Patient leaflet - Riprazo

SUMMARY OF PRODUCT CHARACTERISTICS

Riprazo 150 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 150 mg aliskiren (as hemifumarate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet

Light-pink, biconvex, round tablet, imprinted “IL” on one side and “NVR” on the other side

4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications

Treatment of essential hypertension in adults.

4.2 Posology and method of administration

Posology

The recommended dose of Riprazo is 150 mg once daily. In patients whose blood pressure is not adequately controlled, the dose may be increased to 300 mg once daily.

The antihypertensive effect is substantially present within two weeks (85–90%) after initiating therapy with 150 mg once daily.

Riprazo may be used alone or in combination with other antihypertensive agents 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).

Special popula tions

Renal impairment

No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see sections 4.4 and 5.2). Riprazo is not recommended in patients with severe renal impairment (GFR < 30 ml/min/1.73 m2). Concomitant use of Riprazo with ARBs or ACEIs is contraindicated in patients with renal impairment (GFR < 60 ml/min/1.73 m2) (see section 4.3).

Hepatic impairment

No adjustment of the initial dose is required for patients with mild to severe hepatic impairment (see section 5.2).

Elderly patients aged 65 years and over

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 Riprazo in children aged below 18 years have not yet been established. No data are available.

Method of administration

Oral use. The tablets should be swallowed whole with some water. Riprazo should be taken with a light meal once a day, preferably at the same time each day. Grapefruit juice should not be taken together with Riprazo (see section 4.5).

4.3 Contraindications

– Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
– History of angioedema with aliskiren.

Hereditary or idiopathic angioedema.

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

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

The concomitant use of aliskiren with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.2, 4.4, 4.5 and

5.1).

4.4 Special warnings and precautions for use

General

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

Aliskiren should be used with caution in patients with serious congestive heart failure (New York

Heart Association [NYHA] functional class III-IV).

Dual blockade of the renin-angiotensin-aldosterone

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

Hypotension, syncope, stroke, hyperkalaemia, and changes in renal function (including acute renal failure) have been reported in susceptible individuals, especially if combining medicinal products that affect this system (see section 5.1). Dual blockade of the renin-angiotensin-aldosterone system by combining aliskiren with an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) is therefore not recommended.

The use of aliskiren in combination with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see section 4.3).

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 system, angioedema or symptoms suggestive of angioedema (swelling of the face, lips, throat and/or tongue) have been reported in patients treated with aliskiren.

A number of these patients had a history of angioedema or symptoms suggestive of angioedema, which in some cases followed use of other medicines that can cause angioedema, including RAAS blockers (angiotensin converting enzyme 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 a history of angioedema may be at increased risk of experiencing angioedema during treatment with aliskiren (see sections 4.3 and 4.8). Caution should therefore be exercised when prescribing aliskiren to patients with a history of angioedema, and such patients should be closely monitored during treatment (see section 4.8) especially at the beginning of the treatment.

If anaphylactic reactions or angioedema occur, Riprazo 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.

Sodium and/or volume depleted patients

In patients with marked volume- and/or salt-depletion (e.g. those receiving high doses of diuretics) symptomatic hypotension could occur after initiation of treatment with Riprazo. This condition should be corrected prior to administration of Riprazo, or the treatment should start under close medical supervision.

Renal impairment

In clinical studies Riprazo has not been investigated in hypertensive patients with severe renal impairment (serum creatinine > 150 ^mol/l or 1.70 mg/dl in women and > 177 ^mol/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. Riprazo 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 system, caution should be exercised when aliskiren is given in the presence of conditions pre-disposing to kidney dysfunction such as hypovolaemia (eg. due to blood loss, severe prolonged diarrhoea, prolonged vomiting, etc.), heart disease, liver disease, diabetes mellitus or kidney disease. The concomitant use of aliskiren and ACEIs or ARBs is contraindicated in patients with renal impairment (GFR < 60 ml/min/1.73 m2). Acute renal failure, reversible upon discontinuation of treatment, has been reported in at-risk patients receiving aliskiren in post-marketing experience. In the event that any signs of renal failure occur, aliskiren should be promptly discontinued.

Increases in serum potassium have been observed with aliskiren in post-marketing experience and these may be exacerbated by concomitant use of other agents acting on the RAAS or by non-steroidal anti-inflammatory drugs (NSAIDs). Consistent with standard medical practice, periodic determination of renal function including serum electrolytes is advised if co-administration is considered necessary.

Renal artery stenosis

No controlled clinical data are available on the use of Riprazo 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 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.

4.5 Interaction with other medicinal products and other forms of interaction

Contraindicated (see section 4.3)

Dual RAAS blockade

The combination of aliskiren with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) and is not recommended in other patients (see sections 4.3, 4.4 and 5.1).

P-glycoprotein (P-gp) potent inhibitors

A single dose 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) Grapefruit juice

Administration of grapefruit juice with aliskiren resulted in a decrease in AUC and Cmax of aliskiren. Co-administration with aliskiren 150 mg resulted in a 61% decrease in aliskiren AUC and coadministration with aliskiren 300 mg resulted in a 38% decrease in aliskiren AUC. This decrease is likely due to an inhibition of organic anion transporting polypeptide-mediated uptake of aliskiren by grapefruit juice in the gastrointestinal tract. Therefore, because of the risk of therapeutic failure, grapefruit juice should not be taken together with Riprazo.

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. 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 Riprazo. 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. The combination of aliskiren with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) and is not recommended in other patients (see sections 4.3, 4.4 and 5.1).

As with other agents acting on the renin-angiotensin system, NSAIDs may reduce the antihypertensive 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

When aliskiren was co-administered with furosemide, the AUC and Cmax of furosemide were reduced by 28% and 49%, respectively. It is therefore recommended that the effects be monitored when initiating and adjusting furosemide therapy to avoid possible under-utilisation in clinical situations volume overload.

Warfarin

The effects of Riprazo on warfarin pharmacokinetics have not been evaluated.

Food interactions

Meals (low or high fat content) have been shown to reduce the absorption of Riprazo substantially (see section 4.2).

No interactions

– Compounds that have been investigated in 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 (128%), amlodipine ($29%) or cimetidine ($19%) resulted in between 20% and 30% change in Cmax or AUC of Riprazo. When administered with atorvastatin, steady-state Riprazo AUC and Cmax increased by 50%. Coadministration of Riprazo had no significant impact on atorvastatin, metformin or amlodipine pharmacokinetics. As a result no dose adjustment for Riprazo or these co-administered medicinal products is necessary.

Digoxin and verapamil bioavailability may be slightly decreased by Riprazo.

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

- Organic anion transporting polypeptide (OATP) inhibitors

Preclinical studies indicate that aliskiren might be a substrate of organic anion transporting polypeptides. Therefore, the potential exists for interactions between OATP inhibitors and aliskiren when administered concomitantly (see interaction with Grapefruit juice).

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data on the use of aliskiren in pregnant women. Riprazo 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, Riprazo should not be used during the first trimester of pregnancy or in women planning to become pregnant and is contraindicated during the second and third trimesters (see section 4.3). Healthcare professionals prescribing any agents acting on the RAAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy. If pregnancy is detected during therapy, Riprazo should be discontinued accordingly.

Breast-feeding

It is not known whether aliskiren is excreted in human milk. Riprazo was secreted in the mi lactating rats. Its use is therefore not recommended in women who are breast-feeding.

Fertility

There are no clinical data on fertility.

