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

Rasilez may be taken with or without food.

Elderly (>65 years): No adjustment of the initial dose is required for elderly patients.

Children and Adolescents (<18 years): The safety and efficacy of Rasilez have not been investigated in children and adolescents (<18 years). Rasilez is therefore not recommended for use in this patient group.

Renal Impairment: No adjustment of the initial dose is required for patients with mild to severe renal impairment (see Pharmacokinetics under Actions and Precautions).

Hepatic Impairment: No adjustment of the initial dose is required for patients with mild to severe hepatic impairment (see Pharmacokinetics under Actions).

Effects on the Ability to Drive or Operate Machinery: No studies of 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.

Use in pregnancy: There are no suitable data on the use of aliskiren in pregnant women. Aliskiren was not teratogenic in rats or rabbits. Other substances that act directly on the renin-angiotensin system (RAS) have been associated with serious fetal malformations and neonatal death. Like any agent that acts directly on the RAS, Rasilez must therefore not be used during pregnancy or in women planning to become pregnant (see Contraindications). Healthcare professionals prescribing any medicinal products that act on the RAS should inform women of childbearing potential about the potential risk of these products during pregnancy. If pregnancy is detected during therapy, Rasilez must be discontinued as soon as possible.

Use in lactation: Rasilez must not be used during lactation.

It is not known whether aliskiren is excreted in human milk. It was secreted in the milk of lactating rats.

Rasilez use was not associated with an increased incidence of dry cough, as typically occurs with ACE inhibitors. The incidence of cough was similar in placebo (0.6%) and Rasilez-treated (0.9%) patients.

The adverse drug reactions are ranked under heading of frequency, the most frequent first, using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000), including isolated reports. Within each frequency grouping, adverse effects are presented in the order of decreasing severity.

Gastrointestinal Disorders: Common: Diarrhea.

Skin: Uncommon: Rash.

Laboratory Findings: In controlled clinical trials, clinically relevant changes in standard laboratory parameters were only rarely associated with the administration of Rasilez. In clinical studies in hypertensive patients, Rasilez had no clinically important effects on total cholesterol, high-density lipoproteins (HDL), 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 because of anaemia. This effect is also seen with other agents acting on the renin-angiotensin system eg, 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, routine monitoring of electrolytes and renal function is indicated in the diabetic population when using Rasilez.

A 20-30% change in aliskiren Cmax or AUC resulted when aliskiren was combined with valsartan (28% reduction), metformin (28% reduction), amlodipine (29% increase) and cimetidine (19% increase). On co-administration with atorvastatin, steady-state aliskiren AUC and Cmax increased by 50%. Co-administration of aliskiren had no significant impact on atorvastatin, valsartan, metformin or amlodipine pharmacokinetics. As a result, no dose adjustment is necessary when these substances are co-administered.

CYP-450 Interactions: Aliskiren does not inhibit the CYP-450 isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A), nor does it induce CYP3A4. Aliskiren is metabolized minimally by the cytochrome P-450 enzymes; therefore, interactions with agents that inhibit, induce or are metabolized by these enzymes are not expected.

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 to monitor the effect when initiating therapy and, if necessary, to adjust the dose of furosemide in order to avoid possible underdosage in clinical situations of volume overload.

Ketoconazole: Co-administration of ketoconazole with aliskiren resulted in a 1.8-fold increase in plasma levels of aliskiren (AUC and Cmax). The change in plasma levels in the presence of ketoconazole is expected to be within the range that would be achieved if the dose were doubled; aliskiren doses of up to 600 mg, or twice the highest recommended therapeutic dose, have been found to be safe in controlled clinical trials. Preclinical studies indicate that aliskiren and ketoconazole co-administration enhances aliskiren gastrointestinal absorption and decreases biliary excretion. It follows that no dose adjustment is necessary for aliskiren.

Rasilez acts on the RAS by binding to the enzyme renin, thereby preventing conversion of angiotensinogen to angiotensin I. In this way, it decreases plasma renin activity and levels of angiotensin I and angiotensin II.

Pharmacodynamics: Renin is secreted by the kidney in response to a decrease in blood volume and renal perfusion.

This reaction initiates a cycle that involves the renin-angiotensin system (RAS) and a homeostatic feedback loop. Renin cleaves angiotensinogen to generate the inactive decapeptide angiotensin I (Ang I). Ang I is converted by angiotensin-converting enzyme (ACE) and non-ACE pathways to the active octapeptide angiotensin II (Ang II). Ang II is a potent vasoconstrictor and leads to the release of catecholamines from the adrenal medulla and presynaptic nerve endings. It also stimulates aldosterone secretion and sodium reabsorption. The net result of these actions is an increase in blood pressure. Chronic Ang II elevation causes the release of markers and mediators of inflammation and fibrosis, ultimately leading to end-organ damage. Ang II also inhibits renin release, thus providing negative feedback. Elevated plasma renin activity (PRA) is independently associated with increased cardiovascular risk in hypertensive and normotensive patients. All substances that inhibit this system, including renin inhibitors, suppress the negative feedback loop, leading to a compensatory increase in plasma renin concentration. When this increase occurs on treatment with an ACEI or angiotensin II receptor blocker (ARB), it is accompanied by increased PRA. During treatment with aliskiren, by contrast, the effects on the feedback loop are neutralized, with PRA, Ang I and Ang II all decreased as a result, regardless of whether aliskiren is used as monotherapy or in combination with other antihypertensives. Treatment with Rasilez decreases PRA in hypertensive patients. In clinical studies the decrease in PRA ranged from 50-80%. Similar reductions were found when aliskiren was combined with other antihypertensive agents.

