English
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

Enviage (aliskiren) – Summary of product characteristics - C09XA02

Updated on site: 06-Oct-2017

Medication nameEnviage
ATC CodeC09XA02
Substancealiskiren
ManufacturerNovartis Europharm Ltd.
Treatment of essential hypertension.
1. NAME OF THE MEDICINAL PRODUCT
Enviage 150 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 150 mg aliskiren (as hemifumarate). For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

 

Film-coated tablet

 

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

4.

CLINICAL PARTICULARS

authorised

4.1

Therapeutic indications

 

 

4.2 Posology and method of administration

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

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

Enviage may be used alone or in combination with other antihypertensive agents (see sections 4.4 and 5.1).

Enviage should be taken with a light meal once a day, preferably at the same time each day. Grapefruit

product

juiceMedicinalshould not be taken together with Enviage. Renal impairme t

No adjustment of the i itial dose is required for patients with mild to severe renal impairment (see sections 4.4 and 5.2).

Hepatic impairment

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

Elderly patients (over 65 years)

No adjustment of the initial dose is required for elderly patients.

Paediatric patients (below 18 years)

Enviage is not recommended for use in children and adolescents below age 18 due to a lack of data on safety and efficacy (see section 5.2).

4.3Contraindications

Hypersensitivity to the active substance or to any of the excipients.

History of angioedema with aliskiren.

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

The concomitant use of aliskiren with ciclosporin, a highly potent P-gp inhibitor, and other potent P- gp inhibitors (quinidine, verapamil), is contraindicated (see section 4.5).

4.4 Special warnings and precautions for use

Patients receiving other medicinal products inhibiting the renin-angiotensin system (RAS), and/or those with reduced kidney function and/or diabetes mellitus are at an increased risk of hyperkalaemia during aliskiren therapy.

Aliskiren should be used with caution in patients with serious congestive heart failure (New York Heart Association [NYHA] functional class III-IV).

In the event of severe and persistent diarrhoea, Enviage therapy should be stopped.

Angioedema

As with other agents acting on the renin-angiotensin system, angioedema has been reported in patients treated with aliskiren. If angioedema occurs, Enviage should be promptly discontinued and appropriate

authorised

therapy and monitoring provided until complete and sustained resolution of signs and symptoms has occurred. Where there is involvement of the tongue, glottis or larynx ad enaline should be administered. In addition, measures necessary to ensure patient airways should be provided.

Sodium and/or volume depleted patients

In patients with marked volume- and/or salt-depletion (e.g. th se receiving high doses of diuretics)

In clinical studies Enviage has not been investigated in hypertensive patients with severe renal impairment (serum creatinine ≥ 150 μmol/l or 1.70 mg/dl in women and ≥ 177 μmol/l or 2.00 mg/dl in men and/or estimated glomerular filtration rate (GFR) < 30 ml/min), history of dialysis, nephrotic syndrome or renovascular hype tensi n. Caution should be exercised in hypertensive patients with severe renal impairment due to the lack of safety information for Enviage.

symptomatic hypotension could occur after initiati n f treatment with Enviage. This condition should

 

 

 

longer

be corrected prior to administration of Enviage, r the treatment should start under close medical

supervision.

product

no

 

Renal impairment

 

 

 

 

 

 

Medicinal

As for other agents

cting on the renin-angiotensin system, caution should be exercised when aliskiren

is given in the prese

ce of conditions pre-disposing to kidney dysfunction such as hypovolaemia (eg.

due to blood loss, severe prolonged diarrhoea, prolonged vomiting, etc.), heart disease, liver disease or kidney disease. A ute renal failure, reversible upon discontinuation of treatment, has been reported in at-risk pat ents receiving aliskiren in post-marketing experience. In the event that any signs of renal failure occur, aliskiren should be promptly discontinued.

Renal artery stenosis

No controlled clinical data are available on the use of Enviage in patients with unilateral or bilateral renal artery stenosis, or stenosis to a solitary kidney. However, as with other agents acting on the renin-angiotensin system, there is an increased risk of renal insufficiency, including acute renal failure, when patients with renal artery stenosis are treated with aliskiren. Therefore, caution should be exercised in these patients. If renal failure occurs, treatment should be discontinued.

Moderate P-gp inhibitors

Co-administration of aliskiren 300 mg with ketoconazole 200 mg resulted in a 76% increase in aliskiren AUC but P-gp inhibitors such as ketoconazole are expected to increase tissue concentrations

more than plasma concentrations. Therefore caution should be exercised when aliskiren is administered with moderate P-gp inhibitors such as ketoconazole (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Enviage has no known clinically relevant interactions with medicinal products commonly used to treat hypertension or diabetes.

Compounds that have been investigated in clinical pharmacokinetic studies include acenocoumarol, atenolol, celecoxib, pioglitazone, allopurinol, isosorbide-5-mononitrate, ramipril and hydrochlorothiazide. No interactions have been identified.

Co-administration of aliskiren with either valsartan (↓28%), metformin (↓28%), amlodipine (↑29%) or cimetidine (↑19%) resulted in between 20% and 30% change in Cmax or AUC of Enviage. Wh n administered with atorvastatin, steady-state Enviage AUC and Cmax increased by 50%. Co- administration of Enviage had no significant impact on atorvastatin, valsartan, metfo m n or

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

medicinal products is necessary.