4.7 Effects on ability to drive and use machines

Riprazo has negligible influence on the ability to drive and use machines. However, when driving vehicles or operating machinery it must be borne in mind that dizziness or weariness may occasionally occur when taking Riprazo.

4.8 Undesirable effects

Summary of the safety profile

Riprazo has been evaluated for safety in more

0 patients, including over 2,300 treated for

over 6 months, and more than 1,200 for over 1 year. The incidence of adverse reactions showed no association with gender, age, body mass index, race or ethnicity. Serious adverse reactions include anaphylactic reaction and angioedema which have been reported in post-marketing experience and may occur rarely (less than 1 case per 1,000 patients). The most common adverse reaction is diarrhoea.

Tabulated list of adverse reactions:

The adverse drug reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1

Immune system disorders

Rare:

Nervous system disorders

Common:

Cardiac disorders

Uncommon:

Vascular disorders

Uncommon:

Anaphylactic reactions, hypersensitivity reactions

Dizziness

Palpitations

Hypotension

Respiratory, thoracic and mediastinal disorders

Uncommon:

Gastrointestinal disorders

Common:

Cough

Diarrhoea

Skin and subcutaneous tissue disorders

Uncommon:

Rare:

Severe cutaneous adverse reactions (SCARs) including Stevens Johnson syndrome, toxic epidermal necrolysis (TEN) and oral mucosal reactions, rash, pruritus, urticaria

Angioedema, erythema

Musculoskeletal and connective tissue disorders

Common:

Arthralgia

Renal and urinary disorders

Uncommon:

Acute renal failure, renal impairment

General disorders and administration site conditions

Uncommon:

Investigations

Common:

Uncommon:

Rare:

Oedema peripheral

Hyperkalaemia

Liver enzyme increased

Haemoglobin decreased, haematocrit decreased, blood creatinine increased

Description of se lected 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.

Cases of angioedema or symptoms suggestive of angioedema (swelling of the face, lips, throat and/or tongue) have also been reported in post-marketing experience. A number of these patients had a history of angioedema or symptoms suggestive of angioedema which in some cases was associated with the administration of other medicines known to cause angioedema, including 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 re patients at risk (see section 4.4).

Laboratory findings

In controlled clinical trials, clinically relevant changes in standard laboratory parame uncommonly associated with the administration of Riprazo. In clinical studies in hypertensive patients, Riprazo had no clinically important effects on total cholesterol, high density lipoprotein cholesterol (HDL-C), fasting triglycerides, fasting glucose or uric acid.

Haemoglobin and haematocrit : Small decreases in haemoglobin and haematocrit (mean decreases of approximately 0.05 mmol/l and 0.16 volume percent, respectively) were observed. No patients discontinued therapy due to anaemia. This effect is also seen with other agents acting on the reninangiotensin system, 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. The combination of aliskiren with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) and is not recommended in other patients (see sections 4.3, 4.4 and 5.1).

4.9 Overdose

Symptoms

Limited data are available related to overdose in humans. The most likely manifestations of overdosage would be hypotension, related to the antihypertensive effect of aliskiren.

Treatment

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

In a study cond

dialysis tre

over-exposure.

cted in patients with end stage renal disease (ESRD) receiving haemodialysis, e of aliskiren was low (< 2% of oral clearance). Therefore dialysis is not adequate to

5. PHARMACOLOGICAL PROPERTIES
- 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system; renin inhibitor, ATC code: C09XA02

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

By inhibiting the enzyme renin, aliskiren inhibits the 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 agents 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 agents. The clinical implications of the differences in effect on PRA are not known at the present time.

Hypertension

In hypertensive patients, once-daily administration of Riprazo 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 bloodpressure-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. Riprazo has been studied in 1,864 patients aged 65 years or older, and in 426 patients aged 75 years or older.

Riprazo monotherapy studies have shown blood pressure lowering effects comparable to other classes of antihypertensive agents including ACEI and ARB. Compared to a diuretic (hydrochlorothiazide -HCTZ), Riprazo 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 Riprazo added to the diuretic hydrochlorothiazide, the calcium channel blocker amlodipine and the beta blocker atenolol. These combinations were well tolerated. Riprazo induced an additive blood-pressure-lowering effect when added to hydrochlorothiazide. In patients who did not adequately respond to 5 mg of the calcium channel blocker amlodipine, the addition of Riprazo 150 mg had a blood-pressure-lowering effect similar to that obtained by increasing amlodipine dose to 10 mg, but had a lower incidence of oedema (aliskiren

150 mg/amlodipine 5 mg 2.1% vs. amlodipine 10 mg 11.2%).

The efficacy and safety of aliskiren-based therapy were comp

The efficacy and safety of aliskiren-based therapy were compared to ramipril-based therapy in a 9-month non-inferiority study in 901 elderly patients (> 65 years) with essential systolic hypertension. Aliskiren 150 mg or 300 mg per day or ramipril 5 mg or 10 mg per day were administered for 36 weeks with optional add-on therapy of hydrochlorothiazide (12.5 mg or 25 mg) at week 12, and amlodipine (5 mg or 10 mg) at week 22. Over the 12 week period, aliskiren monotherapy lowered systolic/diastolic blood pressure by 14.0/5.1 mmHg, compared to 11.6/3.6 mmHg for ramipril, consistent with aliskiren being non-inferior to ramipril at the dosages chosen and the differences in systolic and diastolic blood pressure were statistically significant. Tolerability was comparable in both treatment arms, however cough was more often reported with the ramipril regimen than the aliskiren regimen (14.2% vs. 4.4%), whilst diarrhoea was more common with the aliskiren regimen than for the ramipril regimen (6.6% vs. 5.0%).

In a 8-week study in 754 hypertensive elderly (> 65 years) and very elderly patients (30% > 75 years) aliskiren at doses of 75 mg, 150 mg and 300 mg provided statistically significant superior reduction in blood pressure (both systolic and diastolic) when compared to placebo. No additional blood pressure lowering effect was detected with 300 mg aliskiren compared to 150 mg aliskiren. All three doses were well tolerated in both elderly and very elderly patients.

In obese hypertensive patients who did not adequately respond to HCTZ 25 mg, add-on treatment with Riprazo 300 mg provided additional blood pressure reduction that was comparable to add-on treatment with irbesartan 300 mg or amlodipine 10 mg.

There has been no evidence of first-dose hypotension and no effect on pulse rate in patients treat controlled clinical studies. Excessive hypotension was uncommonly (0.1%) seen in patients with uncomplicated hypertension treated with Riprazo alone. Hypotension was also uncommon during combination therapy with other antihypertensive agents. With cessation of treatmen 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 dysfunct ventricular remodelling as assessed by left ventricular end systolic volume were d aliskiren compared to placebo on top of background therapy.

, no changes in ted with

The combined rates of cardiovascular death, hospitalisation for heart failure, recurrent heart attack, stroke and resuscitated sudden death were similar in the aliskiren group and the placebo group. However, in patients receiving aliskiren there was a significantly higher rate of hyperkalaemia, hypotension and kidney dysfunction when compared to the placebo group.

Aliskiren was evaluated for cardiovascular and/or renal benefit in a double-blind placebo controlled randomised trial in 8,606 patients with type 2 diabetes and chronic kidney disease (evidenced by proteinuria and/or GFR < 60 ml/min/1.73 m2) with or without cardiovascular disease. In most patients arterial blood pressure was well controlled at baseline. The primary endpoint was a composite of cardiovascular and renal complications.

