Direct Renin Inhibition:
New Treatments for Hypertension
Mechanism of Action

Renin is secreted by the kidney in response to decreases in blood volume and renal perfusion. Renin cleaves angiotensinogen to form the inactive decapeptide angiotensin I (Ang I). Ang I is converted to the active octapeptide angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) and non-ACE pathways. Ang II is a powerful vasoconstrictor and leads to the release of catecholamines from the adrenal medulla and prejunctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption. Together, these effects increase blood pressure. Ang II also inhibits renin release, thus providing a negative feedback to the system. This cycle, from renin through angiotensin to aldosterone and its associated negative feedback loop, is known as the renin-angiotensin-aldosterone system (RAAS). Aliskiren is a direct renin inhibitor, decreasing plasma renin activity (PRA) and inhibiting the conversion of angiotensinogen to Ang I. Whether aliskiren affects other RAAS components, e.g., ACE or non-ACE pathways, is not known.

All agents that inhibit the RAAS, including renin inhibitors, suppress the negative feedback loop, leading to a compensatory rise in plasma renin concentration. When this rise occurs during treatment with ACE inhibitors and ARBs, the result is increased levels of PRA. During treatment with aliskiren, however, the effect of increased renin levels is blocked, so that PRA, Ang I and Ang II are all reduced, whether aliskiren is used as monotherapy or in combination with other antihypertensive agents. PRA reductions in clinical trials ranged from approximately 50%-80%, were not dose-related and did not correlate with blood pressure reductions. The clinical implications of the differences in effect on PRA are not known.


Aliskiren is a poorly absorbed (bioavailability about 2.5%) drug with an approximate accumulation half life of 24 hours. Steady-state blood levels are reached in about 7-8 days.

Absorption and Distribution

Following oral administration, peak plasma concentrations of aliskiren are reached within 1 to 3 hours. When taken with a high fat meal, mean AUC and Cmax of aliskiren are decreased by 71% and 85%, respectively. In the clinical trials of aliskiren, it was administered without requiring a fixed relation of administration to meals.

Metabolism and Elimination

About one-fourth of the absorbed dose appears in the urine as parent drug. How much of the absorbed dose is metabolized is unknown. Based on the in vitro studies, the major enzyme responsible for aliskiren metabolism appears to be CYP 3A4.

Special Populations


The pharmacokinetics of aliskiren have not been investigated in patients <18 years of age.


The pharmacokinetics of aliskiren were studied in the elderly (≥65 years). Exposure (measured by AUC) is increased in elderly patients. Adjustment of the starting dose is not required in these patients (see DOSAGE AND ADMINISTRATION).


The pharmacokinetic differences between Blacks, Caucasians and the Japanese are minimal.

Renal Insufficiency

The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renal insufficiency. Rate and extent of exposure (AUC and Cmax) of aliskiren in subjects with renal impairment did not show a consistent correlation with the severity of renal impairment. Adjustment of the starting dose is not required in these patients (see DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency

The pharmacokinetics of aliskiren were not significantly affected in patients with mild-to-severe liver disease. Consequently, adjustment of the starting dose is not required in these patients (see DOSAGE AND ADMINISTRATION).

Cardiac Electrophysiology

Aliskiren’s effects on ECG intervals were studied in a randomized, double-blind, placebo and active-controlled (moxifloxacin), 7-day repeat dosing study with Holter-monitoring and 12-lead ECGs throughout the interdosing interval. No effect of aliskiren on QT interval was seen.

Drug Interactions

Effects of Other Drugs on Aliskiren

Based on in-vitro studies, aliskiren is metabolized by CYP 3A4.

Co-administration of lovastatin, atenolol, warfarin, furosemide, digoxin, celecoxib, hydrochlorothiazide, ramipril, valsartan, metformin and amlodipine did not result in clinically significant increases in aliskiren exposure.

Co-administration of irbesartan reduced aliskiren Cmax up to 50% after multiple dosing.

Co-administration of atorvastatin resulted in about a 50% increase in aliskiren Cmax and AUC after multiple dosing.


Co-administration of 200 mg twice-daily ketoconazole with aliskiren resulted in an approximate 80% increase in plasma levels of aliskiren. A 400 mg once-daily dose was not studied but would be expected to increase aliskiren blood levels further.

Effects of Aliskiren on Other Drugs

Aliskiren does not inhibit the CYP450 isoenzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and CYP 3A) or induce CYP 3A4.

