren should be used with caution in patients with heart failure treated with furosemide or 

torasemide (see section 4.5). 

 

Risk of symptomatic hypotension 

Symptomatic hypotension could occur after initiation of treatment with Rasilamloin the following 

cases: 

 Patients with marked volume depletion or patients with salt depletion (e.g. those receiving high 
doses of diuretics) or 

 Combined use of aliskiren with other agents acting on the RAAS. 
The volume or salt depletion should be corrected prior to administration of Rasilamlo, or the 

treatment should start under close medical supervision. In patients with uncomplicated hypertension 

treated with Rasilamlo in short-term controlled trials, the incidence of hypotension was low (0.2%). 

 

Renal impairment 

In clinical studies aliskiren has not been investigated in hypertensive patients with severe renal 

impairment (serum creatinine ≥150 μmol/l or 1.70 mg/dl in women and ≥177 μmol/l or 2.00 mg/dl in 

men and/or estimated GFR <30 ml/min/1.73 m2), history of dialysis, nephrotic syndrome or 

renovascular hypertension. Rasilamlo is not recommended in patients with severe renal impairment 

(GFR <30 ml/min/1.73 m2). 

 

As for other medicinal products acting on the renin-angiotensin-aldosterone system, caution should be 

exercised when Rasilamlo 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, diabetes mellitus 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. 

 



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Increases in serum potassium have been observed with aliskiren in post-marketing experience and 

these may be exacerbated by concomitant use of other agents acting on the RAAS or by non-steroidal 

anti-inflammatory drugs (NSAIDs). Consistent with standard medical practice, periodic 

determination of renal function including serum electrolytes is advised if co-administration is 

considered necessary. 

 

Hepatic impairment 

The half life of amlodipine is prolonged and AUC values are higher in patients with impaired liver 

function; dosage recommendations have not been established. Caution should be exercised when 

administering Rasilamlo to patients with hepatic impairment (see sections 4.2 and 5.2). 

 

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy 

As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral 

stenosis, or obstructive hypertrophic cardiomyopathy. 

 

Renal artery stenosis 

No controlled clinical data are available on the use of Rasilamlo in patients with unilateral or 

bilateral renal artery stenosis, or stenosis to a solitary kidney. However, as with other medicinal 

products acting on the renin-angiotensin-aldosterone system, there is an increased risk of renal 

insufficiency, including acute renal failure, when patients with renal artery stenosis are treated with 

aliskiren. Therefore caution should be exercised in these patients. If renal failure occurs, treatment 

should be discontinued. 

 

Anaphylactic reactions and angioedema 

Anaphylactic reactions have been observed during treatment with aliskiren from post-marketing 

experience (see section 4.8). As with other medicinal products acting on the renin-angiotensin-

aldosterone system, angioedema or symptoms suggestive of angioedema (swelling of the face, lips, 

throat and/or tongue) have been reported in patients treated with aliskiren. 

 

A number of these patients had a history of angioedema or symptoms suggestive of angioedema, 

which in some cases followed use of other medicinal products that can cause angioedema, including 

RAAS blockers (angiotensin converting enzyme inhibitors or angiotensin receptor blockers) (see 

section 4.8). 

 

In post-marketing experience, angioedema or angioedema-like reactions have been reported when 

aliskiren was co-administered with ACEIs and/or ARBs (see section 4.8). 

 

Special caution is necessary in patients with a hypersensitivity predisposition. 

 

Patients with history of angioedema may be at increased risk of experiencing angioedema during 

treatment with aliskiren (see sections 4.3 and 4.8). Caution should therefore be exercised when 

prescribing aliskiren to patients with a history of angioedema, and such patients should be closely 

monitored during treatment (see section 4.8) especially at the beginning of the treatment. 

 

If anaphylactic reactions or angioedema occur, Rasilamlo should be promptly discontinued and 

appropriate therapy and monitoring provided until complete and sustained resolution of signs and 

symptoms has occurred. Patients should be informed to report to the physician any signs suggestive of 

allergic reactions, in particular difficulties in breathing or swallowing, swelling of face, extremities, 

eyes, lips or tongue. Where there is involvement of the tongue, glottis or larynx adrenaline should be 

administered. In addition, measures necessary to maintain patent airways should be provided. 

 



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Paediatric population 

Aliskiren is a P-glycoprotein (P-gp) substrate, and there is a potential for aliskiren overexposure in 

children with an immature P-gp drug transporter system. The age at which the transporter system is 

mature cannot be determined (see sections 5.2 and 5.3). Therefore, Rasilamlo is contraindicated in 

children from birth to less than 2 years and should not be used in children aged 2 to less than 6 years. 

 

Limited safety data are available from a pharmacokinetic study of aliskiren treatment in 39 

hypertensive children aged 6 to less than 18 years (see sections 4.8 and 5.2). 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Information on Rasilamlo interactions 

No interaction studies with other medicinal products were performed with Rasilamlo. Therefore, 

information on interactions with other medicinal products that are known for the individual active 

substances is provided in this section. 

 

Co-administration of aliskiren and amlodipine does not cause meaningful changes in the steady-state 

pharmacokinetic exposure (AUC) and the maximum concentration (Cmax) of either component in 

healthy volunteers. 

 

Information on aliskiren interactions 

Contraindicated (see section 4.3) 

- P-gp potent inhibitors 
A single dose drug interaction study in healthy subjects has shown that ciclosporin (200 and 600 mg) 

increases Cmax of aliskiren 75 mg approximately 2.5-fold and AUC approximately 5-fold. The 

increase may be higher with higher aliskiren doses. In healthy subjects, itraconazole (100 mg) 

increases AUC and Cmax of aliskiren (150 mg) by 6.5-fold and 5.8-fold, respectively. Therefore, 

concomitant use of aliskiren and P-gp potent inhibitors is contraindicated (see section 4.3). 

 

Not recommended (see section 4.2) 

- Fruit juice and drinks containing plant extracts 
Administration of fruit juice with aliskiren resulted in a decrease in AUC and Cmax of aliskiren. Co-

administration of grapefruit juice with aliskiren 150 mg resulted in a 61% decrease in aliskiren AUC 

and co-administration with aliskiren 300 mg resulted in a 38% decrease in aliskiren AUC. Co-

administration of orange or apple juice with aliskiren 150 mg resulted in a 62% decrease in aliskiren 

AUC or in a 63% decrease in aliskiren AUC, respectively. This decrease is likely due to an 

inhibition of organic anion transporting polypeptide-mediated uptake of aliskiren by components of 

fruit juice in the gastrointestinal tract. Therefore, because of the risk of therapeutic failure, fruit juice 

should not be taken together with Rasilamlo. The effect of drinks containing plant extracts (including 

herbal teas) on the absorption of aliskiren has not been investigated. However, compounds potentially 

inhibiting organic anion transporting polypeptide-mediated uptake of aliskiren are widely present in 

fruits, vegetables, and many other plant products. Therefore, drinks containing plant extracts, 

including herbal teas, should not be taken together with Rasilamlo. 

 

Dual blockade of the RAAS with aliskiren, ARBs or ACEIs 

Clinical trial data has shown that dual blockade of the RAAS through the combined use of ACEIs, 

ARBs or aliskiren is associated with a higher frequency of adverse events such as hypotension, stroke, 

hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a 

single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). 

 



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Caution required with concomitant use 

- P-gp 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 (see section 5.2). Rifampicin, which is an 

inducer of P-gp, reduced aliskiren bioavailability by approximately 50% in a clinical study. Other 

inducers of P-gp (St. John’s wort) might decrease the bioavailability of 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. 

 

- Moderate P-gp inhibitors 
Co-administration of ketoconazole (200 mg) or verapamil (240 mg) with aliskiren (300 mg) resulted 

in a 76% or 97% increase in aliskiren AUC, respectively. The change in plasma levels of aliskiren in 

the presence of ketoconazole or verapamil is expected to be within the range that would be achieved 

if the dose of aliskiren were doubled; aliskiren doses of up to 600 mg, or twice the highest 

recommended therapeutic dose, have been found to be well tolerated in controlled clinical trials. 

Preclinical studies indicate that aliskiren and ketoconazole co-administration enhances aliskiren 

gastrointestinal absorption and decreases biliary excretion. Therefore, caution should be exercised 

when aliskiren is administered with ketoconazole, verapamil or other moderate P-gp inhibitors 

(clarithromycin, telithromycin, erythromycin, amiodarone). 

 

- Medicinal products affecting serum potassium levels 
Concomitant use of other agents affecting the RAAS, of NSAIDs or of agents that increase serum 

potassium levels (e.g. potassium-sparing diuretics, potassium supplements, salt substitutes containing 

potassium, heparin) may lead to increases in serum potassium. If co-medication with an agent 

affecting the level of serum potassium is considered necessary, caution is advisable. 

 

- Non-steroidal anti-inflammatory drugs (NSAIDs) 
As with other medicinal products acting on the renin-angiotensin-aldosterone 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. 

 

- Furosemide and torasemide 
Oral co-administration of aliskiren and furosemide had no effect on the pharmacokinetics of aliskiren 

but reduced exposure to furosemide by 20-30% (the effect of aliskiren on furosemide administered 

intramuscularly or intravenously has not been investigated). After multiple doses of furosemide 

(60 mg/day) co-administered with aliskiren (300 mg/day) to patients with heart failure the urinary 

sodium excretion and the urine volume were reduced during the first 4 hours by 31% and 24%, 

respectively, as compared to furosemide alone. The mean weight of patients concomitantly treated 

with furosemide and 300 mg aliskiren (84.6 kg) was higher than the weight of patients treated with 

furosemide alone (83.4 kg). Smaller changes in furosemide pharmacokinetics and efficacy were 

observed with aliskiren 150 mg/day. 

 

The available clinical data did not indicate that higher doses of torasemide were used after co-

administration with aliskiren. Torasemide renal excretion is known to be mediated by organic anion 

transporters (OATs). Aliskiren is minimally excreted via the renal route, and only 0.6% of the 

aliskiren dose is recovered in urine following oral administration (see section 5.2). However, since 

aliskiren has been shown to be a substrate for the organic anion-transporting polypeptide 1A2 

(OATP1A2) (see interaction with organic anion transporting polypeptide (OATP) inhibitors), there is 

a potential for aliskiren to reduce plasma torasemide exposure by an interference with the absorption 

process. 



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In patients treated with both aliskiren and oral furosemide or torasemide, it is therefore recommended 

that the effects of furosemide or torasemide be monitored when initiating and adjusting furosemide, 

torasemide or aliskiren therapy to avoid changes in extracellular fluid volume and possible situations 

of volume overload (see section 4.4). 

 

- Warfarin 
The effects of aliskiren on warfarin pharmacokinetics have not been evaluated. 

 

- Food interactions 
Meals (low or high fat content) have been shown to reduce the absorption of aliskiren substantially 

(see section 4.2). The available clinical data do not suggest an additive effect of different types of 
foods and/or drinks, however the potential for decreased aliskiren bioavailability due to this additive 

effect has not been studied and therefore cannot be excluded. Concomitant administration of aliskiren 

with fruit juice or drinks containing plant extracts, including herbal teas, should be avoided. 