In this study, aliskiren 300 mg was compared to placebo when added to standard of care which included either an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. The study was discontinued prematurely because the participants were unlikely to benefit from aliskiren. Preliminary study results indicated a hazard ratio for the primary endpoint of 1.09 in favour of placebo (95% Confidence Interval: 0.97, 1.22, 2-sided p=0.17). In addition, an increased incidence of serious adverse outcomes was observed with aliskiren compared to placebo for renal complications (4.7% versus 3.3%), hyperkalaemia (36.9% versus 27.1%), hypotension (18.4% versus 14.6%) and stroke (2.7% versus 2.0%). The increased incidence of non-fatal stroke was greater in patients with renal insufficiency.

Beneficial effects of Riprazo on mortality and cardiovascular morbidity and target organ damage are currently unknown.

Cardiac electrophysiology

No effect on QT interval was reported in a randomised, double-blind, placebo, and active-controlled study using standard and Holter electrocardiography.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Riprazo in one or more subsets of the paediatric population in hypertension (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Following oral absorption, peak plasma concentrations of aliskiren are reached after 1–3 hours. The absolute bioavailability of aliskiren is approximately 2–3%. Meals with a high fat content reduce Cmax by 85% and AUC by 70%. At steady state meals with low fat content reduce Cmax by 76% and AUC0-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.

Distribution

Following intravenous administration, the mean volume of distribution at steady state is approximately 135 litres, indicating that aliskiren distributes extensively into the extravascula 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 elimi

unchanged

compound in the faeces (78%). Approximately 1.4% of the total oral dose is metabolised. The enzyme responsible for this metabolism is CYP3A4. Approximately 0.6% of the dose is recovered in urine following oral administration. Following intravenous administration, the mean plasma clearance is approximately 9 l/h.

Linearity

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.

Characteristics in patients

Aliskiren is an effective once-a-day anti age, body mass index and ethnicity.

nsive treatment in adult patients, regardless of gender,

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 Riprazo is required in patients with mild to moderate renal impairment (see sections 4.2 and 4.4). Riprazo is not recommended in patients with severe renal impairment (glomerular filtration rate (GFR) < 30 ml/min/1.73 m2). Concomitant use of Riprazo with ARBs or ACEIs is contraindicated in patients with renal impairment (GFR < 60 ml/min/1.73 m2) (see section 4.3).

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.

5.3 Preclinical safety data

Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic mouse study. No carcinogenic potential was detected. One colonic adenoma and one caecal adenocarcinoma recorded in rats at the dose of 1,500 mg/kg/day were not statistically significant. Although aliskiren has known irritation potential, safety margins obtained in humans at the dose of 300 mg during a study in healthy volunteers were considered to be appropriate at 9–11-fold based on faecal concentrations or 6-fold based on mucosa concentrations in comparison with 250 mg/kg/day in the rat carcinogenicity study.

Aliskiren was devoid of any mutagenic potential in the in vitro and in vivo mutagenicity studies. The assays included in vitro assays in bacterial and mammalian cells and in vivo assessments in rats.

Reproductive toxicity studies with aliskiren did not reveal any evidence of embryofoetal toxicity or teratogenicity at doses up to 600 mg/kg/day in rats or 100 mg/kg/day in rabbits. Fertility, pre-natal development and post-natal development were unaffected in rats at doses up to 250 mg/kg/day. The doses in rats and rabbits provided systemic exposures of 1 to 4 and 5 times higher, respectively, than the maximum recommended human dose (300 mg).

Safety pharmacology studies did not reveal any adverse effects on central nervous, respiratory or cardiovascular function. Findings during repeat-dose toxicity studies in animals were consistent with the known local irritation potential or the expected pharmacological effects of aliskiren.

6. PHARMACEUTICAL PARTICULARS
- 6.1 List of excipients

Crospovidone

Magnesium stearate

Cellulose, microcrystalline

Povidone

Silica, colloidal anhydrous

Hypromellose

Macrogol

Talc

Iron oxide, black (E 172)

Iron oxide, red (E 172)

Titanium dioxide (E 171)

6.2 Incompatibilities

Not applicable

6.3 Shelf life 2 years
6.4 Special precautions for storage

Do not store above 30°C. Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

PA/Alu/PVC – Alu blisters:

Packs containing 7, 14, 28, 30, 50, 56, 84, 90, 98 or 280 tablets.

Packs containing 84 (3×28), 98 (2×49) or 280 (20×14) tablets are multi-packs.

PVC/polychlorotrifluoroethylene (PCTFE) – Alu blisters:

Packs containing 14, 28, 30, 50, 56, 90, 98 or 280 tablets.

Packs containing 98 (2×49) or 280 (20×14) tablets are multi-packs.

Packs containing 56 and 98 (2×49) tablets are perforated unit-dose blisters.

Not all pack sizes 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.

7. MARKETING AUTHORISATION HOLDER

Novartis Europharm Limited Wimblehurst Road Horsham

West Sussex, RH12 5AB United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/07/409/001–010

EU/1/07/409/021–030

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 22 August 2007 Date of latest renewal:

10. DATE OF REVISION OF THE TEXT

Medicines

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

Agency

1. NAME OF THE MEDICINAL PRODUCT

Riprazo 300 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 300 mg aliskiren (as hemifumarate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet

Light-red, biconvex, ovaloid tablet, imprinted “IU” on one side and “NVR” on

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of essential hypertension in adults.

4.2 Posology and method of administration

Posology

The recommended dose of Riprazo is 150 mg once daily. In patients whose blood pressure is not adequately controlled, the dose may be increased to 300 mg once daily.

The antihypertensive effect is substantially present within two weeks (85–90%) after initiating therapy with 150 mg once daily.

Special popula tions

Renal impairment

Hepatic impairment

No adjustment of the initial dose is required for patients with mild to severe hepatic impairment (see section 5.2).

Elderly patients aged 65 years and over

Paediatric population

The safety and efficacy of Riprazo in children aged below 18 years have not yet been established. No data are available.

Method of administration

4.3 Contraindications

– Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
– History of angioedema with aliskiren.

Hereditary or idiopathic angioedema.

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

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

The concomitant use of aliskiren with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.2, 4.4, 4.5 and

5.1).

4.4 Special warnings and precautions for use

General

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

Aliskiren should be used with caution in patients with serious congestive heart failure (New York

Heart Association [NYHA] functional class III-IV).

Dual blockade of the renin-angiotensin-aldosterone

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

The use of aliskiren in combination with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see section 4.3).

Anaphylactic reactions and angioedema

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.

Sodium and/or volume depleted patients

Renal impairment

In clinical studies Riprazo has not been investigated in hypertensive patients with severe renal impairment (serum creatinine > 150 ^mol/l or 1.70 mg/di in women and > 177 ^mol/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. Riprazo is not recommended in patients with severe renal impairment (GFR < 30 ml/min/1.73 m2).

Renal artery stenosis

4.5 Interaction with other medicinal products and other forms of interaction

Contraindicated (see section 4.3)

Dual RAAS blockade

P-glycoprotein (P-gp) potent inhibitors

Not recommended (see section 4.2) Grapefruit juice

Caution required with concomitant use P-gp interactions

Moderate P-gp inhibitors

Medicinal products affecting serum potassium levels

Non-steroidal anti-inflammatory drugs (NSAIDs)

Furosemide

Warfarin

The effects of Riprazo on warfarin pharmacokinetics have not been evaluated.

Food interactions

Meals (low or high fat content) have been shown to reduce the absorption of Riprazo substantially (see section 4.2).

No interactions

– Compounds that have been investigated in clinical pharmacokinetic studies include

acenocoumarol, atenolol, celecoxib, pioglitazone, allopurinol, isosorbide-5-mononitrate and hydrochlorothiazide. No interactions have been identified.