Co-administration of aliskiren did not significantly affect the pharmacokinetics of lovastatin, digoxin, valsartan, amlodipine, metformin, celecoxib, atenolol, atorvastatin, ramipril or hydrochlorothiazide.


The effects of aliskiren on warfarin pharmacokinetics have not been evaluated in a well-controlled clinical trial.


When aliskiren was co-administered with furosemide, the AUC and Cmax of furosemide were reduced by about 30% and 50%, respectively.

Indications and Usage
Rasilez® (aliskiren) is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. Use with maximal doses of ACE inhibitors has not been adequately studied.


Fetal/Neonatal Morbidity and Mortality

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin-converting enzyme inhibitors. When pregnancy is detected, Rasilez® (aliskiren) should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to a renin inhibitor only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should advise the patient to discontinue the use of Rasilez as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, Rasilez should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in-utero exposure to a renin inhibitor should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

There is no clinical experience with the use of Rasilez in pregnant women. Reproductive toxicity studies of aliskiren hemifumarate did not reveal any evidence of teratogenicity at oral doses up to 600 mg aliskiren/kg/day (20 times the maximum recommended human dose (MRHD) of 300 mg/day on a mg/m2 basis) in pregnant rats or up to 100 mg aliskiren/kg/day (seven times the MRHD on a mg/m2 basis) in pregnant rabbits. Fetal birth weight was adversely affected in rabbits at 50 mg/kg/day (3.2 times the MRHD on a mg/m2 basis). Aliskiren was present in placenta, amniotic fluid and fetuses of pregnant rabbits.

Head and Neck Angioedema

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with aliskiren. This may occur at any time during treatment. ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients, but whether angioedema rates are higher in Blacks with aliskiren is not known. Rasilez should be promptly discontinued and appropriate therapy and monitoring provided until complete and sustained resolution of signs and symptoms has occurred. Experience with ACE inhibitors indicates that even in those instances where only swelling of the tongue is seen initially, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient to prevent respiratory involvement. Very rarely, fatalities have been reported in patients with angioedema associated with laryngeal edema or tongue edema with ACE inhibitors. Patients with involvement of the tongue, glottis or larynx are more likely to experience airway obstruction, especially those with a history of airway surgery. Where there is involvement of the tongue, glottis or larynx, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and measures necessary to ensure a patent airway should be promptly provided (see ADVERSE REACTIONS).


An excessive fall in blood pressure was rarely seen (0.1%) in patients with uncomplicated hypertension treated with Rasilez alone. Hypotension was also infrequent during combination therapy with other antihypertensive agents (<1%). In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (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.

If an excessive fall in blood pressure occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline (see DOSAGE AND ADMINISTRATION). A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.


Impaired Renal Function

Patients with greater than moderate renal dysfunction (creatinine 150 umol/L for women and 177 umol/L for men and/or estimated GFR <30 mL/min), a history of dialysis, nephrotic syndrome, or renovascular hypertension were excluded from clinical trials of Rasilez® (aliskiren) in hypertension. Caution should be exercised in these patients because of the paucity of safety information with Rasilez in these patients and the potential for other drugs acting on the renin-angiotensin system to increase serum creatinine and blood urea nitrogen.

Increases in serum potassium > 5.5 meq/L were infrequent with Rasilez alone (0.9% compared to 0.6% with placebo). However, when used in combination with an ACE inhibitor in a diabetic population, increases in serum potassium were more frequent (5.5%). Routine monitoring of electrolytes and renal function is indicated in this population.

Information for Patients


Female patients of childbearing age should be told about the consequences of exposure to drugs that act on the renin-angiotensin system. Discuss other treatment options with female patients planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.


Angioedema, including laryngeal edema, may occur at any time during treatment with Rasilez. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician.

Drug Interactions

Patients should report any medications they take with aliskiren.


When aliskiren was given with furosemide, the blood concentrations of furosemide were reduced significantly. Patients receiving furosemide could find its effect diminished after starting aliskiren.
Carcinogenesis/Mutagenesis/Impairment of Fertility

Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic (rasH2) mouse study with aliskiren hemifumarate at oral doses of up to 1500 mg aliskiren/kg/day. Although there were no statistically significant increases in tumor incidence associated with exposure to aliskiren, mucosal epithelial hyperplasia (with or without erosion/ulceration) was observed in the lower gastrointestinal tract at doses of 750 or more mg/kg/day in both species,with a colonic adenoma identified in one rat and a cecal adenocarcinoma identified in another, rare tumors in the strain of rat studied. On a systemic exposure (AUC0-24hr) basis, 1500 mg/kg/day in the rat is about 4 times, and is in the mouse about 1.5 times, the maximum recommended human dose (300 mg aliskiren/day). Mucosal hyperplasia in the cecum or colon of rats was also observed at oral doses of 250 mg/kg/day (the lowest tested dose) as well as at higher doses in 4- and 13-week studies.