 

Digoxin bioavailability may be slightly decreased by Enviage.

 

Preliminary data suggest that irbesartan may decrease Enviage AUC and Cmax.

 

authorised

In experimental animals, it has been shown that P-gp is a major d t rminant of Enviage bioavailability. Inducers of P-gp (St. John’s wort, rifampici ) mi ht therefore decrease the bioavailability of Enviage.

CYP450 interactions

 

longer

 

 

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

 

no

 

CYP450 isoenzymes are not expected. However, CYP3A4 inhibitors often also affect P-gp. Increased aliskiren exposure during co-administration of CYP3A4 inhibitors that also inhibit P-gp can therefore be expected (see P-glycoprotein interactions below).

Aliskiren does not induce CYP3A4. Therefore aliskiren is not expected to affect the systemic exposure of substances that inhibit,productinduce or are me abolised by these enzymes. Aliskiren is metabolised minimally by the cytochrome P450 enzymes. Hence, interactions due to inhibition or induction of

P-glycoprotein interactions

MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption and biliaryMedicinalexcretion of liskiren in preclinical studies. Inducers of P-gp (St. John’s wort, rifampicin) might therefore decre se the bioavailability of Enviage. Although this has not been investigated for

aliskiren, it is k own 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 gree of inhibition of this transporter.

P-gp substrates or weak inhibitors

No relevant interactions with atenolol, digoxin, amlodipine or cimetidine have been observed. When administered with atorvastatin (80 mg), steady-state aliskiren (300 mg) AUC and Cmax increased by 50%.

Moderate P-gp inhibitors

Co-administration of ketoconazole (200 mg) with aliskiren (300 mg) resulted in an 80% increase in plasma levels of aliskiren (AUC and Cmax). Preclinical studies indicate that aliskiren and ketoconazole co-administration enhances aliskiren gastrointestinal absorption and decreases biliary excretion. The change in plasma levels of aliskiren in the presence of ketoconazole is expected to be within the range that would be achieved if the dose of aliskiren were doubled; aliskiren doses of up to 600 mg, or twice the highest recommended therapeutic dose, have been found to be well tolerated in controlled clinical

trials. Yet, P-gp inhibitors are expected to increase tissue concentrations more than plasma concentrations. Therefore, caution should be exercised when aliskiren is administered with ketoconazole or other moderate pgp inhibitors (itraconazol, clarithromycin, telithromycin, erythromycin, amiodarone).

P-gp potent inhibitors

A single dose drug interaction study in healthy subjects has shown that ciclosporin (200 and 600 mg) increases Cmax of aliskiren 75 mg approximately 2.5-fold and AUC approximately 5-fold. The increase may be higher with higher aliskiren doses. Therefore, concomitant use of aliskiren and P-gp potent inhibitors is contraindicated (see section 4.3).

Furosemide

authorised

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

Non-steroidal anti-inflammatory drugs (NSAIDs)

As with other agents acting on the renin-angiotensin system, NSAIDs may red ce e anti- hypertensive effect of aliskiren. In some patients with compromised renal f nction (dehydrated patients or elderly patients) aliskiren given concomitantly with NSAIDs m y result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore the combination of aliskiren with an NSAID requires caution, especially in elderly patients.

Potassium and potassium-sparing diuretics

Based on experience with the use of other substances that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing

Due to the lack of data a potential intera tion between grapefruit juice and aliskiren cannot be excluded. Grapefruit juice should not be taken together with Enviage.

potassium or other substances that may increase serum potassium levels (e.g. heparin) may lead to

 

 

 

longer

increases in serum potassium. If co-medication is c nsidered necessary, caution is advisable.

Grapefruit juice

product

no

 

 

 

 

 

 

Warfarin

The effects of Enviage on wa fa in pharmacokinetics have not been evaluated.

Food intake

4.6 Pregnan y a d lactation

MealsMedicinalwith a high f t content have been shown to reduce the absorption of Enviage substantially.

Pregnancy

Th re are no ata on the use of aliskiren in pregnant women. Enviage was not teratogenic in rats or rabbits (s section 5.3). Other substances that act directly on the RAS have been associated with serious foetal malformations and neonatal death. As for any medicine that acts directly on the RAS, Enviage should not be used during the first trimester of pregnancy or in women planning to become pregnant and is contraindicated during the second and third trimesters (see section 4.3). Healthcare professionals prescribing any agents acting on the RAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy. If pregnancy is detected during therapy, Enviage should be discontinued accordingly.

Lactation

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

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, when driving vehicles or operating machinery it must be borne in mind that dizziness or weariness may occasionally occur when taking any antihypertensive therapy. Enviage has negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Enviage has been evaluated for safety in more than 7,800 patients, including over 2,300 treated for

generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The most common adverse drug reaction is diarrhoea.

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. Treatmentauthorisedwith Enviage resulted in an overall incidence of adverse reactions similar to placebo up to 300 mg. Adverse reactions have

The incidence of cough was similar in placebo (0.6%) and Enviage treated (0.9%) patients.

The adverse drug reactions (Table 1) are ranked under heading of frequency, he most frequent first, using the following convention: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports. Within each frequency grouping, undesirable effects are presented in o der of decreasing seriousness.