 

No interactions 

- Compounds that have been investigated in aliskiren clinical pharmacokinetic studies include 
acenocoumarol, atenolol, celecoxib, pioglitazone, allopurinol, isosorbide-5-mononitrate and 

hydrochlorothiazide. No interactions have been identified. 

 

- Co-administration of aliskiren with either metformin (↓28%), amlodipine (↑29%) or cimetidine 
(↑19%) resulted in between 20% and 30% change in Cmax or AUC of aliskiren. When 

administered with atorvastatin, steady-state aliskiren AUC and Cmax increased by 50%. Co-

administration of aliskiren had no significant impact on atorvastatin, metformin or amlodipine 

pharmacokinetics. As a result no dose adjustment for aliskiren or these co-administered 

medicinal products is necessary. 

 

- Digoxin and verapamil bioavailability may be slightly decreased by aliskiren. 
 

- CYP450 interactions 
Aliskiren does not inhibit the CYP450 isoenzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A). 

Aliskiren does not induce CYP3A4. Therefore aliskiren is not expected to affect the systemic 

exposure of substances that inhibit, induce or are metabolised by these enzymes. Aliskiren is 

metabolised minimally by the cytochrome P450 enzymes. Hence, interactions due to inhibition or 

induction of CYP450 isoenzymes are not expected. However, CYP3A4 inhibitors often also affect P-

gp. Increased aliskiren exposure during co-administration of CYP3A4 inhibitors that also inhibit P-gp 

can therefore be expected (see other P-gp references in section 4.5). 

 

- P-gp substrates or weak inhibitors 
No relevant interactions with atenolol, digoxin, amlodipine or cimetidine have been observed. When 

administered with atorvastatin (80 mg), steady-state aliskiren (300 mg) AUC and Cmax increased by 

50%. In experimental animals, it has been shown that P-gp is a major determinant of aliskiren 

bioavailability. Inducers of P-gp (St. John’s wort, rifampicin) might therefore decrease the 

bioavailability of aliskiren. 

 

- Organic anion transporting polypeptide (OATP) inhibitors 

Preclinical studies indicate that aliskiren might be a substrate of organic anion transporting 

polypeptides. Therefore, the potential exists for interactions between OATP inhibitors and aliskiren 

when administered concomitantly (see interaction with fruit juice). 

 



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Information on amlodipine interactions 

Effects of other medicinal products on amlodipine 

Caution required with concomitant use 

- CYP3A4 inhibitors 
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, 

azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give 

rise to significant increase in amlodipine exposure. The clinical translation of these pharmacokinetic 

variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus 

be required. 

 

- CYP3A4 inducers 
There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant 

use of CYP3A4 inducers (e.g. rifampicin, hypericum perforatum) may give a lower plasma 

concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 

inducers. 

 

- Grapefruit juice 
Administration of amlodipine with grapefruit or grapefruit juice is not recommended as 

bioavailability may be increased in some patients, resulting in increased blood pressure lowering 

effects. 

 

- Dantrolene (infusion) 
In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with 

hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of 

hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as 

amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of 

malignant hyperthermia. 

 

Effects of amlodipine on other medicinal products 

- The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects 
of other antihypertensive medicinal products. 

 

- Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in 
a 77% increase in exposure to simvastatin compared to simvastatin alone. It is recommended to 

limit the dose of simvastatin to 20 mg daily in patients on amlodipine. 

 

No interactions 

- In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, 
digoxin, warfarin or ciclosporin. 

 

4.6 Fertility, pregnancy and lactation 

 

Women of child-bearing potential/contraception in males and females 

Healthcare professionals prescribing Rasilamlo should counsel women of childbearing potential about 

the potential risk during pregnancy. A switch to a suitable alternative antihypertensive treatment 

should be carried out in advance of a planned pregnancy since Rasilamlo should not be used in 

women planning to become pregnant. 

 

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 RAAS have been associated with 

serious foetal malformations and neonatal death. As for any medicine that acts directly on the RAAS, 

aliskiren should not be used during the first trimester of pregnancy and is contraindicated during the 

second and third trimesters (see section 4.3). 

 



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The safety of amlodipine in human pregnancy has not been established. Reproductive studies in rats 

have shown no toxicity except for delayed date of delivery and prolonged duration of labour at 

dosages 50 times greater than the maximum recommended dosage for humans (see section 5.3). Use 

in pregnancy is only recommended when there is no safer alternative and when the disease itself 

carries greater risk for the mother and foetus. 

 

Rasilamlo should not be used during the first trimester of pregnancy. Rasilamlo is contraindicated 

during the second and third trimesters (see section 4.3). 

 

If pregnancy is detected during therapy, Rasilamlo should be discontinued accordingly as soon as 

possible. 

 

Breast-feeding 

It is unknown whether aliskiren and/or amlodipine are excreted in human milk. Aliskiren was 

secreted in the milk of lactating rats. 

 

Since there is insufficient/limited information on the excretion of aliskiren and amlodipine in human 

or animal breast milk, a risk to the newborns/infants cannot be excluded. It is therefore not 

recommended for women who are breast-feeding to use Rasilamlo. 

 

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from 

Rasilamlo therapy taking into account the benefit of breast-feeding for the child and the benefit of 

therapy for the woman. 

 

Fertility 

There are no clinical data on fertility with the use of Rasilamlo. 

 

Reversible biochemical changes in the head of spermatozoa have been reported in some patients 

treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of 

amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3). 

The fertility of rats was unaffected at doses of up to aliskiren 250 mg/kg/day (see section 5.3). 

 

4.7 Effects on ability to drive and use machines 

 

When driving vehicles or using machines it must be borne in mind that dizziness or drowsiness may 

occasionally occur when taking Rasilamlo. 

 

Amlodipine can have minor or moderate influence on the ability to drive and use machines. If 

patients taking amlodipine suffer from dizziness, headache, fatigue or nausea, the ability to react may 

be impaired. 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

The safety profile of Rasilamlo presented below is based on clinical studies performed with 

Rasilamlo and the known safety profile of the individual components aliskiren and amlodipine. 

Safety information for Rasilamlo in patients aged 75 years and older is limited. 

 

The most frequent adverse reactions for Rasilamlo are hypotension and peripheral oedema. The 

adverse reactions previously reported with one of the individual components of Rasilamlo (aliskiren 

and amlodipine) and included in the tabulated list of adverse reactions may occur with Rasilamlo. 

 



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Tabulated list of adverse reactions: 

The adverse reactions are ranked by frequency, the most frequent first, 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, adverse reactions are presented in order of decreasing 

seriousness. The adverse reactions observed with Rasilamlo or with monotherapy with one or both of 

the two components are included in the table below. For adverse reactions observed with more than 
one component of a fixed-dose combination, the highest frequency is listed in the table below. 

 

Blood and lymphatic system disorders 

Very rare Leukopeniaam, thrombocytopeniaam 

Immune system disorders 

Rare Anaphylactic reactionsa, hypersensitivity 

reactionsa 

Very rare Allergic reactionsam 

Metabolism and nutrition disorders 

Very rare Hyperglycaemiaam 

Psychiatric disorders 

Uncommon Insomniaam, mood changes (including anxiety)am, 

depressionam 

Rare Confusionam 

Nervous system disorders 

Common Somnolenceam, headache (especially at the 

beginning of treatment)am 

Uncommon Tremoram, dysgeusiaam, syncopeam, hypoesthesiaam, 

paraesthesiaam 

Very rare Hypertoniaam, peripheral neuropathyam 

Eye disorders 

Uncommon Visual disturbance (including diplopia)am 

Ear and labyrinth disorders 

Uncommon Tinnitusam 

Not known Vertigoa 

Cardiac disorders 

Common Dizzinessa,am, palpitationsa,am, peripheral 

oedemac,a,am* 

Very rare Myocardial infarctionam, arrhythmia (including 

bradycardia, ventricular tachycardia, and atrial 

fibrillation)am 

Vascular disorders 

Common Flushingam, hypotensionc,a,am 

Very rare Vasculitisam 

Respiratory, thoracic and mediastinal disorders 

Uncommon Dyspnoeaa, am, rhinitisam, cougha,am 

Gastrointestinal disorders 

Common Diarrhoeaa, abdominal painam, nauseaa,am 

Uncommon Vomitinga,am, dyspepsiaam, altered bowel habits 

(including diarrhoea and constipation)am, dry 

moutham 

Very rare Pancreatitisam, gastritisam, gingival hyperplasiaam 

Hepatobiliary disorders 

Very rare Hepatitisa,am, jaundicea,am, hepatic enzymes 

increased (mostly consistent with cholestasis)am 

Not known Liver disordera,**, liver failurea,*** 



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Skin and subcutaneous tissue disorders 

Uncommon Severe cutaneous adverse reactions (SCARs) 

including Stevens Johnson syndromea, toxic 

epidermal necrolysis (TEN)a, oral mucosal 

reactionsa, rasha,am, pruritusa,am, urticariaa,am, 

alopeciaam, purpuraam, skin decolourationam, 

hyperhidrosisam, exanthemaam 

Rare Angioedemaa, erythemaa 

Very rare Erythema multiformeam, exfoliative dermatitisam, 

Stevens-Johnson syndromeam, Quincke oedemaam, 

photosensitivityam 

Musculoskeletal and connective tissue disorders 

Common Arthralgiaa,am, ankle swellingam 

Uncommon Myalgiaam, muscle crampsam, back painam 

Renal and urinary disorders 

Uncommon Acute renal failurea, renal impairmenta, 

micturition disorderam, nocturiaam, increased 

urinary frequencyam 

Reproductive system and breast disorders 

Uncommon Impotenceam, gynaecomastiaam 

General disorders and administration site conditions 

Common Fatigueam 

Uncommon Chest painam, astheniaam, painam, malaiseam 

Investigations 

Common Hyperkalaemiaa 

Uncommon Liver enzyme increaseda, weight increaseam, 

weight decreaseam 

Rare Haemoglobin decreaseda, haematocrit decreaseda, 

blood creatinine increaseda 

Not known Hyponatraemiaa 
c Adverse reaction observed with Rasilamlo; 
a Adverse reaction observed with monotherapy with aliskiren; 
am Adverse reaction observed with monotherapy with amlodipine; 

* Peripheral oedema is a known, dose-dependent adverse reaction of amlodipine and has also been 

reported with aliskiren therapy in post-marketing experience. The most frequently reported adverse 

reaction for Rasilamlo in clinical trials was peripheral oedema, which occurred at a frequency lower 

than or equal to that of the corresponding amlodipine doses, but higher than with aliskiren; 

** Isolated cases of liver disorder with clinical symptoms and laboratory evidence of more marked 

hepatic dysfunction; 

***Including one case of “liver failure fulminant” reported in the post-marketing experience, for 

which a causal relationship with aliskiren cannot be excluded. 

 

Additional information on individual components 

Adverse reactions previously reported with one of the individual components may occur with 

Rasilamlo even if not observed in clinical trials. 

 

Aliskiren 

Description of selected adverse reactions: 

Hypersensitivity reactions including anaphylactic reactions and angioedema have occurred during 

treatment with aliskiren. 

 

In controlled clinical trials, angioedema and hypersensitivity reactions occurred rarely during 

treatment with aliskiren with rates comparable to treatment with placebo or comparators. 