Clinical Efficacy: In hypertensive patients, Rasilez achieves a sustained dose-dependent reduction in both systolic and diastolic blood pressure. Once-daily administration of Rasilez at doses of 150 mg and 300 mg provided effective blood pressure reduction over the entire 24 hrs dose interval (maintaining benefit in the early morning), with a trough-to-peak ratio for diastolic blood pressure of 98% for the 300 mg dose. After 2 weeks, 85-90% of the maximum blood pressure-lowering effect was observed. The blood pressure-lowering effect was sustained in patients treated for up to 1 year, as was shown by a statistically significant difference from placebo 4 weeks after randomized withdrawal. 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.

There has been no evidence of first-dose hypotension or of an effect on pulse rate in patients treated in controlled studies. Severe hypotension was uncommonly (0.1%) seen in patients with uncomplicated hypertension treated with Rasilez. Hypotension was also uncommonly (<1%) seen during combination therapy with other antihypertensive agents.

In controlled studies, the blood pressure-lowering effect of Rasilez was additive in combination with hydrochlorothiazide or ramipril, and the combinations were well tolerated.

The combination of Rasilez and the ACE inhibitor, ramipril, had a lower incidence of cough (1.8%) than ramipril alone (4.7%). In patient who did not adequately respond to 5 mg of the calcium channel blocker (CCB) amlodipine, Rasilez 150 mg likewise had an additive blood pressure-lowering effect and was well tolerated. Efficacy was similar to that of 10 mg amlodipine, but the incidence of edema was lower (aliskiren/amlodipine 2.1% vs. amlodipine 11.2%). Co-administration with ARB, valsartan, was well tolerated.

Rasilez shows a blood pressure-lowering effect comparable to other classes of antihypertensive agents, including ACEI, ARB and CCB.

The antihypertensive effect of Rasilez was compared with that of hydrochlorothiazide (HCTZ) in a 26-week randomized, double blind study with the option of adding amlodipine. After 12 weeks of monotherapy with 300 mg aliskiren or 25 mg HCTZ, the reduction from baseline systolic/diastolic blood pressure was 17/12.3 mmHg for aliskiren and 14.4/10.5 mmHg for HCTZ. At endpoint, systolic/diastolic blood pressure had decreased by 19.6/14.2 mmHg from baseline on treatment with 300 mg aliskiren and by 17.9/13 mmHg on treatment with 25 mg HCTZ.

In diabetic hypertensive patients, Rasilez monotherapy was safe and effective. In combination with ramipril, Rasilez provided additional blood pressure reduction, as compared with the monotherapies.

In obese hypertensive patients who were inadequately treated with HCTZ, Rasilez provided additional blood pressure reduction that was comparable to add-on treatment with irbesartan or amlodipine.

The antihypertensive effect of Rasilez was independent of age, sex, body mass index and ethnicity.

Pharmacokinetics: Absorption: Following oral dosing, peak plasma concentrations of aliskiren were reached after 1-3 hrs. The absolute bioavailability of aliskiren is 2.6%. Food reduces Cmax and exposure (AUC) but has minimal impact on pharmacodynamics; thus, aliskiren can be taken with or without food. Steady-state plasma concentrations are reached within 5-7 days on once-daily dosing and are approximately twice as high as levels after the initial dose.

Distribution: Aliskiren undergoes uniform systemic distribution after oral dosing. Following IV administration the mean volume of distribution at steady-state is approximately 135 L, 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 elimination half-life is about 40 hrs (range 34-41 hrs). Aliskiren is mainly eliminated as unchanged compound in the feces (91%). Approximately 1.4% of the total oral dose is recovered in the urine following oral administration. Following IV administration, the mean plasma clearance is approximately 9 L/hr.

Linearity/Non-Linearity: Peak plasma concentrations (Cmax) and exposure (AUC) of aliskiren increase linearly with increasing dose over the range of 75-600 mg.

Pharmacokinetics in Special Patient Populations: Rasilez is an effective once-a-day antihypertensive treatment in adult patients, regardless of sex, age, body mass index and race.

The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renal impairment. Relative AUC and Cmax of aliskiren in subjects with renal impairment ranged from 0.8 to 2 times the levels in healthy subjects following single-dose administration and at steady-state. The observed changes, however, did not correlate with the severity of renal impairment. No initial dose adjustment is required in patients with mild to severe renal impairment, but caution should be exercised in patients with severe renal impairment. No data are available on the use of Rasilez in dialysis patients.

The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe hepatic impairment. Consequently, no initial dose adjustment is required in patients with mild to severe hepatic impairment.

Also, no initial dose adjustment is required for elderly patients.

Toxicology: Preclinical Data: Carcinogenicity: Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic mouse study. No carcinogenic potential was detected. Inflammatory and proliferative changes were observed in the lower gastrointestinal tract in both species at doses of 750-1500 mg/kg/day.

One colonic adenoma and one caecal adenocarcinoma recorded in rats at a dose of 1500 mg/kg/day were not statistically significant. These findings were attributed to the known irritation potential of aliskiren. Local concentrations in the faeces in the rat carcinogenicity study at the no-observed-adverse-effect-level (NOAEL) of 250 mg/kg/day were 16-24 times higher than those in humans on the highest recommended clinical dose of 300 mg and do not suggest a significant human risk.

Mutagenicity: Aliskiren was devoid of any mutagenic potential in the in vitro and in vivo mutagenicity studies. The studies 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 embryofetal toxicity or teratogenicity at doses up to 600 mg/kg/day in rats or 100 g/kg/day in rabbits. Fertility, prenatal development and postnatal development were unaffected in rats at doses up to 250 mg/kg/day. On a mg/m2 basis, the doses in rats and rabbits were 6-16 and 6 times higher, respectively, than the maximum recommended human dose of 300 mg (calculations based on a 50 kg patient).