Table 1

Gastrointestinal disorders

 

 

longer

Common:

Diarrhoea

 

Skin and subcutaneous tissue disorders

no

Uncommon:

Rash

 

Rare:

Angioedema

 

Angioedema has occurred during treatment with Enviage. In controlled clinical trials, angioedema

(frequency unknown). In the event f any signs suggesting an allergic reaction (in particular

occurred rarely during treatmentproductwith Enviage with rates comparable to treatment with placebo or hydrochlorothiazide. Cases of angioe ema have also been reported in post-marketing experience

difficulties in breathing, or swallowing, or swelling of the face, extremities, eyes, lips and/or tongue)

patients should discontinue treatment and contact the physician (see section 4.4). LaboratoryMedicinalfindings

In controlled cl cal trials, clinically relevant changes in standard laboratory parameters were uncommonly asso ated with the administration of Enviage. In clinical studies in hypertensive patients, Env age had no clinically important effects on total cholesterol, high density lipoprotein cholesterol (HDL-C), fasting triglycerides, fasting glucose or uric acid.

Haemoglobin and haematocrit: Small decreases in haemoglobin and haematocrit (mean decreases of approximately 0.05 mmol/l and 0.16 volume percent, respectively) were observed. No patients discontinued therapy due to anaemia. This effect is also seen with other agents acting on the renin- angiotensin system, such as angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers.

Serum potassium: Increases in serum potassium were minor and infrequent in patients with essential hypertension treated with Enviage alone (0.9% compared to 0.6% with placebo). However, in one study where Enviage was used in combination with an ACEI in a diabetic population, increases in serum potassium were more frequent (5.5%). Therefore as with any agent acting on the RAS system, routine monitoring of electrolytes and renal function is indicated in patients with diabetes mellitus, kidney disease, or heart failure.

In obese hypertensive patients who did not adequately respond to HCTZ 25 mg, add-on treatment with Enviage 300 mg provided additional blood pressure reduction that was comparable to add-on treatment with irbesartan 300 mg or amlodipine 10 mg. In diabetic hypertensive patients, Enviage
7
Pharmacotherapeutic group: Renin inhibitor, ATC code: C09XA02

5.1 Pharmacodynamic properties

Aliskiren is an orally active, non-peptide, potent and selective direct inhibitorauthorisedof human renin. By inhibiting the enzyme renin, aliskiren inhibits the RAS at the point of activa ion, blocking the
conversion of angiotensinogen to angiotensin I and decreasing levels of ngiotensin I and angiotensin II. Whereas other agents that inhibit the RAS (ACEI and angiotensin II receptor blockers (ARB)) cause a compensatory rise in plasma renin activity (PRA),longertreatment 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 administratinon f Enviage at doses of 150 mg and 300 mg
provided dose-dependent reductions in both syst lic and diastolic blood pressure that were maintained over the entire 24-hour doseproductinterval (main ai i g be efit in the early morning) with a mean peak to trough ratio for diastolic response of up to 98% for the 300 mg dose. 85 to 90% of the maximal blood-
pressure-lowering effect was observed after 2 weeks. The blood-pressure-lowering effect was sustained during long-term treatment, and was independent of age, gender, body mass index and ethnicity. Enviage has been studied in 1,864 patients aged 65 years or older, and in 426 patients aged 75 years or older.
Enviage monotherapy studies have shown blood pressure lowering effects comparable to other classes Medicinalof antihypertensive gents including ACEI and ARB. Compared to a diuretic (hydrochlorothiazide - HCTZ), Enviage 300 mg lowered systolic/diastolic blood pressure by 17.0/12.3 mmHg, compared to
14.4/10.5 mmHg for HCTZ 25 mg after 12 weeks of treatment. In diabetic hypertensive patients, Enviage monotherapy was safe and effective.
Combination therapy studies are available for Enviage added to the diuretic hydrochlorothiazide, the ACEI ramipril, the calcium channel blocker amlodipine, the angiotensin receptor antagonist valsartan, and the beta blocker atenolol. These combinations were well tolerated. Enviage induced an additive blood-pressure-lowering effect when added to hydrochlorothiazide and to ramipril. In patients who did not adequately respond to 5 mg of the calcium channel blocker amlodipine, the addition of Enviage 150 mg had a blood-pressure-lowering effect similar to that obtained by increasing amlodipine dose to 10 mg, but had a lower incidence of oedema (aliskiren 150 mg/amlodipine 5 mg 2.1% vs. amlodipine 10 mg 11.2%). Enviage in combination with the angiotensin receptor antagonist valsartan showed an additive antihypertensive effect in the study specifically designed to investigate the effect of the combination therapy.
In post-marketing experience, renal dysfunction and cases of acute renal failure have been reported in patients at risk (see section 4.4).

4.9 Overdose

Limited data are available related to overdose in humans. The most likely manifestations of overdosage would be hypotension, related to the antihypertensive effect of aliskiren. If symptomatic hypotension should occur, supportive treatment should be initiated.

5. PHARMACOLOGICAL PROPERTIES

provided additive blood pressure reductions when added to ramipril, while the combination of Enviage and ramipril had a lower incidence of cough (1.8%) than ramipril (4.7%).