 



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Cases of angioedema or symptoms suggestive of angioedema (swelling of the face, lips, throat and/or 

tongue) have also been reported in post-marketing experience. A number of these patients had a 

history of angioedema or symptoms suggestive of angioedema which in some cases was associated 

with the administration of other medicinal products known to cause angioedema, including RAAS 

blockers (ACEIs or ARBs). 

 

In post-marketing experience, cases of angioedema or angioedema-like reactions have been reported 

when aliskiren was co-administered with ACEIs and/or ARBs. 

 

Hypersensitivity reactions including anaphylactic reactions have also been reported in post-marketing 

experience (see section 4.4). 

 

In the event of any signs suggesting a hypersensitivity reaction/angioedema (in particular difficulties 

in breathing or swallowing, rash, itching, hives or swelling of the face, extremities, eyes, lips and/or 

tongue, dizziness) patients should discontinue treatment and contact the physician (see section 4.4). 

 

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

hypersensitivity reaction. 

 

In post-marketing experience, renal dysfunction and cases of acute renal failure have been reported in 

patients at risk (see section 4.4). 

 

Investigations 

In controlled clinical trials, clinically relevant changes in standard laboratory parameters were 

uncommonly associated with the administration of aliskiren. In clinical studies in hypertensive 

patients, aliskiren had no clinically important effects on total cholesterol, high density lipoprotein 

cholesterol (HDL-C), fasting triglycerides, fasting glucose or uric acid. 

 

Haemoglobin and haematocrit: Small decreases in haemoglobin and haematocrit (mean decreases of 

approximately 0.05 mmol/l and 0.16 volume percent, respectively) were observed. No patients 

discontinued therapy due to anaemia. This effect is also seen with other medicinal products acting on 

the RAAS, such as ACEIs and ARBs. 

 

Serum potassium: Increases in serum potassium have been observed with aliskiren and these may be 

exacerbated by concomitant use of other agents acting on the RAAS or by NSAIDs. Consistent with 

standard medical practice, periodic determination of renal function including serum electrolytes is 

advised if co-administration is considered necessary. 

 

Paediatric population 

Based on the limited amount of safety data available from a pharmacokinetic study of aliskiren 

treatment in 39 hypertensive children 6-17 years of age, the frequency, type and severity of adverse 

reactions in children are expected to be similar to that seen in hypertensive adults. As for other RAAS 

blockers, headache is a common adverse event in children treated with aliskiren. 

 

Amlodipine 

Exceptional cases of extrapyramidal syndrome have been reported. 

 

Reporting of suspected adverse reactions 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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4.9 Overdose 

 

Symptoms 

There is no experience of overdose with Rasilamlo. The most likely manifestation of overdose for 

Rasilamlo would be hypotension, related to the antihypertensive effect of aliskiren and amlodipine. 

 

With aliskiren, the most likely manifestation of overdose would be hypotension, related to the 

antihypertensive effect of aliskiren. 

 

With amlodipine, available data suggest that gross overdose could result in excessive peripheral 

vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension 

up to and including shock with fatal outcome, have been reported with amlodipine. 

 

Treatment 

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

 

Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular 

support including frequent monitoring of cardiac and respiratory function, elevation of extremities 

and attention to circulating fluid volume and urine output. 

 

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is 

no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the 

effects of calcium channel blockade. 

 

Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 

2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of 

amlodipine. 

 

Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit. 

 

In a study conducted in patients with end stage renal disease (ESRD) receiving haemodialysis, 

dialysis clearance of aliskiren was low (<2% of oral clearance). Therefore dialysis is not adequate to 

treat aliskiren over-exposure. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1 Pharmacodynamic properties 

 

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, renin inhibitors, ATC 

code: C09XA53 

 

Rasilamlo combines two antihypertensive compounds with complementary mechanisms to control 

blood pressure in patients with essential hypertension: aliskiren belongs to the class of direct renin 

inhibitors and amlodipine belongs to the calcium antagonist class. 

 



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Rasilamlo 

The use of combined treatment with aliskiren and amlodipine arises from the actions of these two 

medicinal products on different but complementary systems that regulate blood pressure. Calcium 

channel blockers act to prevent the influx of calcium into the vascular smooth muscle cells in the 

vessel wall, thereby preventing smooth muscle cell contraction and vasoconstriction. Renin inhibitors 

suppress the enzymatic activity of renin, and thereby block the formation of Angiotensin II, the major 

effector molecule of the renin-angiotensin-aldosterone system (RAAS). Angiotensin II causes 

vasoconstriction and sodium and water reabsorption. Thus, amlodipine directly inhibits 

vasoconstriction and reduces vascular resistance, while aliskiren, by controlling Ang II production, 

can also inhibit vasoconstriction but additionally shifts water and sodium balance toward levels 

necessary for normotensive conditions. The combined action of aliskiren and amlodipine on these two 

central blood pressure-regulating factors (vasoconstriction and RAAS-mediated hypertensive effects) 

results in more effective antihypertensive effects than seen with monotherapy. 

 

Rasilamlo was studied in a number of active and placebo-controlled trials and long-term trials which 

included a total of 5,570 hypertensive patients with mild to moderate hypertension (diastolic blood 

pressure between 90 mmHg and 109 mmHg). 

 

In hypertensive patients not controlled by the component monotherapies, once-daily administration of 

Rasilamlo provided dose-dependent clinically meaningful reductions in both systolic and diastolic 

blood pressure. 

 

When given to patients whose blood pressure was not adequately controlled by either aliskiren or 

amlodipine, Rasilamlo results in greater blood pressure reductions after one week of treatment than 

the component monotherapies and a near-maximal effect is achieved after four weeks of therapy. 

 

In a study in 820 randomised patients not adequately responsive to aliskiren 300 mg treatment, the 

combination of aliskiren/amlodipine 300 mg/10 mg produced systolic/diastolic mean blood pressure 

reductions of 18.0/13.1 mmHg, which were statistically significantly greater than aliskiren 300 mg 

monotherapy. The combination at a dose of 300 mg/5 mg also showed statistically significantly 

greater blood pressure reduction than aliskiren 300 mg monotherapy. In a subset of 584 patients, the 

combination of aliskiren/amlodipine produced additional systolic/diastolic mean blood pressure 

reductions of 7.9/4.8 mmHg and 11.7/7.7 mmHg for the 300/5 mg and 300/10 mg strengths 

respectively compared to aliskiren 300 mg (the subset constitutes patients without aberrant readings, 

defined as difference in systolic blood pressure (SBP) ≥10 mmHg at baseline or endpoint). 

 

In a study in 847 randomised patients not adequately responsive to amlodipine 10 mg treatment, the 

combination of aliskiren/amlodipine 150 mg/10 mg and 300 mg/10 mg produced systolic/diastolic 

mean blood pressure reductions of 11.0/9.0 mmHg and 14.4/11.0 mmHg respectively, which were 

statistically greater than for amlodipine 10 mg monotherapy. In a subset of 549 patients, the 

combination of aliskiren/amlodipine produced additional systolic/diastolic mean blood pressure 

reductions of 4.0/2.2 mmHg and 7.6/4.7 mmHg for the 150/10 mg and 300/10 mg strengths 

respectively compared to amlodipine 10 mg (the subset constitutes patients without aberrant readings, 

defined as difference in SBP ≥10 mmHg at baseline or endpoint). 

 

In a study in 545 randomised patients not adequately responsive to 5 mg amlodipine, the combination 

of aliskiren 150 mg/amlodipine 5 mg resulted in greater blood pressure reduction than those patients 

remaining on amlodipine 5 mg. 

 



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In an 8-week randomised, double-blind, placebo-controlled, parallel group factorial study in 

1,688 randomised patients with mild to moderate hypertension, treatment with Rasilamlo at doses 

from 150 mg/5 mg to 300 mg/10 mg produced dose-dependent clinically meaningful mean blood 

pressure reductions (systolic/diastolic) ranging between 20.6/14.0 mmHg and 23.9/16.5 mmHg, 

respectively, compared to 15.4/10.2 mmHg for aliskiren 300 mg, 21.0/13.8 mmHg for amlodipine 

10 mg and 6.8/5.4 mmHg with placebo in a population of patients with mean baseline blood pressure 

of 157.3/99.7 mmHg. These were statistically significant versus placebo and aliskiren for all doses. 

The blood pressure reductions with the combination were maintained throughout the entire 24-hour 

dose interval. In a subset of 1,069 patients, Rasilamlo produced mean blood pressure reductions 

(systolic/diastolic) ranging between 20.6/13.6 mmHg and 24.2/17.3 mmHg (the subset of patients 

without aberrant readings, defined as difference in SBP ≥10 mmHg at baseline or endpoint). 

 

The safety of Rasilamlo has been evaluated in studies of up to one year duration. 

 

The effects of Rasilamlo on all cause and cardiovascular mortality and on cardiovascular morbidity 

and target organ damage are currently unknown. 

 

Rasilamlo has been administered to more than 2,800 patients in completed clinical trials, including 

372 patients for one year or more. Treatment with Rasilamlo at doses up to 300 mg/10 mg had an 

overall incidence of adverse experiences similar to the component monotherapies. The incidence of 

adverse events did not show any association with gender, age, body mass index, race or ethnicity. 

There were no new adverse reactions which occurred specifically with Rasilamlo in addition to those 

known to be associated with the individual monotherapies. In a double-blind, randomised placebo-

controlled study in 1,688 patients with mild or moderate hypertension, discontinuation of therapy due 

to a clinical adverse event occurred in 1.7% of patients treated with Rasilamlo versus 1.5% of 

patients given placebo. 

 

Aliskiren 

Aliskiren is an orally active, non-peptide, potent and selective direct inhibitor of human renin. 

 

By inhibiting the enzyme renin, aliskiren inhibits the RAAS at the point of activation, blocking the 

conversion of angiotensinogen to angiotensin I and decreasing levels of angiotensin I and 

angiotensin II. Whereas other medicinal products that inhibit the RAAS (ACEI and angiotensin II 

receptor blockers (ARB)) cause a compensatory rise in plasma renin activity (PRA), treatment with 

aliskiren decreases PRA in hypertensive patients by approximately 50 to 80%. Similar reductions 

were found when aliskiren was combined with other antihypertensive medicinal products. The 

clinical implications of the differences in effect on PRA are not known at the present time. 

 

Hypertension 

In hypertensive patients, once-daily administration of 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, and was independent of age, gender, body mass 

index and ethnicity. Aliskiren has been studied in 1,864 patients aged 65 years or older, and in 

426 patients aged 75 years or older. 

 

Aliskiren monotherapy studies have shown blood-pressure-lowering effects comparable to other 

classes of antihypertensive medicinal products including selected ACEI and ARB. Compared to a 

diuretic (hydrochlorothiazide, HCTZ), aliskiren 300 mg lowered systolic/diastolic blood pressure by 

17.0/12.3 mmHg, compared to 14.4/10.5 mmHg for HCTZ 25 mg after 12 weeks of treatment. 

 

Combination therapy studies are available for aliskiren added to the diuretic hydrochlorothiazide and 

the beta blocker atenolol. These combinations were well tolerated. Aliskiren induced an additive 

blood-pressure-lowering effect when added to hydrochlorothiazide. 