Digoxin and verapamil bioavailability may be slightly decreased by Riprazo.

CYP450 interactions

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

- P-gp substrates or weak inhibitors

- Organic anion transporting polypeptide (OATP) inhibitors

4.6 Fertility, pregnancy and lactation

Pregnancy

Breast-feeding

It is not known whether aliskiren is excreted in human milk. Riprazo was secreted in the mi lactating rats. Its use is therefore not recommended in women who are breast-feeding.

Fertility

There are no clinical data on fertility.

4.7 Effects on ability to drive and use machines

4.8 Undesirable effects

Summary of the safety profile

Riprazo has been evaluated for safety in more than 7,800 patients, including over 2,300 treated for over 6 months, and more than 1,200 for over 1 year. The incidence of adverse reactions showed no association with gender, age, body mass index, race or ethnicity. Serious adverse reactions include anaphylactic reaction and angioedema which have been reported in post-marketing experience and may occur rarely (less than 1 case per 1,000 patients). The most common adverse reaction is diarrhoea.

Tabulated list of adverse reactions:

Table 1

Immune system disorders

Rare:

Nervous system disorders

Common:

Cardiac disorders

Uncommon:

Vascular disorders

Uncommon:

Anaphylactic reactions, hypersensitivity reactions

Dizziness

Palpitations

Hypotension

Respiratory, thoracic and mediastinal disorders

Uncommon:

Gastrointestinal disorders

Common:

Cough

Diarrhoea

Skin and subcutaneous tissue disorders

Uncommon:

Rare:

Severe cutaneous adverse reactions (SCARs) including Stevens Johnson syndrome, toxic epidermal necrolysis (TEN) and oral mucosal reactions, rash, pruritus, urticaria

Angioedema, erythema

Musculoskeletal and connective tissue disorders

Common:

Arthralgia

Renal and urinary disorders

Uncommon:

Acute renal failure, renal impairment

General disorders and administration site conditions

Uncommon:

Investigations

Common:

Uncommon:

Rare:

Oedema peripheral

Hyperkalaemia

Liver enzyme increased

Haemoglobin decreased, haematocrit decreased, blood creatinine increased

Description of se lected 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.

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).

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 re patients at risk (see section 4.4).

Laboratory findings

4.9 Overdose

Symptoms

Limited data are available related to overdose in humans. The most likely manifestations of overdosage would be hypotension, related to the antihypertensive effect of aliskiren.

Treatment

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

In a study cond

dialysis cl treat aliski

cted in patients with end stage renal disease (ESRD) receiving haemodialysis, e of aliskiren was low (< 2% of oral clearance). Therefore dialysis is not adequate to

over-exposure.

5. PHARMACOLOGICAL PROPERTIES
- 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system; renin inhibitor, ATC code: C09XA02

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

Hypertension

, no changes in ted with

Beneficial effects of Riprazo on mortality and cardiovascular morbidity and target organ damage are currently unknown.

Cardiac electrophysiology

No effect on QT interval was reported in a randomised, double-blind, placebo, and active-controlled study using standard and Holter electrocardiography.

Paediatric population

5.2 Pharmacokinetic properties

Absorption

Distribution

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, the mean plasma clearance is approximately 9 l/h.

Linearity

Characteristics in patients

Aliskiren is an effective once-a-day anti age, body mass index and ethnicity.

nsive treatment in adult patients, regardless of gender,

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.

5.3 Preclinical safety data

6. PHARMACEUTICAL PARTICULARS
- 6.1 List of excipients

c WxQ

Crospovidone

Magnesium stearate

Cellulose, microcrystalline

Povidone

Silica, colloidal anhydrous

Hypromellose

Macrogol

Talc

Iron oxide, black (E 172)

Iron oxide, red (E 172)

Titanium dioxide (E 171)

6.2 Incompatibilities

Not applicable

6.3 Shelf life 2 years
6.4 Special precautions for storage

Do not store above 30°C. Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

in accordance with local

PA/Alu/PVC – Alu blisters:

Packs containing 7, 14, 28, 30, 50, 56, 84, 90, 98 or 280 tablets.

Packs containing 84 (3×28), 90 (3×30), 98 (2×49) or 280 (20×14) tablets are multi-packs.

PVC/polychlorotrifluoroethylene (PCTFE) – Alu blisters:

Packs containing 14, 28, 30, 50, 56, 90, 98 or 280 tablets.

Packs containing 98 (2×49) or 280 (20×14) tablets are multi-packs.

Packs containing 56 and 98 (2×49) tablets are perforated unit-dose blisters.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be di requirements.

7. MARKETING AUTHORISATION HOLDER

Novartis Europharm Limited Wimblehurst Road Horsham

West Sussex, RH12 5AB

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/07/409/011–020

EU/1/07/409/031–040

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 22 August 2007 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

ANNEX II

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

NS REGARDING SUPPLY

CONDITIONS OR REST AND USE

OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING

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

I-80058 Torre Annunziata/NA

Italy

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

Pharmacovigilance system

The MAH must ensure that the system of pharmacovigilance presented in M 1.8.1 of the

Marketing Authorisation, is in place and functioning before and whilst the medicinal product is on the market.

Risk Management Plan (RMP)

The MAH shall perform the pharmacovigilance activities detailed in the Pharmacovigilance Plan, as agreed in the RMP presented in Module 1.8.2 of the Marketing Authorisation and any subsequent updates of the RMP agreed by the Committee for Medicinal Products for Human Use (CHMP).

As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the updated RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR).

In addition, an updated RMP should be submitted within 1 month after the Commission Decision of the renewal procedure. The RMP shall include the following:

Deadlines for submission of the APOLLO study results.

A description and timelines for the new study replacing APOLLO and designed to elucidate efficacy and safety in the elderly, including gastrointestinal cancer as a pre-specified endpoint. Timelines to submit further data on colorectal hyperplasia events from ALTITUDE study. A commitment to submit the final study report of the epidemiological study on ischaemic colitis.

A description and timelines for the new observational study on incidence of colorectal hyperplasia in aliskiren-treated patients.

In addition, an updated RMP should be submitted:

When new information is received that may impact on the current Safety Specification, Pharmacovigilance Plan or risk minimisation activities.

Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached.

At the request of the European Medicines Agency.

PSURs

The PSUR cycle for the medicinal product should follow the yearly cycle until otherwise agreed by the CHMP.

CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND

EFFECTIVE USE OF THE MEDICINAL PRODUCT

Not applicable.

OBLIGATION TO CONDUCT POST-AUTHORISATION MEASURES

The MAH shall complete, within the stated timeframe, the following measures:

Description

Due date

The MAH shall submit the final results and study report for the active treatment phase of the ALTITUDE study when available

31 July 2012

The MAH shall submit an updated risk management plan (RMP) that adequately describes all the safety concerns, the pharmacovigilance activities and the interventions designed to identify, characterise, prevent or minimise the risks within a month following the Commission Decision of the renewal procedure (EMEA/H/C/853/R/068). The RMP shall include: – Deadlines for submission of the APOLLO study results.

– A description and timelines for the new study replacing APOLLO and

designed to elucidate efficacy and safety in the elderly, including gastrointestinal cancer as a pre-specified endpoint.

– Timelines to submit further data on colorectal hyperplasia events from

ALTITUDE study.

– A commitment to submit the final study report of the epidemiological

study on ischaemic colitis.

– A description and timelines for the new observational study on incidence

of colorectal hyperplasia in aliskiren-treated patients.