There has been no evidence of first-dose hypotension and no effect on pulse rate in patients treated in controlled clinical studies. Excessive hypotension was uncommonly (0.1%) seen in patients with uncomplicated hypertension treated with Enviage alone. Hypotension was also uncommon (<1%) during combination therapy with other antihypertensive agents. With cessation of treatment, blood pressure gradually returned towards baseline levels over a period of several weeks, with no evidence of a rebound effect for blood pressure or PRA.

clinical significance of this reduction is unknown.

In a 3-month study of 302 patients with mild stable heart failure, all of whom were receiving standard therapy for stable heart failure, addition of Enviage 150 mg was well tolerated.authorisedB-type natriuretic peptide (BNP) levels were reduced by 25% in the Enviage arm compared to placebo. Howev r the

In a 6-month study of 599 patients with hypertension, type 2 diabetes mellitus, and neph pathy, all of whom were receiving losartan 100 mg and optimised antihypertensive background t erapy, addition of Enviage 300 mg achieved a 20% reduction versus placebo in urinary albumin:crea inine ratio (UACR), i.e. from 58 mg/mmol to 46 mg/mmol. The proportion of patients who had UACR reduced at least 50% from baseline to endpoint was 24.7% and 12.5% for Enviage nd pl cebo, respectively. The clinical relevance of a reduction in UACR is not established in the absence of n effect on blood pressure. Enviage did not affect the serum concentration of creatinine but was associated with an increased frequency (4.2% vs. 1.9% for placebo) of serum potassium concentration ≥6.0 mmol/l, although this was not statistically significant.

 

longer

Beneficial effects of Enviage on mortality and cardiovascu ar morbidity and target organ damage are

currently unknown.

 

No effect on QT interval was reported in a ra domised,no double-blind, placebo, and active-controlled study using standard and Holter electro ardiography.

Cardiac electrophysiology

absolute bioavailability of productaliskiren is approximately 2-3%. Meals with a high fat content reduce Cmax by 85% and AUC by 70%. Steady-state-plasma concentrations are reached within 5-7 days following

5.2 Pharmacokinetic properties

Absorption

Following oral absorption, eak plasma concentrations of aliskiren are reached after 1-3 hours. The

Distribut on

onceMedicinal-daily admi istr tion and steady-state levels are approximately 2-fold greater than with the initial dose.

Following intravenous administration, the mean volume of distribution at steady state is approximately 135 litr s, indicating that aliskiren distributes extensively into the extravascular space. Aliskiren plasma protein binding is moderate (47-51%) and independent of the concentration.

Metabolism and elimination

The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as unchanged compound in the faeces (78%). Approximately 1.4% of the total oral dose is metabolised. The enzyme responsible for this metabolism is CYP3A4. Approximately 0.6% of the dose is recovered in urine following oral administration. Following intravenous administration, the mean plasma clearance is approximately 9 l/h.

Linearity/non-linearity

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

administration in the dose range of 75 to 600 mg, a 2-fold increase in dose results in a ~2.3 and 2.6- fold increase in AUC and Cmax, respectively. At steady state the non-linearity may be more pronounced. Mechanisms responsible for deviation from linearity have not been identified. A possible mechanism is saturation of transporters at the absorption site or at the hepatobiliary clearance route.

Characteristics in patients

Aliskiren is an effective once-a-day antihypertensive treatment in adult patients, regardless of gender, age, body mass index and ethnicity.

The AUC is 50% higher in elderly (>65 years) than in young subjects. Gender, weight and ethnicity have no clinically relevant influence on aliskiren pharmacokinetics.

severe hepatic impairment.

authorised

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 b tw n 0.8 to 2 times the levels in healthy subjects following single dose administration and at steady tate. These observed changes, however, did not correlate with the severity of renal impairment. No adjustment of the initial dosage of Enviage is required in patients with mild to severe renal impairment, however caution should be exercised in patients with severe renal impairment.

The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe liver disease. Consequently, no adjustment of the initial dose of aliskiren is equired in patients with mild to

5.3 Preclinical safety data

Carcinogenic potential was assessed in a 2-year rat studylongerand 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 statisticallyno significant. Although aliskiren has known

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

irritation potential, safety margins obtained in huma s at the dose of 300 mg during a study in healthy volunteers were consideredproductto be appropria e at 9-11-fold based on faecal concentrations or 6-fold

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 developmentMedicinaland post-n t development were unaffected in rats at doses up to 250 mg/kg/day. The

doses in rats a d r bbits provided systemic exposures of 1 to 4 and 5 times higher, respectively, than the maximum re ommended 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

6.1List of excipients

Crospovidone

Magnesium stearate

Cellulose, microcrystalline

Povidone

Silica, colloidal anhydrous

2 years
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

6.4 Special precautions for storage

Do not store above 30°C.

authorised

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

6.5 Nature and contents of container

PA/Alu/PVC blisters

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

Packs containing 84 (3x28), 98 (2x49) or 280 (20x14) tablets are multi-packs.

Not all pack sizes may be marketed.

longer

6.6 Special precautions for disposal

Any unused product or waste material should benodisposed of in accordance with local requirements.

7.

MARKETING AUTHORISATION HOLDER

Novartis Europharm Limited

 

Wimblehurst Road

product

 

Horsham

 

West Sussex, RH12 5AB

 

 

 

United Kingdom

 

 

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/07/406/001-010

 

 

Medicinal

 

 

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22.08.2007

10. DATE OF REVISION OF THE TEXT

Treatment of essential hypertension.