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The efficacy and safety of aliskiren-based therapy were compared to ramipril-based therapy in a 9-

month non-inferiority study in 901 elderly patients (≥65 years) with essential systolic hypertension. 

Aliskiren 150 mg or 300 mg per day or ramipril 5 mg or 10 mg per day were administered for 

36 weeks with optional add-on therapy of hydrochlorothiazide (12.5 mg or 25 mg) at week 12, and 

amlodipine (5 mg or 10 mg) at week 22. Over the 12 week period, aliskiren monotherapy lowered 

systolic/diastolic blood pressure by 14.0/5.1 mmHg, compared to 11.6/3.6 mmHg for ramipril, 

consistent with aliskiren being non-inferior to ramipril at the dosages chosen and the differences in 

systolic and diastolic blood pressure were statistically significant. Tolerability was comparable in 

both treatment arms, however cough was more often reported with the ramipril regimen than the 

aliskiren regimen (14.2% vs. 4.4%), whilst diarrhoea was more common with the aliskiren regimen 

than for the ramipril regimen (6.6% vs. 5.0%). 

 

In a 8-week study in 754 hypertensive elderly (≥65 years) and very elderly patients (30% ≥75 years) 

aliskiren at doses of 75 mg, 150 mg and 300 mg provided statistically significant superior reduction 

in blood pressure (both systolic and diastolic) when compared to placebo. No additional blood 

pressure lowering effect was detected with 300 mg aliskiren compared to 150 mg aliskiren. All three 

doses were well tolerated in both elderly and very elderly patients. 

 

There has been no evidence of first-dose hypotension and no effect on pulse rate in patients treated in 

controlled clinical studies. Excessive hypotension was uncommonly (0.1%) seen in patients with 

uncomplicated hypertension treated with aliskiren alone. Hypotension was also uncommon (<1%) 

during combination therapy with other antihypertensive medicinal products. With cessation of 

treatment, blood pressure gradually returned towards baseline levels over a period of several weeks, 

with no evidence of a rebound effect for blood pressure or PRA. 

 

In a 36-week study involving 820 patients with ischaemic left ventricular dysfunction, no changes in 

ventricular remodelling as assessed by left ventricular end systolic volume were detected with 

aliskiren compared to placebo on top of background therapy. 

 

The combined rates of cardiovascular death, hospitalisation for heart failure, recurrent heart attack, 

stroke and resuscitated sudden death were similar in the aliskiren group and the placebo group. 

However, in patients receiving aliskiren there was a significantly higher rate of hyperkalaemia, 

hypotension and kidney dysfunction when compared to the placebo group. 

 

Aliskiren was evaluated for cardiovascular and/or renal benefit in a double-blind placebo controlled 

randomised trial in 8,606 patients with type 2 diabetes and chronic kidney disease (evidenced by 

proteinuria and/or GFR <60 ml/min/1.73 m2) with or without cardiovascular disease. In most patients 

arterial blood pressure was well controlled at baseline. The primary endpoint was a composite of 

cardiovascular and renal complications. 

 

In this study, aliskiren 300 mg was compared to placebo when added to standard of care which 

included either an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. The 

study was discontinued prematurely because the participants were unlikely to benefit from aliskiren. 

The final study results indicated a hazard ratio for the primary endpoint of 1.097 in favour of placebo 

(95.4% Confidence Interval: 0.987, 1.218, 2-sided p=0.0787). In addition, an increased incidence of 

adverse events was observed with aliskiren compared to placebo (38.2% versus 30.3%). In particular 

there was an increased incidence of renal dysfunction (14.5% versus 12.4%), hyperkalaemia (39.1% 

versus 29.0%), hypotension-related events (19.9% versus 16.3%) and adjudicated stroke endpoints 

(3.4% versus 2.7%). The increased incidence of stroke was greater in patients with renal 

insufficiency. 

 



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Aliskiren 150 mg (increased to 300 mg if tolerated) added to conventional therapy was evaluated in a 

double-blind placebo-controlled randomised trial in 1,639 patients with reduced ejection fraction 

hospitalised for an episode of acute heart failure (NYHA Class III–IV) who were haemodynamically 

stable at baseline. The primary endpoint was cardiovascular death or heart failure rehospitalisation 

within 6 months; secondary endpoints were assessed within 12 months. 

 

The study showed no benefit of aliskiren when administered on top of standard therapy for acute 

heart failure and an increased risk of cardiovascular events in patients with diabetes mellitus. Study 

results indicated a non-significant effect of aliskiren with a hazard ratio of 0.92 (95% Confidence 

Interval: 0.76-1.12; p=0.41, aliskiren vs. placebo). Different treatment effects of aliskiren were 

reported for overall mortality within 12 months dependent on diabetes mellitus status. In the subgroup 

of patients with diabetes mellitus the hazard ratio was 1.64 in favour of placebo (95% Confidence 

Interval: 1.15-2.33), whereas the hazard ratio in the subgroup of patients without diabetes was 0.69 in 

favour of aliskiren (95% Confidence Interval: 0.50-0.94); p-value for interaction = 0.0003. An 

increased incidence of hyperkalaemia (20.9% versus 17.5%), renal impairment/renal failure (16.6% 

versus 12.1%) and hypotension (17.1% versus 12.6%) was observed in the aliskiren group compared 

with placebo and was greater in patients with diabetes. 

 

Effects of aliskiren on mortality and cardiovascular morbidity are currently unknown. 

 

No long-term efficacy data for aliskiren in patients with heart failure are currently available. 

 

Cardiac electrophysiology 

No effect on QT interval was reported in a randomised, double-blind, placebo, and active-controlled 

study using standard and Holter electrocardiography. 

 

Amlodipine 

The amlodipine component of Rasilamlo inhibits the transmembrane entry of calcium ions into 

cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is 

due to a direct relaxant effect on vascular smooth muscle, causing reductions in peripheral vascular 

resistance and in blood pressure. Experimental data suggest that amlodipine binds to both 

dihydropyridine and non-dihydropyridine binding sites. 

 

The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the 

movement of extracellular calcium ions into these cells through specific ion channels. 

 

Following administration of therapeutic doses to patients with hypertension, amlodipine produces 

vasodilatation resulting in a reduction of supine and standing blood pressures. These decreases in 

blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine 

levels with chronic dosing. 

 

Plasma concentrations correlate with effect in both young and elderly patients. 

 

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a 

decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal 

plasma flow without change in filtration fraction or proteinuria. 

 

As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest and 

during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have 

generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on 

left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been 

associated with a negative inotropic effect when administered in the therapeutic dose range to intact 

animals and humans, even when co-administered with beta blockers to humans. 

 



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Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals 

or humans. In clinical studies in which amlodipine was administered in combination with beta 

blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic 

parameters were observed. 

 

Amlodipine has demonstrated beneficial clinical effects in patients with chronic stable angina, 

vasospastic angina and angiographically documented coronary artery disease. 

 

Use in patients with heart failure 

Calcium channel blockers, including amlodipine, should be used with caution in patients with 

congestive heart failure, as they may increase the risk of future cardiovascular events and mortality. 

 

Use in patients with hypertension 

A randomised double-blind morbidity-mortality study called the Antihypertensive and Lipid-

Lowering treatment to prevent Heart Attack Trial (ALLHAT) was performed to compare newer 

therapies: amlodipine 2.5-10 mg/day (calcium channel blocker) or lisinopril 10-40 mg/day (ACE-

inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/day in mild 

to moderate hypertension. 

 

A total of 33,357 hypertensive patients aged 55 or older were randomised and followed for a mean of 

4.9 years. The patients had at least one additional coronary heart disease risk factor, including: 

previous myocardial infarction or stroke (>6 months prior to enrollment) or documentation of other 

atherosclerotic cardiovascular disease (overall 51.5%), type 2 diabetes (36.1%), high density 

lipoprotein - cholesterol <35 mg/dl or <0.906 mmol/l (11.6%), left ventricular hypertrophy diagnosed 

by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%). 

 

The primary endpoint was a composite of fatal coronary heart disease or non-fatal myocardial 

infarction. There was no significant difference in the primary endpoint between amlodipine-based 

therapy and chlorthalidone-based therapy: risk ratio (RR) 0.98 95% CI (0.90-1.07) p=0.65. Among 

secondary endpoints, the incidence of heart failure (component of a composite combined 

cardiovascular endpoint) was significantly higher in the amlodipine group as compared to the 

chlorthalidone group (10.2% vs 7.7%, RR 1.38, 95% CI [1.25-1.52] p<0.001). However, there was 

no significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-

based therapy RR 0.96 95% CI [0.89-1.02] p=0.20. 

 

Paediatric population 

The European Medicines Agency has waived the obligation to submit the results of studies with 

Rasilamlo in all subsets of the paediatric population in essential hypertension (see section 4.2 for 

information on paediatric use). 

 

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 Cmax 
by 85% and AUC by 70%. At steady state meals with low fat content reduce Cmax by 76% and AUC 

0-tau by 67% in hypertensive patients. 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. 

 

Transporters 

MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption 

and biliary excretion of aliskiren in pre-clinical studies. 

 



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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. 

 

Biotransformation and elimination 

The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as 

unchanged compound in the faeces (78%). Approximately 1.4% of the total oral dose is metabolised. 

The enzyme responsible for this metabolism is CYP3A4. Approximately 0.6% of the dose is 

recovered in urine following oral administration. Following intravenous administration, mean plasma 

clearance is approximately 9 l/h. 

 

Linearity 

Exposure to aliskiren increased more than in proportion to the increase in dose. After single dose 

administration in the dose range of 75 to 600 mg, a 2-fold increase in dose results in a ~2.3 and 2.6-

fold increase in AUC and Cmax, respectively. At steady state the non-linearity may be more 

pronounced. Mechanisms responsible for deviation from linearity have not been identified. A possible 

mechanism is saturation of transporters at the absorption site or at the hepatobiliary clearance route. 

 

Paediatric population 

In a pharmacokinetic study of aliskiren treatment in 39 paediatric hypertensive patients aged 6 to 

17 years given daily doses of 2 mg/kg or 6 mg/kg aliskiren administered as granules 

(3.125 mg/tablet), pharmacokinetic parameters were similar to those in adults. The results of this 

study did not suggest that age, body weight or gender have any significant effect on aliskiren 

systemic exposure (see section 4.2). 

 

Results from an in vitro MDR1 human tissue study suggested an age and tissue dependent pattern of 

MDR1 (P-gp) transporter maturation. A high inter-individual variability of mRNA expression levels 

was observed (up to 600-fold). Hepatic MDR1 mRNA expression was statistically significantly lower 

in samples from foetuses, neonates and infants up to 23 months. 

 

The age at which the transporter system is mature cannot be determined. There is a potential for 

aliskiren overexposure in children with an immature MDR1 (P-gp) system (see “Transporters” above 

and sections 4.2, 4.4 and 5.3). 

 

Amlodipine 

Absorption 

After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations of 

amlodipine are reached in 6-12 hours. Absolute bioavailability has been estimated as between 64% 

and 80%. Amlodipine bioavailability is unaffected by food ingestion. 

 

Distribution 

The volume of distribution is approximately 21 l/kg. In vitro studies with amlodipine have shown that 

approximately 97.5% of circulating amlodipine is bound to plasma proteins. 