Aliskiren hemifumarate was devoid of genotoxic potential in the Ames reverse mutation assay with S. typhimurium and E. coli, the in vitro Chinese hamster ovary cell chromosomal aberration assay, the in vitro Chinese hamster V79 cell gene mutation test and the in vivo mouse bone marrow micronucleus assay. Fertility of male and female rats was unaffected at doses of up to 250 mg aliskiren/kg/day (8 times the maximum recommended human dose of 300 mg Rasilez/60 kg on a mg/m2 basis.

Pregnancy Categories C (first trimester) and D (second and third trimesters) (see WARNINGS, Fetal/Neonatal Morbidity and Mortality).

Nursing Mothers

It is not known whether aliskiren is excreted in human milk. Aliskiren was secreted in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of aliskiren in pediatric patients have not been established.

Geriatric Use

Of the total number of patients receiving aliskiren in clinical studies, 1,275 (19%) were 65
years or older and 231 (3.4%) were 75 years or older. Blood pressure responses and adverse
effects were generally similar to those in younger patients.

Adverse Reactions:

Rasilez® (aliskiren) has been evaluated for safety in more than 6,460 patients, including over 1,740 treated for longer than 6 months, and more than 1,250 for longer than 1 year. In placebo-controlled clinical trials, discontinuation of therapy due to a clinical adverse event, including uncontrolled hypertension occurred in 2.2% of patients treated with Rasilez, vs 3.5% of patients given placebo.

Two cases of angioedema with respiratory symptoms were reported with aliskiren use in the clinical studies. Two other cases of periorbital edema without respiratory symptoms were reported as possible angioedema and resulted in discontinuation. The rate of these angioedema cases in the completed studies was 0.06%.

In addition, 26 other cases of edema involving the face, hands, or whole body were reported with aliskiren use, including 4 leading to discontinuation. In the placebo controlled studies, however, the incidence of edema involving the face, hands or whole body was 0.4% with aliskiren compared with 0.5% with placebo. In a long term active control study with aliskiren and HCTZ arms, the incidence of edema involving the face, hand or whole body was 0.4% in both treatment arms.

Aliskiren produces dose-related gastrointestinal (GI) adverse effects. Diarrhea was reported by 2.3% of patients at 300 mg, compared to 1.2% in placebo patients. In women and the elderly (age 65) increases in diarrhea rates were evident starting at a dose of 150 mg daily, with rates for these subgroups at 150 mg comparable to those seen at 300 mg for men or younger patients (all rates about 2.0%-2.3%). Other GI symptoms included abdominal pain, dyspepsia, and gastroesophageal reflux, although increased rates for abdominal pain and dyspepsia were distinguished from placebo only at 600 mg daily. Diarrhea and other GI symptoms were typically mild and rarely led to discontinuation.

Aliskiren was associated with a slight increase in cough in the placebo-controlled studies (1.1% for any aliskiren use vs. 0.6% for placebo). In active-controlled trials with ACE inhibitor (ramipril, lisinopril) arms, the rates of cough for the aliskiren arms were about onethird to one-half the rates in the ACE inhibitor arms. Other adverse effects with increased rates for aliskiren compared to placebo included rash (1% vs. 0.3%), elevated uric acid (0.4% vs. 0.1%), gout (0.2% vs. 0.1%), and renal stones (0.2% vs. 0%).

Single episodes of tonic-clonic seizures with loss of consciousness were reported in two patients treated with aliskiren in the clinical trials. One of these patients did have predisposing causes for seizures and had a negative electroencephalogram (EEG) and cerebral imaging following the seizures (for the other patient EEG and imaging results were not reported). Aliskiren was discontinued and there was no re-challenge. The following adverse events occurred in placebo-controlled clinical trials at an incidence of more than 1% of patients treated with aliskiren, but also occurred at about the same or greater incidence in patients receiving placebo: headache, nasopharyngitis, dizziness, fatigue, upper respiratory tract infection, back pain and cough.