Within a month following the Commission Decision of the renewal procedure

ANNEX III

LABELLING AND PACKAGE LEAFLET

FOLDING BOX FOR UNIT PACK CONTAINING PA/ALU/PVC BLISTERS

1. NAME OF THE MEDICINAL PRODUCT

Riprazo 150 mg film-coated tablets Aliskiren

DMINISTRATION

2.	STATEMENT OF ACTIVE SUBSTANCE(S)
Eac	h film-coated tablet contains 150 mg aliskiren (as hemifumarate).
3.	LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS 7 film-coated tablets

14 film-coated tablets

28 film-coated tablets

30 film-coated tablets

50 film-coated tablets

56 film-coated tablets

90 film-coated tablets

5. METHOD AND ROUTE

Oral use.

Read the package leaflet b

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF T HE 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

Do not store above 30°C.

Store in the original package in order to protect from moisture.

EU/1/07/409/005 50 film-coated tablets

EU/1/07/409/006 56 film-coated tablets

EU/1/07/409/008 90 film-coated tablets

14. GENERAL CLASSIFICATION FOR SUPPLY

FOLDING BOX FOR UNIT PACK CONTAINING PCTFE/PVC BLISTERS

1. NAME OF THE MEDICINAL PRODUCT

Riprazo 150 mg film-coated tablets Aliskiren

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 150 mg aliskiren (as hemifumarate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets

28 film-coated tablets

30 film-coated tablets

50 film-coated tablets

56 film-coated tablets

90 film-coated tablets

98 film-coated tablets

5. METHOD AND ROUTE

DMINISTRATION

Oral use.

Read the package leaflet b

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF T HE 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

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

14 film-coated tablets

28 film-coated tablets

30 film-coated tablets

50 film-coated tablets

56 film-coated tablets
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/07/409/021

EU/1/07/409/022

EU/1/07/409/023

EU/1/07/409/024

EU/1/07/409/025

EU/1/07/409/026

EU/1/07/409/027

EU/1/07/409/028

56 film-coated tablets, (perforated unit-dose blister)

90 film-coated tablets^

98 film-coated tablets

13. BATCH NUMBER

Lot

Medicina

14. GENE

SSIFICATION FOR SUPPLY
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE

Riprazo 150 mg

BLISTER

BLISTER (CALENDAR)

Novartis Europharm Limited

14 film-coated tablets

Component of a multipack comprising 20 packs, each conta'ning 14 tablets.

28 film-coated tablets

Component of a multipack comprising 3 packs, each containing 28 tablets.

49 film-coated tablets

Component of a multipack comprising 2 packs, each containing 49 tablets.

5. METHOD AND ROUTE(S) O F ADMINISTRATION

Oral use.

Read the package leaflet before use.

_____x/Q ______________________

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF T HE 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

Do not store above 30°C.

Store in the original package in order to protect from moisture.

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/07/409/007 84 film-coated tablets (3×28) J

EU/1/07/409/009 98 film-coated tablets (2×49)

EU/1/07/409/010 280 film-coated tablets (20×14)

Riprazo 150 mg

84 film-coated tablets

Multipack comprising 3 packs, each containing 28 tablets 98 film-coated tablets

Multipack comprising 2 packs, each containing 49 tablets.

280 film-coated tablets

Multipack comprising 20 packs, each containing i4 tablets.

5. METHOD AND ROUTE(S) O F ADMINISTRATION

Oral use.

Read the package leaflet before use.

_____x/Q ______________________

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF T HE 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

Do not store above 30°C.

Store in the original package in order to protect from moisture.

14 film-coated tablets

Component of a multipack comprising 20 packs, each containing 14 tablets.

49 film-coated tablets

Component of a multipack comprising 2 packs, each containing 49 tablets.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.

Read the package leaflet before use.

6. SPECIAL WAR NING 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. XOTHER SPECIAL WARNING(S), IF NECESSARY

<?r

8. EXPIRY DATE

EXP

Do not store above 30°C.

Store in the original package in order to protect from moisture.

EU/1/07/409/029

EU/1/07/409/030

98 film-coated tablets (2×49) (perforated unit-dose blister) 280 film-coated tablets (20×14)x>^

280 film-coated tablets

Multipack comprising 20 packs, each containing 14 tables.

98 film-coated tablets

Multipack comprising 2 packs, each containing 49 tablets.

__>______________

5. METHOD AND ROUTE(S) OF AD MINISTRATION _______________________

Oral use.

Read the package leaflet before use.

6. SPECIAL WAR NING 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. XOTHER SPECIAL WARNING(S), IF NECESSARY

<?r

8. EXPIRY DATE

EXP

Do not store above 30°C.

Store in the original package in order to protect from moisture.

EU/1/07/409/029

EU/1/07/409/030

98 film-coated tablets (2×49) (perforated unit-dose blister) 280 film-coated tablets (20×14)x>^

FOLDING BOX FOR UNIT PACK CONTAINING PA/ALU/PVC BLISTERS

1. NAME OF THE MEDICINAL PRODUCT

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

Do not store above 30°C.

Store in the original package in order to protect from moisture.

EU/1/07/409/015

EU/1/07/409/016

50 film-coated tablets

56 film-coated tablets^^^

13. BATCH NUMBER

Lot

14. GENERAL CLA SSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INST RUCTIONS ON USE __________

16. INFORMATION IN BRAILLE

Riprazo 300 mg

FOLDING BOX FOR UNIT PACK CONTAINING PCTFE/PVC BLISTERS

1. NAME OF THE MEDICINAL PRODUCT

Riprazo 300 mg film-coated tablets Aliskiren

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 300 mg aliskiren (as hemifumarate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets

28 film-coated tablets

30 film-coated tablets

50 film-coated tablets

56 film-coated tablets

90 film-coated tablets

98 film-coated tablets

5. METHOD AND ROUTE

DMINISTRATION

Oral use

Read the package leaflet b

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF T HE 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

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

14 film-coated tablets

28 film-coated tablets

30 film-coated tablets

50 film-coated tablets

56 film-coated tablets
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/07/409/031

EU/1/07/409/032

EU/1/07/409/033

EU/1/07/409/034

EU/1/07/409/035

EU/1/07/409/036

EU/1/07/409/037

EU/1/07/409/038

56 film-coated tablets, (perforated unit-dose blister)

90 film-coated tablets^

98 film-coated tablets

13. BATCH NUMBER

Lot

Medicina

14. GENE

SSIFICATION FOR SUPPLY
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE

Riprazo 300 mg

BLISTER

BLISTER (CALENDAR)

Novartis Europharm Limited

14 film-coated tablets

Component of a multipack comprising 20 packs, each conta'ning 14 tablets.

28 film-coated tablets

Component of a multipack comprising 3 packs, each containing 28 tablets.

30 film-coated tablets

Component of a multipack comprising 3 packs, each containing 30 tablets.

49 film-coated tablets

Component of a multipack comprising 2 packs, each containing 49 tablets.

5. METHOD AND ROU TE (S) OF ADMINISTRATION

Oral use.

Read the package leaflet before use.

EXP

Do not store above 30°C.

Store in the original package in order to protect from moisture.

Medicinal product subject to medical prescription.

84 film-coated tablets

Multipack comprising 3 packs, each containing 28 tablets

90 film-coated tablets

Multipack comprising 3 packs, each containing 30 tablets.

98 film-coated tablets

Multipack comprising 2 packs, each containing 49 tablets.

280 film-coated tablets

Multipack comprising 20 packs, each containing 14 tablets.

5. METHOD AND ROU TE (S) OF ADMINISTRATION

Oral use.

Read the package leaflet before use.

__/y _______________

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF T HE 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

Do not store above 30°C.

Store in the original package in order to protect from moisture.

14. GENERAL CLASSI FICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INST RUCTIONS ON USE
16. INFORMATION IN BRAILLE

14 film-coated tablets

Component of a multipack comprising 20 packs, each containing 14 tablets.

49 film-coated tablets

Component of a multipack comprising 2 packs, each containing 49 tablets.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use

Read the package leaflet before use.

6. SPECIAL WAR NING 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. XOTHER SPECIAL WARNING(S), IF NECESSARY

<?r

8. EXPIRY DATE

EXP

Do not store above 30°C.

Store in the original package in order to protect from moisture.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/07/409/039

EU/1/07/409/040

98 film-coated tablets (2×49) (perforated unit-dose blister) 280 film-coated tablets (20×14)

15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE

Rip.azo 300 mg

280 film-coated tablets

Multipack comprising 20 packs, each containing 14 tables.

98 film-coated tablets

Multipack comprising 2 packs, each containing 49 tablets.

__>______________

5. METHOD AND ROUTE(S) OF AD MINISTRATION _______________________

Oral use

Read the package leaflet before use.

6. SPECIAL WAR NING 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. XOTHER SPECIAL WARNING(S), IF NECESSARY

<?r

8. EXPIRY DATE

EXP

Do not store above 30°C.

Store in the original package in order to protect from moisture.

EU/1/07/409/039

EU/1/07/409/040

98 film-coated tablets (2×49) (perforated unit-dose blister) 280 film-coated tablets (20×14)x>^

Package leaflet: information for the user

Riprazo 150 mg film-coated tablets

Aliskiren

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 the

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.

What is in this leaflet

What Riprazo is and what it is used for

What you need to know before you take Riprazo

How to take Riprazo

Possible side effects

How to store Riprazo

Contents of the pack and other information

What Riprazo is and what it is used for

Riprazo tablets contain an active substance called aliskiren. Aliskiren belongs to a class of medicines called renin inhibitors. Riprazo helps to lower high blood pressure in adult patients. Renin inhibitors reduce the amount of angiotensin II the body can produce. Angiotensin II causes blood vessels to tighten, which increases the blood pressure. Reducing the amount of angiotensin II allows the blood vessels to relax, which lowers blood pressure.

High blood pressure increases the workload of the heart and arteries. If this continues for a long time, it can damage the blood vessels of the brain, heart and kidneys, and may result in a stroke, heart failure, heart attack or kidney failure. Lowering the blood pressure to a normal level reduces the risk of developing these disorders.

2. What you need to know before you take Riprazo

Do not take Riprazo

– if you are allergic to aliskiren or any of the other ingredients of this medicine (listed in section

6). If you think you may be allergic, ask your doctor for advice.

– 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.

during the last 6 months of pregnancy or if you are breast-feeding, see section Pregnancy and breastfeeding.

if you are taking ciclosporin (a medicine used in transplantation to prevent organ rejection or for other conditions, e.g. rheumathoid arthritis or atopic dermatitis), itraconazole (a medicine used to treat fungal infections) or quinidine (a medicine used to correct heart rhythm). if you have diabetes mellitus 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 etc.

– an “angiotensin II receptor blocker” such as valsartan, telmisartan, irbesartan etc.

Warnings and precautions

Talk to your doctor before taking Riprazo:

– if you are taking a diuretic (a type of medicine also known as “water” tablets which increases

the amount of urine you produce).

– if you 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 etc.

– an “angiotensin II receptor blocker” such as valsartan, telmisartan, irbesartan etc.

– if you have impaired kidney function, your doctor will carefully consider whether Riprazo is

suitable for you and may wish to monitor you carefully.

– 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 Riprazo and contact your doctor.

– if you have renal artery stenosis (narrowing of the blood vessels to one or both kidneys).
– if you have serious congestive heart failure (a type of heart disease where the heart cannot

pump enough blood around the body).

Children and adolescents

The use of Riprazo in children and adolescents up to 18 years of age is not recommended.

Elderly

In the majority of patients aged 65 years or older, the 300 mg dose of Riprazo shows no additional benefit in reducing blood pressure compared to the 150 mg dose.

Other medicines and Riprazo

ng, have recently taken or might take any other

Tell your doctor or pharmacist if you medicines.

Do not take Riprazo if you are taking ciclosporin (a medicine used in transplantation to prevent organ rejection or for other conditions, e.g. rheumathoid arthritis or atopic dermatitis), itraconazole (a medicine used to treat fungal infections) or quinidine (a medicine used to correct heart rhythm).

Your doctor may need to change your dose and/or to take other precautions if you are taking one of the following medicines:

– medicines that increase the amount of potassium in your blood. These include potassium-

sparing diuretics, potassium supplements.

– furosemide, a medicine belonging to the type known as diuretics, or “water” tablets, which is

used to increase the amount of urine you produce.

– one of the following classes of medicines used to treat high blood pressure:

– an “angiotensin converting enzyme inhibitor” such as enalapril, lisinopril, ramipril etc.

– an “angiotensin II receptor blocker” such as valsartan, telmisartan, irbesartan etc.

– 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.

– certain types of pain killers called non-steroidal anti-inflammatory medicines (NSAIDs).

Riprazo with food and drink

You should take this medicine with a light meal once a day, preferably at the same time each day. You should not take this medicine together with grapefruit juice.

Pregnancy and breast-feeding

Do not take this medicine if you are pregnant or breast-feeding (see section Do not take Riprazo). 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. If you become pregnant while taking this medicine, stop taking it immediately and talk to your doctor.

Driving and using machines

This medicine may make you feel dizzy and this can affect your ability to concentrate. Before you drive a vehicle, use machinery, or carry out other activities that require concentration, you should make sure you know how you react to the effects of this medicine.

3. How to take Riprazo

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

People who have high blood pressure often do not notice any signs of the problem. Many may feel quite normal. It is very important that you take this medicine exactly as your doctor tells you to get the best results and reduce the risk of side effects. Keep your appointments with the doctor even if you are feeling well.

The usual starting dose is one 150 mg tablet once daily. The blood pressure lowering effect is present within two weeks after beginning treatment.

Depending on how you respond to the treatment your doctor may prescribe a higher dose of one 300 mg tablet once daily. Your doctor may prescribe Riprazo together with other medicines used to treat high blood pressure.

Method of administration

It is recommended that you take the tablets with some water. You should take this medicine with a light meal once a day, preferably at the same time each day. You should not take this medicine together with grapefruit juice.

If you take more Riprazo than you should

If you have accidentally taken too many Riprazo tablets, consult a doctor immediately. You may require medical attention.

If you forget to take Riprazo

If you forget to take a dose of Riprazo, take it as soon as you remember and then take the next dose at its usual time. However, if it is almost time for your next dose you should simply take the next tablet at the usual time. Do not take a double dose to make up for a forgotten dose.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some side effects can be serious:

A few patients have experienced these serious side effects (may affect up to 1 in 1,000 people). If any of the following occur, tell your doctor straight away:

Severe allergic reaction with symptoms such as rash, itching, swelling of face or lips or tongue, difficulty breathing, dizziness.

Possible side effects:

Common (may affect up to 1 in 10people): Diarrhoea, joint pain (arthralgia), high level of potassium in the blood, dizziness.