 

Biotransformation and elimination 

Amlodipine is extensively (approximately 90%) metabolised in the liver to inactive metabolites, with 

10% of the parent compound and 60% of the metabolites excreted in the urine. 

 

Amlodipine elimination from plasma is biphasic with a terminal elimination half-life of 

approximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration 

for 7-8 days. 

 

Linearity 

Amlodipine exhibits linear pharmacokinetics between the therapeutic dose range of 5 mg and 10 mg. 



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Aliskiren/amlodipine 

Following oral administration of Rasilamlo, the median peak plasma concentration time is within 

3 hours for aliskiren and 8 hours for amlodipine. The rate and extent of absorption of Rasilamlo are 

similar in fasting state to those of aliskiren and amlodipine when administered as individual 

monotherapies. A bioequivalence study under light meal conditions has not been conducted for 

Rasilamlo. 

 

The results from a food effect study using a standard high fat meal with the 300 mg/10 mg fixed 

combination tablet showed that food reduced the rate and extent of absorption of aliskiren in the 

fixed combination tablet with a similar magnitude of effect as for aliskiren monotherapy. Consistent 

with the monotherapy formulation, food had no effect on the pharmacokinetics of amlodipine in the 

fixed combination tablet. 

 

Characteristics in patients 

Aliskiren 

Aliskiren is an effective once-a-day antihypertensive treatment in adult patients, regardless of gender, 

age, body mass index and ethnicity. 

 

The AUC is 50% higher in elderly (>65 years) than in young subjects. Gender, weight and ethnicity 

have no clinically relevant influence on aliskiren pharmacokinetics. 

 

The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renal 

insufficiency. Relative AUC and Cmax of aliskiren in subjects with renal impairment ranged between 

0.8 to 2 times the levels in healthy subjects following single dose administration and at steady state. 

These observed changes, however, did not correlate with the severity of renal impairment. No 

adjustment of the initial dosage of aliskiren is required in patients with mild to moderate renal 

impairment (see sections 4.2 and 4.4). Aliskiren is not recommended in patients with severe renal 

impairment (glomerular filtration rate (GFR) <30 ml/min/1.73 m2). 

 

The pharmacokinetics of aliskiren were evaluated in patients with end stage renal disease receiving 

haemodialysis. Administration of a single oral dose of 300 mg aliskiren was associated with very 

minor changes in the pharmacokinetics of aliskiren (change in Cmax of less than 1.2 fold; increase in 

AUC of up to 1.6 fold) compared to matched healthy subjects. Timing of haemodialysis did not 

significantly alter the pharmacokinetics of aliskiren in ESRD patients. Therefore, if administration of 

aliskiren in ESRD patients receiving haemodialysis is considered necessary, no dose adjustment is 

warranted in these patients. However, the use of aliskiren is not recommended in patients with severe 

renal impairment (see section 4.4). 

 

The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe liver 

disease. Consequently, no adjustment of the initial dose of aliskiren is required in patients with mild 

to severe hepatic impairment. 

 

Amlodipine 

The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger 

subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and 

elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with 

congestive heart failure were as expected for the patient age group in this study (see section 4.4). 

 

A population pharmacokinetic study has been conducted in 74 hypertensive children aged from 1 to 

17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving 

amlodipine between 1.25 and 20 mg given either once or twice daily. In children 6 to 12 years and in 

adolescents 13-17 years of age the typical oral clearance (CL/F) was 22.5 and 27.4 l/hr respectively 

in males and 16.4 and 21.3 l/hr respectively in females. Large variability in exposure between 

individuals was observed. Data reported in children below 6 years are limited. 

 



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The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. 

 

Very limited clinical data are available regarding amlodipine administration in patients with hepatic 

impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine with 

resulting increase in AUC of approximately 40-60%. Therefore caution should be exercised in 

patients with hepatic impairment. 

 

5.3 Preclinical safety data 

 

Aliskiren 

Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic mouse study. No 

carcinogenic potential was detected. One colonic adenoma and one caecal adenocarcinoma recorded 

in rats at the dose of 1,500 mg/kg/day were not statistically significant. Although aliskiren has known 

irritation potential, safety margins obtained in humans at the dose of 300 mg during a study in healthy 

volunteers were considered to be appropriate at 9-11-fold based on faecal concentrations or 6-fold 

based on mucosa concentrations in comparison with 250 mg/kg/day in the rat carcinogenicity study. 

 

Aliskiren was devoid of any mutagenic potential in the in vitro and in vivo mutagenicity studies. The 

assays included in vitro assays in bacterial and mammalian cells and in vivo assessments in rats. 

 

Reproductive toxicity studies with aliskiren did not reveal any evidence of embryofoetal toxicity or 

teratogenicity at doses up to 600 mg/kg/day in rats or 100 mg/kg/day in rabbits. Fertility, pre-natal 

development and post-natal development were unaffected in rats at doses up to 250 mg/kg/day. The 

doses in rats and rabbits provided systemic exposures of 1 to 4 and 5 times higher, respectively, than 

the maximum recommended human dose (300 mg). 

 

Safety pharmacology studies did not reveal any adverse effects on central nervous, respiratory or 

cardiovascular function. Findings during repeat-dose toxicity studies in animals were consistent with 

the known local irritation potential or the expected pharmacological effects of aliskiren. 

 

Juvenile Animal Studies 

A repeat-dose toxicity study was conducted in juvenile rats 8 days post-partum for 4 weeks with 

aliskiren dosing at 30, 100 or 300 mg/kg/day. High acute mortality (within hours) and severe 

morbidity were observed at 100 and 300 mg/kg/day (2.3- and 6.8-fold the maximum recommended 

human dose (MRHD) on mg/m2 basis assuming a 60 kg adult patient) with no cause of death 

established and occurring without signs or prodromal symptoms. The ratio of lethal dose of 

100 mg/kg/day and no-observed-adverse-effect-level (NOAEL) of 30 mg/kg/day is unexpectedly low. 

 

Another repeat-dose toxicity study was conducted in juvenile rats 14 days post-partum for 8 weeks 

with aliskiren dosing at 30, 100 or 300 mg/kg/day. Delayed mortality was observed at 300 mg/kg/day 

(8.5-fold the MRHD on mg/m2 basis assuming a 60 kg adult patient) with no cause of death 

established. 

 

For the surviving juvenile rats, no effects on behavioural or reproductive performance were observed. 

 

Plasma aliskiren exposure (AUC) in rats aged 8 days was nearly 4-fold higher than that in rats aged 

14 days at 100 mg/kg/day. Plasma aliskiren exposure in rats aged 14 days was between 85- and 387-

fold higher than that in adult rats aged 64 days. 

 

A single dose study was conducted in juvenile rats aged 14, 21, 24, 28, 31 or 36 days post-partum. 

No mortality or significant toxicity was observed. The plasma exposure was approximately 100-fold 

higher in rats aged 14 days and 3-fold higher in rats aged 21 days compared to adult rats. 

 



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A mechanistic study was conducted to investigate the relationship between age, aliskiren exposure 

and MDR1 and OATP2 expression maturation in rats. The results showed that developmental 

changes of aliskiren exposure correlated with the ontogeny of transporter maturation in jejunum, liver, 

kidney and brain. 

 

The pharmacokinetics of aliskiren was evaluated in rats aged from 8 to 28 days after intravenous 

administration of aliskiren 3 mg/kg. The clearance of aliskiren increased in an age-dependent 

manner. Clearance in rats aged 8 or 14 days was similar, but at these ages the clearance was only 

about 23% of clearance in rats aged 21 days and 16% of clearance in rats aged 28 days. 

 

These studies indicate that excessive aliskiren exposure (>400-fold higher in 8-day old rats compared 

with adult rats) and high acute toxicity in juvenile rats are caused by immature MDR1, which 

suggests that in paediatric patients with immature MDR1, there is a potential for aliskiren 

overexposure (see sections 4.2, 4.3 and 5.2). 

 

Amlodipine 

Safety data for amlodipine are well established both clinically and non-clinically. 

 

Reproductive toxicology 

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of 

labour and decreased pup survival at dosages approximately 50 times greater than the maximum 

recommended dosage for humans based on mg/kg. 

 

Impairment of fertility 

There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 

14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human 

dose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipine 

besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma 

follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in 

the number of mature spermatids and Sertoli cells. 

 

Carcinogenesis, mutagenesis 

Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to 

provide daily dosage levels of 0.5, 1.25 and 2.5 mg/kg/day showed no evidence of carcinogenicity. 

The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose 

of 10 mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats. 

 

Mutagenicity studies revealed no effects related to the medicinal product at either the gene or 

chromosome levels. 

 

*Based on patient weight of 50 kg 

 

Rasilamlo 

Preclinical safety studies have demonstrated that the combination of aliskiren and amlodipine was 

well tolerated in rats. The findings from the 2- and 13-week oral toxicity studies in rats were 

consistent with those of aliskiren and amlodipine when both active substances are administered alone. 

There were no new toxicities or increased severity of the toxicities which were associated with either 

component. 

 

 



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96 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Tablet core 

Cellulose microcrystalline 

Crospovidone 

Povidone 

Magnesium stearate 

Silica colloidal anhydrous 

 

Coating 

Hypromellose 

Macrogol 

Talc 

Iron oxide yellow (E172) 

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

PVC/PCTFE – Alu blisters: 

18 months 

 

PA/Alu/PVC – Alu blisters: 

18 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 

 

PVC/polychlorotrifluoroethylene (PCTFE) - Alu calendar blisters: 

Single pack containing 14, 28, 56, 98 tablets 

Multi-packs containing 280 tablets (20 packs of 14) 

 

PVC/polychlorotrifluoroethylene (PCTFE) - Alu blisters: 

Single pack containing 30, 90 tablets 

Unit dose pack (perforated unit dose blister) containing 56x1 tablet 

Multi-packs of unit dose (perforated unit dose blister) containing 98x1 tablet (2 packs of 49x1) 

 

PA/Alu/PVC – Alu calendar blisters: 

Single pack containing 14, 28, 56 tablets 

Multi-packs containing 98 tablets (2 packs of 49) and 280 tablets (20 packs of 14) 

 

Not all pack sizes or strengths may be marketed. 

 

6.6 Special precautions for disposal 

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 

 

 



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97 

7. MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/686/043-056 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 14 April 2011 

Date of latest renewal: 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this medicinal product is available on the website of the European 

Medicines Agency http://www.ema.europa.eu 



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98 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 

 



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99 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer responsible for batch release 

 

Novartis Farma S.p.A. 

Via Provinciale Schito 131 

IT-80058 Torre Annunziata 

Italy 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to medical prescription. 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic Safety Update Reports 
The marketing authorisation holder shall submit periodic safety update reports for this product in 

accordance with the requirements set out in the list of Union reference dates (EURD list) provided for 

under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk Management Plan (RMP) 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 

agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 

updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result 

of an important (pharmacovigilance or risk minimisation) milestone being reached. 

 

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 

same time. 

 



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100 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

 

 



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101 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

 



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102 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON OF SINGLE PACK/CARTON OF UNIT PACK (perforated unit dose blister) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 150 mg/5 mg film-coated tablets 

Aliskiren/amlodipine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 150 mg aliskiren (as aliskiren hemifumarate) and 5 mg amlodipine (as 

amlodipine besylate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablets 

 

14 tablets 

28 tablets 

30 tablets 

56 tablets 

56x1 tablet 

90 tablets 

98 tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



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103 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30°C. 