1. NAME OF THE MEDICINAL PRODUCT

Enviage 300 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet

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

authorised

4.CLINICAL PARTICULARS

4.1Therapeutic indications

4.2Posology and method of administration

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

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

Enviage may be used alone or in combination with other antihypertensive agents (see sections 4.4 and 5.1).

Enviage should be taken with a light meal once a day, preferably at the same time each day. Grapefruit

product

juiceMedicinalshould not be taken together with Enviage. Renal impairme t

No adjustment of the initial dose is required for patients with mild to severe renal impairment (see sections 4.4 and 5.2).

Hepatic impairment

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

Elderly patients (over 65 years)

No adjustment of the initial dose is required for elderly patients.

Paediatric patients (below 18 years)

Enviage is not recommended for use in children and adolescents below age 18 due to a lack of data on safety and efficacy (see section 5.2).

4.3Contraindications

Hypersensitivity to the active substance or to any of the excipients.

History of angioedema with aliskiren.

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

The concomitant use of aliskiren with ciclosporin, a highly potent P-gp inhibitor, and other potent P- gp inhibitors (quinidine, verapamil), is contraindicated (see section 4.5).

4.4 Special warnings and precautions for use

Patients receiving other medicinal products inhibiting the renin-angiotensin system (RAS), and/or those with reduced kidney function and/or diabetes mellitus are at an increased risk of hyperkalaemia during aliskiren therapy.

Aliskiren should be used with caution in patients with serious congestive heart failure (New York Heart Association [NYHA] functional class III-IV).

In the event of severe and persistent diarrhoea, Enviage therapy should be stopped.

Angioedema

As with other agents acting on the renin-angiotensin system, angioedema has been reported in patients treated with aliskiren. If angioedema occurs, Enviage should be promptly discontinued and appropriate

authorised

therapy and monitoring provided until complete and sustained resolution of signs and symptoms has occurred. Where there is involvement of the tongue, glottis or larynx ad enaline should be administered. In addition, measures necessary to ensure patient airways should be provided.

Sodium and/or volume depleted patients

In patients with marked volume- and/or salt-depletion (e.g. th se receiving high doses of diuretics)

In clinical studies Enviage has not been investigated in hypertensive patients with severe renal impairment (serum creatinine ≥ 150 μmol/l or 1.70 mg/dl in women and ≥ 177 μmol/l or 2.00 mg/dl in men and/or estimated glomerular filtration rate (GFR) < 30 ml/min), history of dialysis, nephrotic syndrome or renovascular hype tensi n. Caution should be exercised in hypertensive patients with severe renal impairment due to the lack of safety information for Enviage.

symptomatic hypotension could occur after initiati n f treatment with Enviage. This condition should

 

 

 

longer

be corrected prior to administration of Enviage, r the treatment should start under close medical

supervision.

product

no

 

Renal impairment

 

 

 

 

 

 

Medicinal

As for other agents

cting on the renin-angiotensin system, caution should be exercised when aliskiren

is given in the prese

ce of conditions pre-disposing to kidney dysfunction such as hypovolaemia (eg.

due to blood loss, severe prolonged diarrhoea, prolonged vomiting, etc.), heart disease, liver disease or kidney disease. A ute renal failure, reversible upon discontinuation of treatment, has been reported in at-risk pat ents receiving aliskiren in post-marketing experience. In the event that any signs of renal failure occur, aliskiren should be promptly discontinued.

Renal artery stenosis

No controlled clinical data are available on the use of Enviage in patients with unilateral or bilateral renal artery stenosis, or stenosis to a solitary kidney. However, as with other agents acting on the renin-angiotensin system, there is an increased risk of renal insufficiency, including acute renal failure, when patients with renal artery stenosis are treated with aliskiren. Therefore, caution should be exercised in these patients. If renal failure occurs, treatment should be discontinued.

Moderate P-gp inhibitors

Co-administration of aliskiren 300 mg with ketoconazole 200 mg resulted in a 76% increase in aliskiren AUC but P-gp inhibitors such as ketoconazole are expected to increase tissue concentrations

more than plasma concentrations. Therefore caution should be exercised when aliskiren is administered with moderate P-gp inhibitors such as ketoconazole (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Enviage has no known clinically relevant interactions with medicinal products commonly used to treat hypertension or diabetes.

Compounds that have been investigated in clinical pharmacokinetic studies include acenocoumarol, atenolol, celecoxib, pioglitazone, allopurinol, isosorbide-5-mononitrate, ramipril and hydrochlorothiazide. No interactions have been identified.

Co-administration of aliskiren with either valsartan (↓28%), metformin (↓28%), amlodipine (↑29%) or cimetidine (↑19%) resulted in between 20% and 30% change in Cmax or AUC of Enviage. Wh n administered with atorvastatin, steady-state Enviage AUC and Cmax increased by 50%. Co- administration of Enviage had no significant impact on atorvastatin, valsartan, metfo m n or

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

medicinal products is necessary.

 

Digoxin bioavailability may be slightly decreased by Enviage.

 

Preliminary data suggest that irbesartan may decrease Enviage AUC and Cmax.

