Enviage - summary of medicine characteristics

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 other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of essential hypertension.

4.2 Posology and method of administration

The recommended dose of Enviage 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.

ation with other antihypertensive agents (see sections 4.4 and light meal once a day, rreferably at the same time each day. Grarefruit er with Enviage.

Renal impairmenl

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

c impairment

ustment of the initial dose is required for patients with mild to severe hepatic impairment (see 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).

4.3 Contraindications

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

Sodium and/or volume depleted patients

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

Renal impairment

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

As for other agents acting on the renin-angiotensin system, caution should be exercised when aliskiren is given in the presence of conditions pre-disposing to kidney dysfunction such as hypovolaemia (eg. due to blood loss, severe prolonged diarrhoea, prolonged vomiting, etc.), heart disease, liver disease or kidney disease. Acute renal failure, reversible upon discontinuation of treatment, has been reported in at-risk patients receiving aliskiren in post-marketing experience. In the event that any signs of renal failure occur, aliskiren should be promptly discontinued.

Renal artery stenosis

No controlled clinical data are available on the use of 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 valsarían (¿28%), metformin (¿28%), amlodipine (¿29%) or cimetidine (¿19%) resulted in between 20% and 30% change in Cmax or AUC of Enviage. When administered with atorvastatin, steady-state Enviage AUC and Cmax increased by 50%. Coadministration of Enviage had no significant impact on atorvastatin, valsartan, metformin 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.

In experimental animals, it has been shown that P-gp is a major determinant of Enviage bioavailability. Inducers of P-gp (St. John’s wort, rifampicin) might therefore decrease the bioavailability of Enviage.

CYP450 interactions

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

Aliskiren does not induce CYP3A4. Therefore aliskiren is not expected to affect the systemic exposure of substances that inhibit, induce or are metabolised by these enzymes. Aliskiren is metabolised minimally by the cytochrome P450 enzymes. Hence, interactions due to inhibition or induction of CYP450 isoenzymes are not expected. However, CYP3A4 inhibitors often also affect P-gp. Increased aliskiren exposure during co-administration of CYP3A4 inhibitors that also inhibit P-gp can therefore be expected (see P-glycoprotein interactions below).

P-glycoprotein interactions

MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption and biliary excretion of aliskiren in preclinical studies. Inducers of P-gp (St. John’s wort, rifampicin) might therefore decrease the bioavailability of Enviage. 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.

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

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 of volume overload.

Non-steroidal anti-inflammatory drugs (NSAIDs)

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.

Potassium and potassium-sparing diuretics

Based on experience with the use of other substances that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other substances that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium. If co-medication is considered necessary, caution is advisable.

Grapefruit juice

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

Warfarin

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

Food intake

Meals with a high fat content have been shown to reduce the absorption of Enviage substantially.

4.6 Pregnancy and lactation

Pregnancy '^\^

There are no data on the use of aliskiren in pregnant women. Enviage was not teratogenic in rats or rabbits (see section 5.3). Other substances that act directly on the RAS have been associated with serious foetal malformations and neonatal death. As for any medicine that acts directly on the RAS, 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 over 6 months, and more than 1,200 for over 1 year. The incidence of adverse reactions showed no association with gender, age, body mass index, race or ethnicity. Treatment with Enviage resulted i an overall incidence of adverse reactions similar to placebo up to 300 mg. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The most common adverse drug reaction is diarrhoea.

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

The adverse drug reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common (>1/10); common (>1/100, <1/i0\ uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1

Angioedema has occurred during treatment with Enviage. In controlled clinical trials, angioedema occurred rarely during treatment with Enviage with rates comparable to treatment with placebo or hydrochlorothi­azide. Cases of angioedema have also been reported in post-marketing experience (frequency unknown). In the event of any signs suggesting an allergic reaction (in particular difficulties in breathing, or swallowing, or swelling of the face, extremities, eyes, lips and/or tongue) patients should discontinue treatment and contact the physician (see section 4.4).

Laboratory finding s^^^

In controlled clinical trials, clinically relevant changes in standard laboratory parameters were uncommonly associated with the administration of Enviage. In clinical studies in hypertensive patients, Enviage 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 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 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 PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Renin inhibitor, ATC code: C09XA02

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

conversion of angiotensinogen to angiotensin I and decreasing levels of angiotensin I and angiotensin II. Whereas other agents that inhibit the RAS (ACEI and angiotensin II receptor blockers (ARB)) cause a compensatory rise in plasma renin activity (PRA), treatment with aliskiren decreases PRA in hypertensive patients by approximately 50 to 80%. Similar reductions were found when aliskiren was combined with other antihypertensive agents. The clinical implications of the differences in effect on PRA are not known at the present time.

H H-

Hypertension

In hypertensive patients, once-daily administration of Enviage 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. 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 of antihypertensive agents 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 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 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.

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. B-type natriuretic peptide (BNP) levels were reduced by 25% in the Enviage arm compared to placebo. However the clinical significance of this reduction is unknown.

In a 6-month study of 599 patients with hypertension, type 2 diabetes mellitus, and n whom were receiving losartan 100 mg and optimised antihypertensive background th

Enviage 300 mg achieved a 20% reduction versus placebo in urinary albumin:creatinine ratio (UACR), i.e. from 58 mg/mmol to 46 mg/mmol. The proportion of patients who had UACR reduced at least 50% from baseline to endpoint was 24.7% and 12.5% for Enviage and placebo, respectively. The clinical relevance of a reduction in UACR is not established in the absence of an 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.

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

Cardiac electrophysiology

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

5.2 Pharmacokinetic properties

Absorption

Following oral absorption, peak plasma concentrations of aliskiren are reached after 1–3 hours. The absolute bioavailability of aliskiren is approximately 2–3%. Meals with a high fat content reduce Cmax by 85% and AUC by 70%. Steady-state-plasma concentrations are reached within 5–7 days following once-daily administration and steady-state levels are approximately 2-fold greater than with the initial dose.

Distributi ons^

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

Metabolism and elimination

The mean half-life is about 40 hours (range 34–41 hours). Aliskiren is mainly eliminated as unchanged compound in the faeces (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.

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 Enviage is required in patients with mild to se impairment, however caution should be exercised in patients with severe renal im

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 PARTICULARS6.1 List of excipients

Crospovidone

Magnesium stearate

Cellulose, microcrystalline

Povidone

Silica, colloidal anhydrous

6.2 Incompatibilities

6.3 Shelf life

2 years

6.4 Special precautions for storage

6.5 Nature and contents of container

6.6 Special precautions for disposal

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT