Drug Class Description
Renin inhibitor

Generic Name
Aliskiren

Drug Description
Each Rasilez 150 mg film-coated tablet contains 150 mg aliskiren (as hemifumarate).Each Rasilez 300 mg film-coated tablet contains 300 mg aliskiren (as hemifumarate).

Presentation
Film-coated tabletRasilez 150 mg film-coated tablets : Light-pink, biconvex, round tablet, imprinted “IL” on one side and “NVR” on the other side.Rasilez 300 mg film-coated tablets : Light-red, biconvex, ovaloid tablet, imprinted “IU” on one side and “NVR” on the other side.

Indications
Treatment of essential hypertension.

Adult Dosage
The recommended dose of Rasilez 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 (8590%) after initiating therapy with 150 mg once daily.Rasilez may be used alone or in combination with other antihypertensive agents.Rasilez should be taken with a light meal once a day, preferably at the same time each day. Grapefruit juice should not be taken together with Rasilez.Renal impairmentNo adjustment of the initial dose is required for patients with mild to severe renal impairment.Hepatic impairmentNo adjustment of the initial dose is required for patients with mild to severe hepatic impairment.Elderly patients (over 65 years)No adjustment of the initial dose is required for elderly patients.Paediatric patients (below 18 years)Rasilez is not recommended for use in children and adolescents below age 18 due to a lack of data on safety and efficacy.

Child Dosage
Paediatric patients (below 18 years) - Rasilez is not recommended for use in children and adolescents below age 18 due to a lack of data on safety and efficacy.

Elderly Dosage
Elderly patients (over 65 years) - No adjustment of the initial dose is required for elderly patients.

Contra Indications
Hypersensitivity to the active substance or to any of the excipients.History of angioedema with aliskiren.Second and third trimesters of pregnancy.The concomitant use of aliskiren with ciclosporin, a highly potent P-gp inhibitor, and other potent P-gp inhibitors (quinidine, verapamil), is contraindicated.

Special Precautions
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, Rasilez therapy should be stopped.AngioedemaAs with other agents acting on the renin-angiotensin system, angioedema has been reported in patients treated with aliskiren. If angioedema occurs, Rasilez 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 patientsIn 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 Rasilez. This condition should be corrected prior to administration of Rasilez, or the treatment should start under close medical supervision.Renal impairmentIn clinical studies Rasilez 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 hypertension. Caution should be exercised in hypertensive patients with severe renal impairment due to the lack of safety information for Rasilez.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 stenosisNo controlled clinical data are available on the use of Rasilez 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 inhibitorsCo-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.

Interactions
Rasilez 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 Rasilez. When administered with atorvastatin, steady-state Rasilez AUC and Cmax increased by 50%. Co-administration of Rasilez had no significant impact on atorvastatin, valsartan, metformin or amlodipine pharmacokinetics. As a result no dose adjustment for Rasilez or these co-administered medicinal products is necessary.Digoxin bioavailability may be slightly decreased by Rasilez.Preliminary data suggest that irbesartan may decrease Rasilez AUC and Cmax.In experimental animals, it has been shown that P-gp is a major determinant of Rasilez bioavailability. Inducers of P-gp (St. John's wort, rifampicin) might therefore decrease the bioavailability of Rasilez.CYP450 interactionsAliskiren 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 interactionsMDR1/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 Rasilez. Although this has not been investigated for aliskiren, it is known that P-gp also controls tissue uptake of a variety of substrates and P-gp inhibitors can increase the tissue-to-plasma concentration ratios. Therefore, P-gp inhibitors may increase tissue levels more than plasma levels. The potential for drug interactions at the P-gp site will likely depend on the degree of inhibition of this transporter.P-gp substrates or weak inhibitorsNo 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 inhibitorsA 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.FurosemideWhen 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 anti-hypertensive effect of aliskiren. In some patients with compromised renal function (dehydrated patients or elderly patients) aliskiren given concomitantly with NSAIDs may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore the combination of aliskiren with an NSAID requires caution, especially in elderly patients.Potassium and potassium-sparing diureticsBased 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 juiceDue to the lack of data a potential interaction between grapefruit juice and aliskiren cannot be excluded. Grapefruit juice should not be taken together with Rasilez.WarfarinThe effects of Rasilez on warfarin pharmacokinetics have not been eva luated.Food intakeMeals with a high fat content have been shown to reduce the absorption of Rasilez substantially.

Adverse Reactions
Rasilez has been eva luated 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 Rasilez resulted in 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 Rasilez 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, <1/10); 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 order of decreasing seriousness.Table 1Gastrointestinal disorders Common:DiarrhoeaSkin and subcutaneous tissue disorders Uncommon: Rare:Rash AngioedeaAngioedema has occurred during treatment with Rasilez. In controlled clinical trials, angioedema occurred rarely during treatment with Rasilez 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.Laboratory findingsIn controlled clinical trials, clinically relevant changes in standard laboratory parameters were uncommonly associated with the administration of Rasilez. In clinical studies in hypertensive patients, Rasilez 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 Rasilez alone (0.9% compared to 0.6% with placebo). However, in one study where Rasilez 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.

Manufacturer
Novartis

Drug Availability
(POM)

Updated
12 August 2009