 

authorised

In experimental animals, it has been shown that P-gp is a major d t rminant of Enviage bioavailability. Inducers of P-gp (St. John’s wort, rifampici ) mi ht therefore decrease the bioavailability of Enviage.

CYP450 interactions

 

longer

 

 

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

 

no

 

CYP450 isoenzymes are not expected. However, CYP3A4 inhibitors often also affect P-gp. Increased aliskiren exposure during co-administration of CYP3A4 inhibitors that also inhibit P-gp can therefore be expected (see P-glycoprotein interactions below).

Aliskiren does not induce CYP3A4. Therefore aliskiren is not expected to affect the systemic exposure of substances that inhibit,productinduce or are me abolised by these enzymes. Aliskiren is metabolised minimally by the cytochrome P450 enzymes. Hence, interactions due to inhibition or induction of

P-glycoprotein interactions

MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption and biliaryMedicinalexcretion of liskiren in preclinical studies. Inducers of P-gp (St. John’s wort, rifampicin) might therefore decre se the bioavailability of Enviage. Although this has not been investigated for

aliskiren, it is k own 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 gree of inhibition of this transporter.

P-gp substrates or weak inhibitors

No relevant interactions with atenolol, digoxin, amlodipine or cimetidine have been observed. When administered with atorvastatin (80 mg), steady-state aliskiren (300 mg) AUC and Cmax increased by 50%.

Moderate P-gp inhibitors

Co-administration of ketoconazole (200 mg) with aliskiren (300 mg) resulted in an 80% increase in plasma levels of aliskiren (AUC and Cmax). Preclinical studies indicate that aliskiren and ketoconazole co-administration enhances aliskiren gastrointestinal absorption and decreases biliary excretion. The change in plasma levels of aliskiren in the presence of ketoconazole is expected to be within the range that would be achieved if the dose of aliskiren were doubled; aliskiren doses of up to 600 mg, or twice the highest recommended therapeutic dose, have been found to be well tolerated in controlled clinical

trials. Yet, P-gp inhibitors are expected to increase tissue concentrations more than plasma concentrations. Therefore, caution should be exercised when aliskiren is administered with ketoconazole or other moderate pgp inhibitors (itraconazol, clarithromycin, telithromycin, erythromycin, amiodarone).

P-gp potent inhibitors

A single dose drug interaction study in healthy subjects has shown that ciclosporin (200 and 600 mg) increases Cmax of aliskiren 75 mg approximately 2.5-fold and AUC approximately 5-fold. The increase may be higher with higher aliskiren doses. Therefore, concomitant use of aliskiren and P-gp potent inhibitors is contraindicated (see section 4.3).

Furosemide

authorised

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

Non-steroidal anti-inflammatory drugs (NSAIDs)

As with other agents acting on the renin-angiotensin system, NSAIDs may red ce e anti- hypertensive effect of aliskiren. In some patients with compromised renal f nction (dehydrated patients or elderly patients) aliskiren given concomitantly with NSAIDs m y result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore the combination of aliskiren with an NSAID requires caution, especially in elderly patients.

Potassium and potassium-sparing diuretics

Based on experience with the use of other substances that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing

Due to the lack of data a potential intera tion between grapefruit juice and aliskiren cannot be excluded. Grapefruit juice should not be taken together with Enviage.

potassium or other substances that may increase serum potassium levels (e.g. heparin) may lead to

 

 

 

longer

increases in serum potassium. If co-medication is c nsidered necessary, caution is advisable.

Grapefruit juice

product

no

 

 

 

 

 

 

Warfarin

The effects of Enviage on wa fa in pharmacokinetics have not been evaluated.

Food intake

4.6 Pregnan y a d lactation

MealsMedicinalwith a high f t content have been shown to reduce the absorption of Enviage substantially.

Pregnancy

Th re are no ata on the use of aliskiren in pregnant women. Enviage was not teratogenic in rats or rabbits (s section 5.3). Other substances that act directly on the RAS have been associated with serious foetal malformations and neonatal death. As for any medicine that acts directly on the RAS, Enviage should not be used during the first trimester of pregnancy or in women planning to become pregnant and is contraindicated during the second and third trimesters (see section 4.3). Healthcare professionals prescribing any agents acting on the RAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy. If pregnancy is detected during therapy, Enviage should be discontinued accordingly.

Lactation

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

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, when driving vehicles or operating machinery it must be borne in mind that dizziness or weariness may occasionally occur when taking any antihypertensive therapy. Enviage has negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Enviage has been evaluated for safety in more than 7,800 patients, including over 2,300 treated for

generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The most common adverse drug reaction is diarrhoea.

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. Treatmentauthorisedwith Enviage resulted in an overall incidence of adverse reactions similar to placebo up to 300 mg. Adverse reactions have

The incidence of cough was similar in placebo (0.6%) and Enviage treated (0.9%) patients.

The adverse drug reactions (Table 1) are ranked under heading of frequency, he most frequent first, using the following convention: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports. Within each frequency grouping, undesirable effects are presented in o der of decreasing seriousness.