Clinical Laboratory Findings

In controlled clinical trials, clinically relevant changes in standard laboratory parameters were rarely associated with the administration of Rasilez. In multiple-dose studies in hypertensive patients Rasilez had no clinically important effects on total cholesterol, HDL, fasting triglycerides, fasting glucose, or uric acid.
Blood Urea Nitrogen, Creatinine

Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 7% of patients with essential hypertension treated with Rasilez alone vs 6% on placebo.

Hemoglobin and Hematocrit

Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.08 g/dL and 0.16 volume percent, respectively, for all aliskiren monotherapy) were observed. The decreases were dose-related and were 0.24 g/dL and 0.79 volume percent for 600 mg daily. This effect is also seen with other agents acting on the renin angiotensin system, such as angiotensin inhibitors and angiotensin receptor blockers, and may be mediated by reduction of angiotensin II which stimulates erythropoietin production via the AT1 receptor. These decreases led to slight increases in rates of anemia with aliskiren compared to placebo were observed (0.1% for any aliskiren use, 0.3% for aliskiren 600 mg daily, vs. 0% for placebo). No patients discontinued therapy due to anemia.

Serum Potassium

Increases in serum potassium >5.5 meq/L were infrequent in patients with essential hypertension treated with Rasilez alone (0.9% compared to 0.6% with placebo). However, when used in combination with an angiotensin-converting enzyme inhibitor (ACEI) in a diabetic population increases in serum potassium were more frequent (5.5%) and routine monitoring of electrolytes and renal function is indicated in this population.
Serum Uric Acid

Aliskiren monotherapy produced small median increases in serum uric acid levels (about 6 µmol/L) while HCTZ produced larger increases (about 30 µmol/L). The combination of aliskiren with HCTZ appears to be additive (about a 40 µmol/L increase). The increases in uric acid appear to lead to slight increases in uric acid-related AEs: elevated uric acid (0.4% vs. 0.1%), gout (0.2% vs. 0.1%), and renal stones (0.2% vs. 0%).

Creatine Kinase

Increases in creatine kinase of >300% were recorded in about 1% of aliskiren monotherapy patients vs. 0.5% of placebo patients. Five cases of creatine kinase rises, three leading to discontinuation and one diagnosed as subclinical rhabdomyolysis and another as myositis, were reported as adverse events with aliskiren use in the clinical trials. No cases were associated with renal dysfunction.


Limited data are available related to overdosage in humans. The most likely manifestation of overdosage would be hypotension. If symptomatic hypotension should occur, supportive treatment should be initiated.

Dosage and Administration

The usual recommended starting dose of Rasilez® (aliskiren) is 150 mg once daily. In patients whose blood pressure is not adequately controlled, the daily dose may be increased to 300 mg. Doses above 300 mg did not give an increased blood pressure response but increased the rate of diarrhea. The antihypertensive effect of a given dose is substantially attained (85%-90%) by 2 weeks. Rasilez may be administered with other antihypertensive agents. Most exposure to date is with diuretics and an angiotensin receptor blocker (valsartan) and the drugs together have a greater effect at their maximum recommended doses than either drug alone. It is not known whether additive effects are present when aliskiren is used with angiotensin-converting enzyme inhibitors or beta blockers. No initial dosage adjustment is required in elderly patients, for patients with mild-to-severe renal impairment, or for patients with mild-to-severe hepatic insufficiency. Care should be exercised when dosing Rasilez in patients with severe renal impairment, as clinical experience with such patients is limited. Patients should establish a routine pattern for taking Rasilez with regard to meals. High fat meals decrease absorption substantially (see Absorption and Distribution).

How Supplied

150 mg and 300 mg


Aliskiren, the active component of Rasilez® Tablets, is an orally active, nonpeptide, potent renin inhibitor. Aliskiren is present in Rasilez Tablets as its hemifumarate salt. Aliskiren hemifumarate is chemically described as (2S,4S,5S,7S)-N-(2-Carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl -8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate.

Molecular formula: C30H53N3O6 • 0.5 C4H4O4

Aliskiren hemifumarate is a white to slightly yellowish crystalline powder with a molecular weight of 609.8 (free base- 551.8). It is soluble in phosphate buffer, n-Octanol, and highly soluble in water.

Rasilez is available for oral administration as film-coated tablets containing 150 mg, and 300 mg of aliskiren base and the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, iron oxide colorants, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc, and titanium dioxide.