Uncommon (may affect up to 1 in 100people): Skin rash (this may also be a sign of allergic reactions or angioedema – see “Rare” side effects below), kidney problems including acute renal fai'urel (severely decreased urine output), swelling of hands, ankles or feet (peripheral oedema), severe skin reactions (toxic epidermal necrolysis and/or oral mucosal reactions – red skin, blistering of the lips, eyes or mouth, skin peeling, fever), low blood pressure, palpitations, cough, itching, itchy rash (urticaria), increased liver enzymes.

Rare (may affect up to 1 in 1,000people): 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).

If any of these affect you severely, tell your doctor. You may need to stop Riprazo.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

5. How to store Riprazo

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. 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 Riprazo contains

– The active substance is aliskiren (as hemifumarate) 150 mg.
– The other ingredients are crospovidone, hypromellose, magnesium stearate, macrogol,

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

What Riprazo looks like and contents of the pack

Riprazo 150 mg film coated tablets are light-pink, biconvex round tablets, imprinted “IL” on one side and “NVR” on the other side.

Riprazo is available in packs containing 7, 14, 28, 30, 50, 56, 84, 90, 98 or 280 tablets. Packs containing 84 (3×28), 98 (2×49) or 280 (20×14) tablets are multi-packs. Not all pack sizes may be available in your country.

Marketing Authorisation Holder

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

Manufacturer

Novartis Farma S.p.A.

Via Provinciale Schito 131

I-80058 Torre Annunziata/NA

Italy

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien

Novartis Pharma N.V.

Tél/Tel: +32 2 246 16 11

Luxembourg/Luxemburg

Novartis Pharma GmbH

Tél/Tel: +49 911 273 0

Efc^rapufl

Novartis Pharma Services Inc.

Tea.: +359 2 489 98 28

Česká republika

Novartis s.r.o.

Tel: +420 225 775 111

Malta

Novartis Pharma Services Inc.

Tel: +356 2122 2872

Magyarorszag

Novartis Hungaria Kft. Pharma

Tel.: +36 1 457 65 00

Danmark

Novartis Healthcare A/S

Tlf: +45 39 16 84 00

Nederland

Novartis Pharma B.V.

Tel: +31 26 37 82 111

Deutschland

Novartis Pharma GmbH

Tel: +49 911 273 0

Norge

Novartis Norge AS

Tlf: +47 23 05 20 00

Eesti

Novartis Pharma Services Inc.

Tel: +372 66 30 810

Österreich

Novartis Pharma GmbH

Tel: +43 1 86 6570

EXÀàôa

Novartis (Hellas) A.E.B.E.

Tql: +30 210 281 17 12

Polska

Novartis Poland Sp. z o.o.

Tel.: +48 22 375 4888

España

Laboratorios Dr. Esteve, S.A.

Tel: +34 93 446 60 00

Portugal

Novartis Farma – Produtos Farmacêuticos, S.A.

Tel: +351 21 000 8600

France

Novartis Pharma S.A.S.

Tél: +33 1 55 47 66 00

Ireland

Novartis Ireland Limited

Tel: +353 1 260 12 55

Island

Vistor hf.

Simi: +354 535 7000

Italia

Novartis Farma S.p.A.

Tel: +39 02 96 54 1

Knnpoç

Novartis Pharma Services Inc.

Tql: +357 22 690 690

România

Novartis Pharma Services Romania SRL

Tel: +40 21 31299 01

Slovenija

Novartis Pharma Services Inc.

Tel: +386 1 300 75 50

Slovenská republika

Novartis Slovakia s.r.o. Tel: +421 2 5542 5439

Suomi/Finland

Novartis Finland Oy

Puh/Tel: +358 (0)10 6133 200

Sverige

Novartis Sverige AB

Tel: +46 8 732 32 00

Latvija

Novartis Pharma Services Inc.

Tel: +371 67 887 070

This leaflet was last revised in

Lietuva

Novartis Pharma Services Inc.

Tel: +370 5 269 16 50

United Kingdom

Novartis Pharmaceuticals UK Ltd.

Tel: +44 1276 698370

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency website:

Package leaflet: information for the user

Riprazo 300 mg film-coated tablets

Aliskiren

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 the

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.

What is in this leaflet

What Riprazo is and what it is used for

What you need to know before you take Riprazo

How to take Riprazo

Possible side effects

How to store Riprazo

Contents of the pack and other information

What Riprazo is and what it is used for

2. What you need to know before you take Riprazo

Do not take Riprazo

– if you are allergic to aliskiren or any of the other ingredients of this medicine (listed in section

6). If you think you may be allergic, ask your doctor for advice.

– 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.

during the last 6 months of pregnancy or if you are breast-feeding, see section Pregnancy and breastfeeding.

– an “angiotensin converting enzyme inhibitor” such as enalapril, lisinopril, ramipril etc.

– an “angiotensin II receptor blocker” such as valsartan, telmisartan, irbesartan etc.

Warnings and precautions

Talk to your doctor before taking Riprazo:

– if you are taking a diuretic (a type of medicine also known as “water” tablets which increases

the amount of urine you produce).

– if you 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 etc.

– an “angiotensin II receptor blocker” such as valsartan, telmisartan, irbesartan etc.

– if you have impaired kidney function, your doctor will carefully consider whether Riprazo is

suitable for you and may wish to monitor you carefully.

– 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 Riprazo and contact your doctor.

– if you have renal artery stenosis (narrowing of the blood vessels to one or both kidneys).
– if you have serious congestive heart failure (a type of heart disease where the heart cannot

pump enough blood around the body).

Children and adolescents

The use of Riprazo in children and adolescents up to 18 years of age is not recommended.

Elderly

In the majority of patients aged 65 years or older, the 300 mg dose of Riprazo shows no additional benefit in reducing blood pressure compared to the 150 mg dose.

Other medicines and Riprazo

ng, have recently taken or might take any other

Tell your doctor or pharmacist if you medicines.

Your doctor may need to change your dose and/or to take other precautions if you are taking one of the following medicines:

– medicines that increase the amount of potassium in your blood. These include potassium-

sparing diuretics, potassium supplements.

– furosemide, a medicine belonging to the type known as diuretics, or “water” tablets, which is

used to increase the amount of urine you produce.

– one of the following classes of medicines used to treat high blood pressure:

– an “angiotensin converting enzyme inhibitor” such as enalapril, lisinopril, ramipril etc.

– an “angiotensin II receptor blocker” such as valsartan, telmisartan, irbesartan etc.

– 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.

– certain types of pain killers called non-steroidal anti-inflammatory medicines (NSAIDs).

Riprazo with food and drink

You should take this medicine with a light meal once a day, preferably at the same time each day. You should not take this medicine together with grapefruit juice.

Pregnancy and breast-feeding

Driving and using machines

3. How to take Riprazo

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

The usual starting dose is one 150 mg tablet once daily. The blood pressure lowering effect is present within two weeks after beginning treatment.

Method of administration

If you take more Riprazo than you should

If you have accidentally taken too many Riprazo tablets, consult a doctor immediately. You may require medical attention.

If you forget to take Riprazo

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some side effects can be serious:

A few patients have experienced these serious side effects (may affect up to 1 in 1,000 people). If any of the following occur, tell your doctor straight away:

Severe allergic reaction with symptoms such as rash, itching, swelling of face or lips or tongue, difficulty breathing, dizziness.

Possible side effects:

Common (may affect up to 1 in 10people): Diarrhoea, joint pain (arthralgia), high level of potassium in the blood, dizziness.