Table 1

Gastrointestinal disorders

 

 

longer

Common:

Diarrhoea

 

Skin and subcutaneous tissue disorders

no

Uncommon:

Rash

 

Rare:

Angioedema

 

Angioedema has occurred during treatment with Enviage. In controlled clinical trials, angioedema

(frequency unknown). In the event f any signs suggesting an allergic reaction (in particular

occurred rarely during treatmentproductwith Enviage with rates comparable to treatment with placebo or hydrochlorothiazide. Cases of angioe ema have also been reported in post-marketing experience

difficulties in breathing, or swallowing, or swelling of the face, extremities, eyes, lips and/or tongue)

patients should discontinue treatment and contact the physician (see section 4.4). LaboratoryMedicinalfindings

In controlled cl cal trials, clinically relevant changes in standard laboratory parameters were uncommonly asso ated with the administration of Enviage. In clinical studies in hypertensive patients, Env age had no clinically important effects on total cholesterol, high density lipoprotein cholesterol (HDL-C), fasting triglycerides, fasting glucose or uric acid.

Haemoglobin and haematocrit: Small decreases in haemoglobin and haematocrit (mean decreases of approximately 0.05 mmol/l and 0.16 volume percent, respectively) were observed. No patients discontinued therapy due to anaemia. This effect is also seen with other agents acting on the renin- angiotensin system, such as angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers.

Serum potassium: Increases in serum potassium were minor and infrequent in patients with essential hypertension treated with Enviage alone (0.9% compared to 0.6% with placebo). However, in one study where Enviage was used in combination with an ACEI in a diabetic population, increases in serum potassium were more frequent (5.5%). Therefore as with any agent acting on the RAS system, routine monitoring of electrolytes and renal function is indicated in patients with diabetes mellitus, kidney disease, or heart failure.

In obese hypertensive patients who did not adequately respond to HCTZ 25 mg, add-on treatment with Enviage 300 mg provided additional blood pressure reduction that was comparable to add-on treatment with irbesartan 300 mg or amlodipine 10 mg. In diabetic hypertensive patients, Enviage
16
Pharmacotherapeutic group: Renin inhibitor, ATC code: C09XA02
5.1 Pharmacodynamic properties
Aliskiren is an orally active, non-peptide, potent and selective direct inhibitorauthorisedof human renin. By inhibiting the enzyme renin, aliskiren inhibits the RAS at the point of activa ion, blocking the
conversion of angiotensinogen to angiotensin I and decreasing levels of ngiotensin I and angiotensin II. Whereas other agents that inhibit the RAS (ACEI and angiotensin II receptor blockers (ARB)) cause a compensatory rise in plasma renin activity (PRA),longertreatment 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 administratinon f Enviage at doses of 150 mg and 300 mg
provided dose-dependent reductions in both syst lic and diastolic blood pressure that were maintained over the entire 24-hour doseproductinterval (main ai i g be efit in the early morning) with a mean peak to trough ratio for diastolic response of up to 98% for the 300 mg dose. 85 to 90% of the maximal blood-
pressure-lowering effect was observed after 2 weeks. The blood-pressure-lowering effect was sustained during long-term treatment, and was independent of age, gender, body mass index and ethnicity. Enviage has been studied in 1,864 patients aged 65 years or older, and in 426 patients aged 75 years or older.
Enviage monotherapy studies have shown blood pressure lowering effects comparable to other classes Medicinalof antihypertensive gents including ACEI and ARB. Compared to a diuretic (hydrochlorothiazide - HCTZ), Enviage 300 mg lowered systolic/diastolic blood pressure by 17.0/12.3 mmHg, compared to
14.4/10.5 mmHg for HCTZ 25 mg after 12 weeks of treatment. In diabetic hypertensive patients, Enviage monotherapy was safe and effective.
Combination therapy studies are available for Enviage added to the diuretic hydrochlorothiazide, the ACEI ramipril, the calcium channel blocker amlodipine, the angiotensin receptor antagonist valsartan, and the beta blocker atenolol. These combinations were well tolerated. Enviage induced an additive blood-pressure-lowering effect when added to hydrochlorothiazide and to ramipril. In patients who did not adequately respond to 5 mg of the calcium channel blocker amlodipine, the addition of Enviage 150 mg had a blood-pressure-lowering effect similar to that obtained by increasing amlodipine dose to 10 mg, but had a lower incidence of oedema (aliskiren 150 mg/amlodipine 5 mg 2.1% vs. amlodipine 10 mg 11.2%). Enviage in combination with the angiotensin receptor antagonist valsartan showed an additive antihypertensive effect in the study specifically designed to investigate the effect of the combination therapy.
In post-marketing experience, renal dysfunction and cases of acute renal failure have been reported in patients at risk (see section 4.4).
4.9 Overdose
Limited data are available related to overdose in humans. The most likely manifestations of overdosage would be hypotension, related to the antihypertensive effect of aliskiren. If symptomatic hypotension should occur, supportive treatment should be initiated.
5. PHARMACOLOGICAL PROPERTIES

provided additive blood pressure reductions when added to ramipril, while the combination of Enviage and ramipril had a lower incidence of cough (1.8%) than ramipril (4.7%).

There has been no evidence of first-dose hypotension and no effect on pulse rate in patients treated in controlled clinical studies. Excessive hypotension was uncommonly (0.1%) seen in patients with uncomplicated hypertension treated with Enviage alone. Hypotension was also uncommon (<1%) during combination therapy with other antihypertensive agents. With cessation of treatment, blood pressure gradually returned towards baseline levels over a period of several weeks, with no evidence of a rebound effect for blood pressure or PRA.

clinical significance of this reduction is unknown.