Store in the original package in order to protect from moisture. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/686/001 14 tablets (PVC/PCTFE blisters) 

EU/1/11/686/010 14 tablets (PA/Alu/PVC blisters) 

EU/1/11/686/002 28 tablets (PVC/PCTFE blisters) 

EU/1/11/686/011 28 tablets (PA/Alu/PVC blisters) 

EU/1/11/686/003 30 tablets (PVC/PCTFE blisters) 

EU/1/11/686/004 56 tablets (PVC/PCTFE blisters) 

EU/1/11/686/012 56 tablets (PA/Alu/PVC blisters) 

EU/1/11/686/007 56x1 tablet (PVC/PCTFE single-unit-dose blisters) 

EU/1/11/686/005 90 tablets (PVC/PCTFE blisters) 

EU/1/11/686/006 98 tablets (PVC/PCTFE blisters) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Rasilamlo 150 mg/5 mg 



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104 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 150 mg/5 mg film-coated tablets 

Aliskiren/amlodipine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 150 mg aliskiren (as aliskiren hemifumarate) and 5 mg amlodipine (as 

amlodipine besylate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablets 

 

Component of a multipack comprising 2 packs, each containing 49 tablets. 

Component of a multipack comprising 2 packs, each containing 49x1 tablet. 

Component of a multipack comprising 20 packs, each containing 14 tablets. 

Not to be sold separately. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



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9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30°C. 

Store in the original package in order to protect from moisture. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/686/013 98 tablets (2x49, PA/Alu/PVC blisters) 

EU/1/11/686/008 98 tablets (2x49x1, PVC/PCTFE single-unit-dose blisters) 

EU/1/11/686/009 280 tablets (20x14, PVC/PCTFE blisters) 

EU/1/11/686/014 280 tablets (20x14, PA/Alu/PVC blisters) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Rasilamlo 150 mg/5 mg 



Me
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106 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF MULTIPACK (WITH BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 150 mg/5 mg film-coated tablets 

Aliskiren/amlodipine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 150 mg aliskiren (as aliskiren hemifumarate) and 5 mg amlodipine (as 

amlodipine besylate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablets 

 

Multipack containing 98 (2 packs of 49) tablets. 
Multipack containing 280 (20 packs of 14) tablets. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



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9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30°C. 

Store in the original package in order to protect from moisture. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/686/013 98 tablets (2x49, PA/Alu/PVC blisters) 

EU/1/11/686/008 98 tablets (2x49x1, PVC/PCTFE single-unit-dose blisters) 

EU/1/11/686/009 280 tablets (20x14, PVC/PCTFE blisters) 

EU/1/11/686/014 280 tablets (20x14, PA/Alu/PVC blisters) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Rasilamlo 150 mg/5 mg 



Me
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108 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS (PVC/PCTFE OR PA/Alu/PVC) 

CALENDAR BLISTERS ONLY 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 150 mg/5 mg film-coated tablets 

Aliskiren/amlodipine 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

Monday 

Tuesday 

Wednesday 

Thursday 

Friday 

Saturday 

Sunday 

 



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109 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

PERFORATED UNIT DOSE BLISTER (PCTFE) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 150 mg/5 mg tablets 

Aliskiren/amlodipine 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON OF SINGLE PACK/CARTON OF UNIT PACK (perforated unit dose blister) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 150 mg/10 mg film-coated tablets 

Aliskiren/amlodipine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 150 mg aliskiren (as aliskiren hemifumarate) and 10 mg amlodipine (as 

amlodipine besylate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablets 

 

14 tablets 

28 tablets 

30 tablets 

56 tablets 

56x1 tablet 

90 tablets 

98 tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



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9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30°C. 

Store in the original package in order to protect from moisture. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/686/015 14 tablets (PVC/PCTFE blisters) 

EU/1/11/686/024 14 tablets (PA/Alu/PVC blisters) 

EU/1/11/686/016 28 tablets (PVC/PCTFE blisters) 

EU/1/11/686/025 28 tablets (PA/Alu/PVC blisters) 

EU/1/11/686/017 30 tablets (PVC/PCTFE blisters) 

EU/1/11/686/018 56 tablets (PVC/PCTFE blisters) 

EU/1/11/686/026 56 tablets (PA/Alu/PVC blisters) 

EU/1/11/686/021 56x1 tablet (PVC/PCTFE single-unit-dose blisters) 

EU/1/11/686/019 90 tablets (PVC/PCTFE blisters) 

EU/1/11/686/020 98 tablets (PVC/PCTFE blisters) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Rasilamlo 150 mg/10 mg 



Me
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112 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 150 mg/10 mg film-coated tablets 

Aliskiren/amlodipine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 150 mg aliskiren (as aliskiren hemifumarate) and 10 mg amlodipine (as 

amlodipine besylate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablets 

 

Component of a multipack comprising 2 packs, each containing 49 tablets. 

Component of a multipack comprising 2 packs, each containing 49x1 tablet. 

Component of a multipack comprising 20 packs, each containing 14 tablets. 

Not to be sold separately. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



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9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30°C. 

Store in the original package in order to protect from moisture. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/686/027 98 tablets (2x49, PA/Alu/PVC blisters) 

EU/1/11/686/022 98 tablets (2x49x1, PVC/PCTFE single-unit-dose blisters) 

EU/1/11/686/023 280 tablets (20x14, PVC/PCTFE blisters) 

EU/1/11/686/028 280 tablets (20x14, PA/Alu/PVC blisters) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Rasilamlo 150 mg/10 mg 



Me
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114 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF MULTIPACK (WITH BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 150 mg/10 mg film-coated tablets 

Aliskiren/amlodipine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 150 mg aliskiren (as aliskiren hemifumarate) and 10 mg amlodipine (as 

amlodipine besylate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablets 

 

Multipack containing 98 (2 packs of 49) tablets. 
Multipack containing 280 (20 packs of 14) tablets. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



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9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30°C. 

Store in the original package in order to protect from moisture. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/686/027 98 tablets (2x49, PA/Alu/PVC blisters) 

EU/1/11/686/022 98 tablets (2x49x1, PVC/PCTFE single-unit-dose blisters) 

EU/1/11/686/023 280 tablets (20x14, PVC/PCTFE blisters) 

EU/1/11/686/028 280 tablets (20x14, PA/Alu/PVC blisters) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Rasilamlo 150 mg/10 mg 



Me
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116 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS (PVC/PCTFE OR PA/Alu/PVC) 

CALENDAR BLISTERS ONLY 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 150 mg/10 mg film-coated tablets 

Aliskiren/amlodipine 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

Monday 

Tuesday 

Wednesday 

Thursday 

Friday 

Saturday 

Sunday 

 



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117 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

PERFORATED UNIT DOSE BLISTER (PCTFE) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 150 mg/10 mg tablets 

Aliskiren/amlodipine 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON OF SINGLE PACK/CARTON OF UNIT PACK (perforated unit dose blister) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 300 mg/5 mg film-coated tablets 

Aliskiren/amlodipine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 300 mg aliskiren (as aliskiren hemifumarate) and 5 mg amlodipine (as 

amlodipine besylate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablets 

 

14 tablets 

28 tablets 

30 tablets 

56 tablets 

56x1 tablet 

90 tablets 

98 tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



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9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30°C. 

Store in the original package in order to protect from moisture. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/686/029 14 tablets (PVC/PCTFE blisters) 

EU/1/11/686/038 14 tablets (PA/Alu/PVC blisters) 

EU/1/11/686/030 28 tablets (PVC/PCTFE blisters) 

EU/1/11/686/039 28 tablets (PA/Alu/PVC blisters) 

EU/1/11/686/031 30 tablets (PVC/PCTFE blisters) 

EU/1/11/686/032 56 tablets (PVC/PCTFE blisters) 

EU/1/11/686/040 56 tablets (PA/Alu/PVC blisters) 

EU/1/11/686/035 56x1 tablet (PVC/PCTFE single-unit-dose blisters) 

EU/1/11/686/033 90 tablets (PVC/PCTFE blisters) 

EU/1/11/686/034 98 tablets (PVC/PCTFE blisters) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Rasilamlo 300 mg/5 mg 



Me
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120 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 300 mg/5 mg film-coated tablets 

Aliskiren/amlodipine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 300 mg aliskiren (as aliskiren hemifumarate) and 5 mg amlodipine (as 

amlodipine besylate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablets 

 

Component of a multipack comprising 2 packs, each containing 49 tablets. 

Component of a multipack comprising 2 packs, each containing 49x1 tablet. 

Component of a multipack comprising 20 packs, each containing 14 tablets. 

Not to be sold separately. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



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121 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30°C. 

Store in the original package in order to protect from moisture. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/686/041 98 tablets (2x49, PA/Alu/PVC blisters) 

EU/1/11/686/036 98 tablets (2x49x1, PVC/PCTFE single-unit-dose blisters) 

EU/1/11/686/037 280 tablets (20x14, PVC/PCTFE blisters) 

EU/1/11/686/042 280 tablets (20x14, PA/Alu/PVC blisters) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Rasilamlo 300 mg/5 mg 



Me
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122 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF MULTIPACK (WITH BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 300 mg/5 mg film-coated tablets 

Aliskiren/amlodipine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 300 mg aliskiren (as aliskiren hemifumarate) and 5 mg amlodipine (as 

amlodipine besylate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablets 

 

Multipack containing 98 (2 packs of 49) tablets. 
Multipack containing 280 (20 packs of 14) tablets. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



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123 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30°C. 

Store in the original package in order to protect from moisture. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/686/041 98 tablets (2x49, PA/Alu/PVC blisters) 

EU/1/11/686/036 98 tablets (2x49x1, PVC/PCTFE single-unit-dose blisters) 

EU/1/11/686/037 280 tablets (20x14, PVC/PCTFE blisters) 

EU/1/11/686/042 280 tablets (20x14, PA/Alu/PVC blisters) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Rasilamlo 300 mg/5 mg 



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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS (PVC/PCTFE OR PA/Alu/PVC) 

CALENDAR BLISTERS ONLY 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 300 mg/5 mg film-coated tablets 

Aliskiren/amlodipine 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

Monday 

Tuesday 

Wednesday 

Thursday 

Friday 

Saturday 

Sunday 

 



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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

PERFORATED UNIT DOSE BLISTER (PCTFE) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 300 mg/5 mg tablets 

Aliskiren/amlodipine 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON OF SINGLE PACK/CARTON OF UNIT PACK (perforated unit dose blister) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 300 mg/10 mg film-coated tablets 

Aliskiren/amlodipine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 300 mg aliskiren (as aliskiren hemifumarate) and 10 mg amlodipine (as 

amlodipine besylate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablets 

 

14 tablets 

28 tablets 

30 tablets 

56 tablets 

56x1 tablet 

90 tablets 

98 tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



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9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30°C. 