If any of these affect you severely, tell your doctor. You may need to stop Riprazo.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

5. How to store Riprazo

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. 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 Riprazo contains

– The active substance is aliskiren (as hemifumarate) 300 mg.
– The other ingredients are crospovidone, hypromellose, magnesium stearate, macrogol,

What Riprazo looks like and contents of the pack

Riprazo 150 mg film coated tablets are light-pink, biconvex round tablets, imprinted “IL” on one side and “NVR” on the other side.

Marketing Authorisation Holder

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

Manufacturer

Novartis Farma S.p.A.

Via Provinciale Schito 131

I-80058 Torre Annunziata/NA

Italy

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien

Novartis Pharma N.V.

Tél/Tel: +32 2 246 16 11

Luxembourg/Luxemburg

Novartis Pharma GmbH

Tél/Tel: +49 911 273 0

Efc^rapufl

Novartis Pharma Services Inc.

Tea.: +359 2 489 98 28

Česká republika

Novartis s.r.o.

Tel: +420 225 775 111

Malta

Novartis Pharma Services Inc.

Tel: +356 2122 2872

Magyarorszag

Novartis Hungaria Kft. Pharma

Tel.: +36 1 457 65 00

Danmark

Novartis Healthcare A/S

Tlf: +45 39 16 84 00

Nederland

Novartis Pharma B.V.

Tel: +31 26 37 82 111

Deutschland

Novartis Pharma GmbH

Tel: +49 911 273 0

Norge

Novartis Norge AS

Tlf: +47 23 05 20 00

Eesti

Novartis Pharma Services Inc.

Tel: +372 66 30 810

Österreich

Novartis Pharma GmbH

Tel: +43 1 86 6570

EXÀàôa

Novartis (Hellas) A.E.B.E.

Tql: +30 210 281 17 12

Polska

Novartis Poland Sp. z o.o.

Tel.: +48 22 375 4888

España

Laboratorios Dr. Esteve, S.A.

Tel: +34 93 446 60 00

Portugal

Novartis Farma – Produtos Farmacêuticos, S.A.

Tel: +351 21 000 8600

France

Novartis Pharma S.A.S.

Tél: +33 1 55 47 66 00

Ireland

Novartis Ireland Limited

Tel: +353 1 260 12 55

Island

Vistor hf.

Simi: +354 535 7000

Italia

Novartis Farma S.p.A.

Tel: +39 02 96 54 1

Knnpoç

Novartis Pharma Services Inc.

Tql: +357 22 690 690

România

Novartis Pharma Services Romania SRL

Tel: +40 21 31299 01

Slovenija

Novartis Pharma Services Inc.

Tel: +386 1 300 75 50

Slovenská republika

Novartis Slovakia s.r.o. Tel: +421 2 5542 5439

Suomi/Finland

Novartis Finland Oy

Puh/Tel: +358 (0)10 6133 200

Sverige

Novartis Sverige AB

Tel: +46 8 732 32 00

Latvija

Novartis Pharma Services Inc.

Tel: +371 67 887 070

This leaflet was last revised in

Lietuva

Novartis Pharma Services Inc.

Tel: +370 5 269 16 50

United Kingdom

Novartis Pharmaceuticals UK Ltd.

Tel: +44 1276 698370

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency website:

Package leaflet: information for the user

Riprazo 300 mg film-coated tablets

Aliskiren

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 the

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.

What is in this leaflet

What Riprazo is and what it is used for

What you need to know before you take Riprazo

How to take Riprazo

Possible side effects

How to store Riprazo

Contents of the pack and other information

What Riprazo is and what it is used for

2. What you need to know before you take Riprazo

Do not take Riprazo

– if you are allergic to aliskiren or any of the other ingredients of this medicine (listed in section

6). If you think you may be allergic, ask your doctor for advice.

– 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.

during the last 6 months of pregnancy or if you are breast-feeding, see section Pregnancy and breastfeeding.

– an “angiotensin converting enzyme inhibitor” such as enalapril, lisinopril, ramipril etc.

– an “angiotensin II receptor blocker” such as valsartan, telmisartan, irbesartan etc.

Warnings and precautions

Talk to your doctor before taking Riprazo:

– if you are taking a diuretic (a type of medicine also known as “water” tablets which increases

the amount of urine you produce).

– if you 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 etc.

– an “angiotensin II receptor blocker” such as valsartan, telmisartan, irbesartan etc.

– if you have impaired kidney function, your doctor will carefully consider whether Riprazo is

suitable for you and may wish to monitor you carefully.

– 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 Riprazo and contact your doctor.

– if you have renal artery stenosis (narrowing of the blood vessels to one or both kidneys).
– if you have serious congestive heart failure (a type of heart disease where the heart cannot

pump enough blood around the body).

Children and adolescents

The use of Riprazo in children and adolescents up to 18 years of age is not recommended.

Elderly

In the majority of patients aged 65 years or older, the 300 mg dose of Riprazo shows no additional benefit in reducing blood pressure compared to the 150 mg dose.

Other medicines and Riprazo

ng, have recently taken or might take any other

Tell your doctor or pharmacist if you medicines.

Your doctor may need to change your dose and/or to take other precautions if you are taking one of the following medicines:

– medicines that increase the amount of potassium in your blood. These include potassium-

sparing diuretics, potassium supplements.

– furosemide, a medicine belonging to the type known as diuretics, or “water” tablets, which is

used to increase the amount of urine you produce.

– one of the following classes of medicines used to treat high blood pressure:

– an “angiotensin converting enzyme inhibitor” such as enalapril, lisinopril, ramipril etc.

– an “angiotensin II receptor blocker” such as valsartan, telmisartan, irbesartan etc.

– 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.

– certain types of pain killers called non-steroidal anti-inflammatory medicines (NSAIDs).

Riprazo with food and drink

You should take this medicine with a light meal once a day, preferably at the same time each day. You should not take this medicine together with grapefruit juice.

Pregnancy and breast-feeding

Driving and using machines

3. How to take Riprazo

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

The usual starting dose is one 150 mg tablet once daily. The blood pressure lowering effect is present within two weeks after beginning treatment.

Method of administration

If you take more Riprazo than you should

If you have accidentally taken too many Riprazo tablets, consult a doctor immediately. You may require medical attention.

If you forget to take Riprazo

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some side effects can be serious:

A few patients have experienced these serious side effects (may affect up to 1 in 1,000 people). If any of the following occur, tell your doctor straight away:

Severe allergic reaction with symptoms such as rash, itching, swelling of face or lips or tongue, difficulty breathing, dizziness.

Possible side effects:

Common (may affect up to 1 in 10people): Diarrhoea, joint pain (arthralgia), high level of potassium in the blood, dizziness.

If any of these affect you severely, tell your doctor. You may need to stop Riprazo.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

5. How to store Riprazo

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. 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 Riprazo contains

– The active substance is aliskiren (as hemifumarate) 300 mg.
– The other ingredients are crospovidone, hypromellose, magnesium stearate, macrogol,

Riprazo - patient leaflet, side effects, dosage

Table of contents

Patient leaflet - Riprazo

2. What you need to know before you take Riprazo

3. How to take Riprazo

4. Possible side effects

5. How to store Riprazo

6. Contents of the pack and other information

2. What you need to know before you take Riprazo

3. How to take Riprazo

4. Possible side effects

5. How to store Riprazo

6. Contents of the pack and other information

What Riprazo is and what it is used for

2. What you need to know before you take Riprazo

3. How to take Riprazo

4. Possible side effects

Possible side effects:

5. How to store Riprazo

6. Contents of the pack and other information