In a 3-month study of 302 patients with mild stable heart failure, all of whom were receiving standard therapy for stable heart failure, addition of Enviage 150 mg was well tolerated.authorisedB-type natriuretic peptide (BNP) levels were reduced by 25% in the Enviage arm compared to placebo. Howev r the

In a 6-month study of 599 patients with hypertension, type 2 diabetes mellitus, and neph pathy, all of whom were receiving losartan 100 mg and optimised antihypertensive background t erapy, addition of Enviage 300 mg achieved a 20% reduction versus placebo in urinary albumin:crea inine ratio (UACR), i.e. from 58 mg/mmol to 46 mg/mmol. The proportion of patients who had UACR reduced at least 50% from baseline to endpoint was 24.7% and 12.5% for Enviage nd pl cebo, respectively. The clinical relevance of a reduction in UACR is not established in the absence of n effect on blood pressure. Enviage did not affect the serum concentration of creatinine but was associated with an increased frequency (4.2% vs. 1.9% for placebo) of serum potassium concentration ≥6.0 mmol/l, although this was not statistically significant.

 

longer

Beneficial effects of Enviage on mortality and cardiovascu ar morbidity and target organ damage are

currently unknown.

 

No effect on QT interval was reported in a ra domised,no double-blind, placebo, and active-controlled study using standard and Holter electro ardiography.

Cardiac electrophysiology

absolute bioavailability of productaliskiren is approximately 2-3%. Meals with a high fat content reduce Cmax by 85% and AUC by 70%. Steady-state-plasma concentrations are reached within 5-7 days following

5.2 Pharmacokinetic properties

Absorption

Following oral absorption, eak plasma concentrations of aliskiren are reached after 1-3 hours. The

Distribut on

onceMedicinal-daily admi istr tion and steady-state levels are approximately 2-fold greater than with the initial dose.

Following intravenous administration, the mean volume of distribution at steady state is approximately 135 litr s, indicating that aliskiren distributes extensively into the extravascular space. Aliskiren plasma protein binding is moderate (47-51%) and independent of the concentration.

Metabolism and elimination

The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as unchanged compound in the faeces (78%). Approximately 1.4% of the total oral dose is metabolised. The enzyme responsible for this metabolism is CYP3A4. Approximately 0.6% of the dose is recovered in urine following oral administration. Following intravenous administration, the mean plasma clearance is approximately 9 l/h.

Linearity/non-linearity

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

administration in the dose range of 75 to 600 mg, a 2-fold increase in dose results in a ~2.3 and 2.6- fold increase in AUC and Cmax, respectively. At steady state the non-linearity may be more pronounced. Mechanisms responsible for deviation from linearity have not been identified. A possible mechanism is saturation of transporters at the absorption site or at the hepatobiliary clearance route.

Characteristics in patients

Aliskiren is an effective once-a-day antihypertensive treatment in adult patients, regardless of gender, age, body mass index and ethnicity.

The AUC is 50% higher in elderly (>65 years) than in young subjects. Gender, weight and ethnicity have no clinically relevant influence on aliskiren pharmacokinetics.

severe hepatic impairment.

authorised

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 b tw n 0.8 to 2 times the levels in healthy subjects following single dose administration and at steady tate. These observed changes, however, did not correlate with the severity of renal impairment. No adjustment of the initial dosage of Enviage is required in patients with mild to severe renal impairment, however caution should be exercised in patients with severe renal impairment.

The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe liver disease. Consequently, no adjustment of the initial dose of aliskiren is equired in patients with mild to

5.3 Preclinical safety data

Carcinogenic potential was assessed in a 2-year rat studylongerand 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 statisticallyno significant. Although aliskiren has known

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

irritation potential, safety margins obtained in huma s at the dose of 300 mg during a study in healthy volunteers were consideredproductto be appropria e at 9-11-fold based on faecal concentrations or 6-fold

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 developmentMedicinaland post-n t development were unaffected in rats at doses up to 250 mg/kg/day. The

doses in rats a d r bbits provided systemic exposures of 1 to 4 and 5 times higher, respectively, than the maximum re ommended 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

6.1List of excipients

Crospovidone

Magnesium stearate

Cellulose, microcrystalline

Povidone

Silica, colloidal anhydrous

2 years
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

6.4 Special precautions for storage

Do not store above 30°C.

authorised

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

6.5 Nature and contents of container

PA/Alu/PVC blisters

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

Packs containing 84 (3x28), 90 (3x30), 98 (2x49) or 280 (20x14) tablets are multi-packs.

Not all pack sizes may be marketed.

longer

6.6 Special precautions for disposal

Any unused product or waste material should benodisposed of in accordance with local requirements.

7.

MARKETING AUTHORISATION HOLDER

Novartis Europharm Limited

 

Wimblehurst Road

product

 

Horsham

 

West Sussex, RH12 5AB

 

 

 

United Kingdom

 

 

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/07/406/011-020

 

 

Medicinal

 

 

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22.08.2007

10. DATE OF REVISION OF THE TEXT

Comments

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
  • Help
  • Get it on Google Play
  • About
  • Info on site by:

  • Presented by RXed.eu

  • 27558

    prescription drugs listed