Store in the original package in order to protect from moisture. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/686/043 14 tablets (PVC/PCTFE blisters) 

EU/1/11/686/052 14 tablets (PA/Alu/PVC blisters) 

EU/1/11/686/044 28 tablets (PVC/PCTFE blisters) 

EU/1/11/686/053 28 tablets (PA/Alu/PVC blisters) 

EU/1/11/686/045 30 tablets (PVC/PCTFE blisters) 

EU/1/11/686/046 56 tablets (PVC/PCTFE blisters) 

EU/1/11/686/054 56 tablets (PA/Alu/PVC blisters) 

EU/1/11/686/049 56x1 tablet (PVC/PCTFE single-unit-dose blisters) 

EU/1/11/686/047 90 tablets (PVC/PCTFE blisters) 

EU/1/11/686/048 98 tablets (PVC/PCTFE blisters) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Rasilamlo 300 mg/10 mg 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 300 mg/10 mg film-coated tablets 

Aliskiren/amlodipine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 300 mg aliskiren (as aliskiren hemifumarate) and 10 mg amlodipine (as 

amlodipine besylate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablets 

 

Component of a multipack comprising 2 packs, each containing 49 tablets. 

Component of a multipack comprising 2 packs, each containing 49x1 tablet. 

Component of a multipack comprising 20 packs, each containing 14 tablets. 

Not to be sold separately. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



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9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30°C. 

Store in the original package in order to protect from moisture. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/686/055 98 tablets (2x49, PA/Alu/PVC blisters) 

EU/1/11/686/050 98 tablets (2x49x1, PVC/PCTFE single-unit-dose blisters) 

EU/1/11/686/051 280 tablets (20x14, PVC/PCTFE blisters) 

EU/1/11/686/056 280 tablets (20x14, PA/Alu/PVC blisters) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Rasilamlo 300 mg/10 mg 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF MULTIPACK (WITH BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 300 mg/10 mg film-coated tablets 

Aliskiren/amlodipine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 300 mg aliskiren (as aliskiren hemifumarate) and 10 mg amlodipine (as 

amlodipine besylate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablets 

 

Multipack containing 98 (2 packs of 49) tablets. 
Multipack containing 280 (20 packs of 14) tablets. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



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9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30°C. 

Store in the original package in order to protect from moisture. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/686/055 98 tablets (2x49, PA/Alu/PVC blisters) 

EU/1/11/686/050 98 tablets (2x49x1, PVC/PCTFE single-unit-dose blisters) 

EU/1/11/686/051 280 tablets (20x14, PVC/PCTFE blisters) 

EU/1/11/686/056 280 tablets (20x14, PA/Alu/PVC blisters) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Rasilamlo 300 mg/10 mg 



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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS (PVC/PCTFE OR PA/Alu/PVC) 

CALENDAR BLISTERS ONLY 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 300 mg/10 mg film-coated tablets 

Aliskiren/amlodipine 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

Monday 

Tuesday 

Wednesday 

Thursday 

Friday 

Saturday 

Sunday 

 



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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

PERFORATED UNIT DOSE BLISTER (PCTFE) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rasilamlo 300 mg/10 mg tablets 

Aliskiren/amlodipine 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 



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B. PACKAGE LEAFLET 

 



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Package leaflet: information for the user 

 

Rasilamlo 150 mg/5 mg film-coated tablets 

Rasilamlo 150 mg/10 mg film-coated tablets 

Rasilamlo 300 mg/5 mg film-coated tablets 

Rasilamlo 300 mg/10 mg film-coated tablets 

Aliskiren/amlodipine 

 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 

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

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. See section 4. 

 

 

What is in this leaflet 

1. What Rasilamlo is and what it is used for 

2. What you need to know before you take Rasilamlo 

3. How to take Rasilamlo 

4. Possible side effects 

5. How to store Rasilamlo 

6. Contents of the pack and other information 

 

 

1. What Rasilamlo is and what it is used for 

 

What Rasilamlo is 

Rasilamlo contains two active substances, called aliskiren and amlodipine. Both of these substances 

help to control high blood pressure (hypertension). 

 

Aliskiren is a renin inhibitor. It reduces the amount of angiotensin II the body can make. 

Angiotensin II causes blood vessels to tighten, which raises blood pressure. Lowering the amount of 

angiotensin II allows the blood vessels to relax; this lowers blood pressure. 

 

Amlodipine belongs to a group of medicines known as calcium channel blockers, which help to 

control high blood pressure. Amlodipine causes blood vessels to dilate and relax, thus blood pressure 

is lowered. 

 

High blood pressure increases the workload of the heart and arteries. If this continues for a long time, 

it can damage the blood vessels of the brain, heart and kidneys, and may result in a stroke, heart 

failure, heart attack or kidney failure. Lowering the blood pressure to a normal level reduces the risk 

of developing these disorders. 

 

What Rasilamlo is used for 

Rasilamlo is used to treat high blood pressure in adult patients whose blood pressure is not 

sufficiently controlled with aliskiren or amlodipine alone. 

 

 



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2. What you need to know before you take Rasilamlo 

 

Do not take Rasilamlo 

- if you are allergic to aliskiren or amlodipine, to any of the other ingredients of this medicine 
(listed in section 6) or to other dihydropyridine-derived medicines (known as calcium channel 

blockers) 

- if you have experienced the following forms of angioedema (difficulties in breathing or 
swallowing, or swelling of the face, hands and feet, eyes, lips and/or tongue): 

- angioedema when taking aliskiren 
- hereditary angioedema 
- angioedema without any known cause 

- if you are between three and nine months pregnant 
- if you are taking any of the following medicines 

- ciclosporin (a medicine used in transplantation to prevent organ rejection or for other 
conditions, e.g. rheumatoid arthritis or atopic dermatitis) 

- itraconazole (a medicine used to treat fungal infections) 
- quinidine (a medicine used to correct heart rhythm) 

- if you have diabetes or impaired kidney function and you are treated with either of the 
following classes of medicines used to treat high blood pressure: 

- an angiotensin converting enzyme inhibitor such as enalapril, lisinopril, ramipril 
or 

- an angiotensin II receptor blocker such as valsartan, telmisartan, irbesartan 
- if the patient is less than 2 years of age 
- if you have very low blood pressure 
- if you are suffering from shock, including cardiogenic shock 
- if you have a narrowing of the aortic heart valve (aortic stenosis) 
- if you have heart failure after an acute heart attack 

If any of the above applies to you, do not take Rasilamlo and talk to your doctor. 

 

Warnings and precautions 

Talk to your doctor before taking Rasilamlo: 

- if you are suffering from vomiting or diarrhoea or if you are taking a diuretic (a medicine to 
increase the amount of urine you produce) 

- if you have already experienced angioedema (difficulties in breathing or swallowing, or 
swelling of the face, hands and feet, eyes, lips and/or tongue). If this happens, stop taking 

Rasilamlo and contact your doctor 

- if you are taking either of the following classes of medicines used to treat high blood pressure: 
- an angiotensin converting enzyme inhibitor such as enalapril, lisinopril, ramipril 
or 

- an angiotensin II receptor blocker such as valsartan, telmisartan, irbesartan 
- if you have diabetes (high blood sugar) 
- if you suffer from heart problems 
- if you are on a low-salt diet 
- if your urine flow has decreased markedly for 24 hours or more and/or if you have serious 

kidney problems (e.g. require dialysis) or a narrowing or blockage of the arteries that supply 

blood to your kidney 

- if you have impaired kidney function, your doctor will carefully consider whether Rasilamlo is 
suitable for you and may wish to monitor you carefully 

- if you suffer from liver problems (impaired liver function) 



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- if you have renal artery stenosis (narrowing of the blood vessels to one of both kidneys) 
- if you have serious congestive heart failure (a type of heart disease where the heart cannot 

pump enough blood around the body) 

 

Your doctor may check your kidney function, blood pressure and the amount of electrolytes (e.g. 

potassium) in your blood at regular intervals. 

 

See also information under the heading “Do not take Rasilamlo”. 

 

Children and adolescents 

Rasilamlo is for use in adults. 

Rasilamlo must not be used in children from birth to less than 2 years of age. It should not be used in 

children from 2 to less than 6 years of age, and is not recommended for use in children and 

adolescents from 6 to less than 18 years of age. 

 

Elderly people 

In the majority of patients aged 65 years or older, the 300 mg dose of aliskiren shows no additional 

benefit in reducing blood pressure compared to the 150 mg dose. 

 

Other medicines and Rasilamlo 

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 

medicines. 

 

Tell your doctor if you are using the following medicines: 

- an angiotensin II receptor blocker or an angiotensin converting enzyme inhibitor (see also 
information under the headings “Do not take Rasilamlo” and “Warnings and precautions”) 

- medicines used to lower blood pressure, diuretics (medicines to increase the amount of urine 
you produce), especially potassium-sparing medicines, potassium supplements, potassium-

containing salt substitutes, or heparin 

- ketoconazole, a medicine used to treat fungal infections 
- verapamil, a medicine used to lower high blood pressure, to correct heart rhythm or to treat 

angina pectoris 

- clarithromycin, telithromycin, erythromycin which are antibiotics used to treat infections 
- amiodarone, a medicine used to treat abnormal heart rhythms 
- atorvastatin, a medicine used to treat high cholesterol 
- furosemide or torasemide, medicines belonging to the type known as diuretics, which are used 

to increase the amount of urine you produce and are also used to treat a certain kind of heart 

problem (heart failure) or oedema (swelling) 

- antiepileptics (e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone) 
- rifampicin, a medicine used to prevent or treat infections 
- St. John’s wort (hypericum perforatum), a herbal medicine used to elevate mood 
- certain types of pain killers called non-steroidal anti-inflammatory medicines (NSAIDs) (used 

especially in patients over 65 years old) 

- diltiazem, a medicine used to treat heart problems 
- ritonavir, a medicine used to treat viral infection 
 

Your doctor may need to change your dose and/or take other precautions if you are taking one of 

the following medicines: 

- furosemide or torasemide, medicines belonging to the type known as diuretics, which are used 
to increase the amount of urine you produce and are also used to treat a certain kind of heart 

problem (heart failure) or oedema (swelling) 

- some medicines used to treat infections, such as ketoconazole 
 

Rasilamlo with food and drink 

You should avoid taking this medicine together with fruit juice and/or drinks containing plant 

extracts (including herbal teas). 



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Pregnancy 

Do not take this medicine if you are pregnant (see section Do not take Rasilamlo). If you become 

pregnant while taking this medicine, stop taking it immediately and talk to your doctor. If you think 

you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before 

taking this medicine. Your doctor will normally advise you to stop taking Rasilamlo before you 

become pregnant and will advise you to take another medicine instead of Rasilamlo. Rasilamlo is not 

recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it 

may cause serious harm to your baby if it is used after the third month of pregnancy. 

 

Breast-feeding 

Tell your doctor if you are breast-feeding or about to start breast-feeding. Rasilamlo is not 

recommended for mothers who are breast-feeding, and your doctor may choose another treatment for 

you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely. 

 

Driving and using machines 

Amlodipine, one of the active substances in Rasilamlo, may make you feel dizzy and drowsy. If you 

experience this symptom, do not drive or use tools or machines. 

 

 

3. How to take Rasilamlo 

 

Always take this medicine exactly as your doctor has told you and do not exceed the recommended 

dose. Check with your doctor or pharmacist if you are not sure. 

 

The usual dose of Rasilamlo is one tablet a day. 

The effect on blood pressure is seen within 1 week and maximum effect is reached at around 4 weeks. 

If your blood pressure is not controlled after 4 to 6 weeks, your doctor may adjust your dose. 

 

Method of administration 

Swallow the tablet whole with some water. You should take this medicine with a light meal once a 

day, preferably at the same time each day. You should avoid taking this medicine together with fruit 

juice and/or drinks containing plant extracts (including herbal teas). During your treatment, your 

doctor may adjust your dose depending on your blood pressure response. 

 

If you take more Rasilamlo than you should 

If you have accidentally taken too many Rasilamlo tablets, talk to a doctor immediately. You may 

require medical attention. 

 

If you forget to take Rasilamlo 

If you forget to take a dose of this medicine, take it as soon as you remember and then take the next 

dose at its usual time. If you only remember the forgotten dose the next day, you should simply take 

the next tablet at the usual time. Do not take a double dose (two tablets at once) to make up for a 

forgotten tablet. 

 

Do not stop taking this medicine, even if you are feeling well unless your doctor tells you to do so. 

People who have high blood pressure often do not notice any signs of the problem. Many may feel 

quite normal. It is very important that you take this medicine exactly as your doctor tells you to get 

the best results and reduce the risk of side effects. Keep your appointments with the doctor even if 

you are feeling well. 

 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

 

 



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4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Fainting and/or light-headedness linked to low blood pressure could occur at the beginning of 

treatment with Rasilamlo. If you experience these, tell your doctor immediately. 

 

As for any combination of two active substances, side effects associated with each individual 

component cannot be excluded. The adverse reactions previously reported with one or both of the two 

active substances (aliskiren and amlodipine) of Rasilamlo and listed below may occur with 

Rasilamlo. 

 

Some side effects can be serious: 

A few patients have experienced these serious side effects. If any of the following occur, tell your 

doctor straight away: 

 Severe skin reactions (toxic epidermal necrolysis and/or oral mucosal reactions - red skin, 

blistering of the lips, eyes or mouth, skin peeling, fever) (uncommon: may affect up to 1 in 

100 people). 

 Severe allergic reaction with symptoms such as rash, itching, swelling of face or lips or tongue, 

difficulty breathing, dizziness (rare: may affect up to 1 in 1,000 people). 

 Nausea, loss of appetite, dark coloured urine or yellowing of skin and eyes (may be signs of 

liver disorder) (frequency not known). 

 

Other side effects may include: 

 

Common (may affect up to 1 in 10 people): 

 low blood pressure 

 swelling, including swelling of hands, ankles or feet (peripheral oedema) 

 diarrhoea 

 joint pain (arthralgia) 

 high level of potassium in the blood 

 dizziness 

 sleepiness 

 headache 

 hot flushes 

 abdominal pain 

 nausea 

 tiredness 

 palpitations (awareness of your heart beat) 
 

Uncommon (may affect up to 1 in 100 people): 

 skin rash (this may also be a sign of allergic reactions or angioedema – see “Rare” side effects 
below) 

 kidney problems including acute renal failure (severely decreased urine output) 

 severe skin reactions (toxic epidermal necrolysis and/or oral mucosal reactions - red skin, 
blistering of the lips, eyes or mouth, skin peeling, fever) 

 cough 

 itching 

 rash (including itchy rash and urticaria) 

 increased liver enzymes 

 insomnia 

 mood changes (including anxiety) 

 depression 

 trembling 



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 disturbed sense of taste 

 sudden, temporary loss of consciousness 

 decreased skin sensitivity 

 tingling or numbness 

 vision disorder (including double vision) 

 ringing noise in ears 

 shortness of breath 

 runny nose 

 vomiting 

 stomach discomfort after meal 

 altered bowel habits (including diarrhoea and constipation) 

 dry mouth 

 hair loss 

 purple skin patches 

 skin discolouration 

 excessive sweating 

 generalised rash 

 muscle pain 

 muscle cramps 

 back pain 

 urination disorders 

 urination at night 

 frequent urination 

 impotence 

 breast enlargement in men 

 chest pain 

 weakness 

 pain 

 feeling unwell 

 weight increase 

 weight decrease 
 

Rare (may affect up to 1 in 1,000 people): 

 severe allergic reaction (anaphylactic reaction) 

 allergic reactions (hypersensitivity) and angioedema (the symptoms of which can include 
difficulties in breathing or swallowing, rash, itching, hives or swelling of the face, hands and 

feet, eyes, lips and/or tongue, dizziness) 

 increased level of creatinine in the blood 

 red skin (erythema) 

 confusion 
 

Very rare (may affect up to 1 in 10,000 people): 

 low level of white blood cells and blood platelets 

 high level of sugar in the blood 

 increased muscle stiffness and inability to stretch 

 sensation of numbness or tingling with sensation of burning in fingers and toes 

 heart attack 

 irregular heart beat 

 inflammation of blood vessels 

 severe upper stomach pain 

 inflammation of the gastric lining 

 bleeding, tender or enlarged gums 

 inflammation of the liver 



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 abnormal liver function test 

 skin reaction with skin reddening and peeling, blistering of lips, eyes or mouth 

 dry skin, rash, itchy rash 

 skin rash with flaking or peeling 

 rash, red skin, blistering of the lips, eyes or mouth, skin peeling, fever 

 swelling mainly of the face and throat 

 increased sensitivity of the skin to sun 
 

Not known (frequency cannot be estimated from the available data): 

 dizziness with spinning sensation 

 low level of sodium in the blood 
 

If any of these affect you severely, tell your doctor. You may need to stop Rasilamlo. 

 

Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects you can help provide more information on the safety 

of this medicine. 

 

 

5. How to store Rasilamlo 

 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The 

expiry date refers to the last day of that month. 

Do not store above 30°C. 

Store in the original package in order to protect from moisture. 

 

 

6. Contents of the pack and other information 

 

What Rasilamlo contains 

- Each Rasilamlo 150 mg/5 mg film-coated tablet contains 150 mg aliskiren (as hemifumarate) 
and 5 mg amlodipine (as besylate). The other ingredients are cellulose microcrystalline, 

crospovidone, povidone, magnesium stearate, silica colloidal anhydrous, hypromellose, 

titanium dioxide (E171), macrogol, talc, yellow iron oxide (E172) and red iron oxide (E172). 

 

- Each Rasilamlo 150 mg/10 mg film-coated tablet contains 150 mg aliskiren (as hemifumarate) 
and 10 mg amlodipine (as besylate). The other ingredients are cellulose microcrystalline, 

crospovidone, povidone, magnesium stearate, silica colloidal anhydrous, hypromellose, 

titanium dioxide (E171), macrogol, talc and yellow iron oxide (E172). 

 

- Each Rasilamlo 300 mg/5 mg film-coated tablet contains 300 mg aliskiren (as hemifumarate) 
and 5 mg amlodipine (as besylate). The other ingredients are cellulose microcrystalline, 

crospovidone, povidone, magnesium stearate, silica colloidal anhydrous, hypromellose, 

titanium dioxide (E171), macrogol, talc and yellow iron oxide (E172). 

 

- Each Rasilamlo 300 mg/10 mg film-coated tablet contains 300 mg aliskiren (as hemifumarate) 
and 10 mg amlodipine (as besylate). The other ingredients are cellulose microcrystalline, 

crospovidone, povidone, magnesium stearate, silica colloidal anhydrous, hypromellose, 

macrogol, talc and yellow iron oxide (E172). 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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What Rasilamlo looks like and contents of the pack 

Rasilamlo 150 mg/5 mg film-coated tablets are light yellow, convex, oval film-coated tablets, with 

“T2” debossed on one side and “NVR” on the other. 

 

Rasilamlo 150 mg/10 mg film-coated tablets are yellow, convex, oval film-coated tablets, with “T7” 

debossed on one side and “NVR” on the other. 

 

Rasilamlo 300 mg/5 mg film-coated tablets are dark yellow, convex, oval film-coated tablets, with 

“T11” debossed on one side and “NVR” on the other. 

 

Rasilamlo 300 mg/10 mg film-coated tablets are brown-yellow, convex, oval film-coated tablets, with 

“T12” debossed on one side and “NVR” on the other. 

 

Rasilamlo is available in packs containing 14, 28, 56 or 98 tablets (in calendar blisters), 30 or 

90 tablets (in normal blisters) and 56x1 tablet (as perforated unit dose blisters). 

 

It is also available in multi-packs of 98 tablets (2 packs of 49) and 280 tablets (20 packs of 14) in 

calendar blisters and 98x1 tablet (2 packs of 49x1) as perforated unit dose blisters. 

 

Not all pack sizes or strengths may be available in your country. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

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 

 

Lietuva 

Novartis Pharma Services Inc. 

Tel: +370 5 269 16 50 

 

България 

Novartis Pharma Services Inc. 

Тел.: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. Pharma 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 



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Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 26 37 82 111 

Eesti 

Novartis Pharma Services Inc. 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

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 50 

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 (0)10 6133 200 

 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

Novartis Pharma Services Inc. 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

 

This leaflet was last revised in 

 

Other sources of information 

Detailed information on this medicine is available on the European Medicines Agency website: 

http://www.ema.europa.eu 



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144 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX IV 

 

SCIENTIFIC CONCLUSIONS AND GROUNDS RECOMMENDING THE VARIATION TO 

THE TERMS OF THE MARKETING AUTHORISATION 



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Scientific conclusions 

 

Taking into account the PRAC Assessment Report on the PSUR for aliskiren / aliskiren, amlodipine 

/ aliskiren, hydrochlorothiazide, the scientific conclusions of CHMP are as follows: 

 

During the reporting a number of serious and non-serious adverse drug reactions (ADRs) from post-

marketing data sources regarding “hyponatraemia” raised a concern that led to the submission of a 

cumulative review from the Marketing Authorisation Holder (MAH). The cumulative review 

retrieved 187 cases out of which 57 were sufficiently documented, in 8 of these cases a causal 

relationship could not be ruled out. In 3 additional cases where severe hyponatremia was associated 

with neurological symptoms such as brain oedema or major confusion and cerebral oedema, 

causality could also not be excluded. 

 

The MAH submitted an analysis with 1407 cases of “dyspnoea”, in 13 of them there was positive 

dechallenge and three cases with positive rechallenge. The PRAC considered the cases of 

dechallenge and rechallenge to be important causal relationship information that contributes to 

confirm the safety signal. 

 

Therefore, in view of available data regarding aliskiren/ aliskiren,amlodipine / aliskiren, 

hydrochlorothiazide, the PRAC considered that changes to the product information were warranted. 

The CHMP agrees with the scientific conclusions made by the PRAC. 

 

Grounds recommending the variation to the terms of the Marketing Authorisation 

 

On the basis of the scientific conclusions for aliskiren / aliskiren, amlodipine / aliskiren, 

hydrochlorothiazide the CHMP is of the opinion that the benefit-risk balance of the medicinal 

product(s) containing aliskiren / aliskiren, amlodipine / aliskiren, hydrochlorothiazide is favourable 

subject to the proposed changes to the product information. 

 

The CHMP recommends that the terms of the Marketing Authorisations should be varied. 

 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS RECOMMENDING THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION