Rasilez

Co-administration of aliskiren with amlodipine, digoxin, furosemide, hydrochlorothiazide, metformin, ramipril and valsartan did not result in clinically significant changes in aliskiren exposure.

Co-administration with irbesartan reduced aliskiren C_max up to 50% after multiple dosing with little effect on AUC (up to a 20% decrease).

When taken with food, mean AUC and C_max of aliskiren were decreased by 71% and 85%, respectively (see Dosage and Administration). There was a delay in median t_max by 1 h.

Based on in-vitro studies, aliskiren is metabolised by the CYP3A4 enzyme system. However, pharmacokinetic studies in human volunteers seem to indicate that metabolism does not play a clinically significant role in the elimination of aliskiren.

MDR1/Mdr1a/1b (Pgp) was found to be involved in absorption and disposition of aliskiren in preclinical studies. The potential for drug interactions at the Pgp site will likely depend on the degree of inhibition of this transporter.

When administered with atorvastatin (80 mg), steady-state aliskiren (300 mg) AUC and C_max increased by 50%. Co-administration of ketoconazole (200 mg b.i.d.) with aliskiren (300 mg) resulted in a 80% increase in plasma levels of aliskiren (AUC and C_max). 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 atorvastatin or 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. As a result no dose adjustment for aliskiren is necessary.

The interaction of aliskiren with herbal medications or supplements has not been studied.

There are no physical restrictions for patients who receive aliskiren.

Co-administration of aliskiren did not affect the steady-state pharmacokinetics of amlodipine, digoxin, hydrochlorothiazide, metformin, ramipril, ramiprilat or valsartan.

Co-administration of aliskiren with furosemide resulted in reductions of furosemide C_max and AUC of 49% and 28%, respectively.

A single dose drug interaction study in healthy subjects has shown that cyclosporine (200 and 600 mg) increases C_max of aliskiren 75 mg by approximately 2.5 fold and the AUC by approximately 5 fold. Therefore, the concomitant use of both drugs is not recommended (see Warnings and Precautions, Renal, Concomitant Use with Cyclosporine A).

No relevant interactions with atenolol, digoxin, amlodipine, and cimetidine have been observed.

Based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of aliskiren with the following medicines may lead to increases in serum potassium: Potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium. If comedication is considered necessary, caution is advisable.

Aliskiren has low potential for drug interactions. Aliskiren is mainly excreted as unchanged drug within the feces and is minimally metabolized in man. Only 1.4% of the total dose is metabolized by the enzyme CYP3A4 of the cytochrome P450 system. Rasilez is poorly absorbed (bioavailability ~2.6% of an oral dose). Metabolism accounted for up to 20% of the absorbed dose in the systemic circulation. A quarter of the absorbed fraction in the systemic circulation is excreted unchanged in the urine. In-vitro studies have shown that aliskiren does not inhibit the CYP450 isoenzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and CYP3A) or induce CYP3A4. As CYP3A4 is the major enzyme responsible for metabolism of aliskiren, complete inhibition may be expected to result in increased plasma levels of aliskiren (see Action and Clinical Pharmacology, Pharmacokinetics).

The usual recommended starting dose of Rasilez is 150 mg once daily. In patients whose blood pressure is not adequately controlled, the daily dose may be increased to 300 mg. Rasilez may be used over a dosage range of 150 mg to 300 mg administered once daily.

The antihypertensive effect is substantially present (85%-90%) within 2 weeks after initiating therapy with 150 mg per day with the maximum effect reached after 4 weeks.

Rasilez may be administered alone or concomitantly with thiazide diuretics or angiotensin converting enzyme inhibitors. Co-administration of 150 mg aliskiren and 5 mg amlodipine has been shown to be safe and effective; higher doses and other calcium channel blockers have not been tested.

Rasilez may be administered with or without food, although a high fat meal decreases drug absorption significantly. Patients should establish a convenient daily schedule of drug-intake and maintain a steady temporal relationship with food intake.

No initial dosage adjustment is required for elderly patients, for patients with mild-to-severe renal impairment, or for patients with mild to severe hepatic impairment. Care should be exercised when dosing Rasilez in patients with severe renal impairment as clinical experience is limited.

If one or several doses of Rasilez are missed, patients should be advised to take the dose as soon as they remember. If it is almost time for the next dose, patients should skip the missed dose and go back to their regular schedule. Patients should not increase the dose of Rasilez to compensate for the missed dose(s).

vertigo, insomnia.

In short-term, 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.

No special monitoring is necessary in patients receiving Rasilez.

muscle spasms, arthralgia, pain in extremity, neck pain, shoulder pain.

In the short-term, placebo-controlled clinical trials, increases in creatine kinase of >300% were found in 22 of the 2233 (~1%) patients on aliskiren monotherapy vs. in 4/746 (0.5%) of patients on placebo. The effect, suggesting to be dose-related, seemed more common in men, and at ages <65 years. No cases were associated with renal dysfunction.

In an active controlled, double-blind, 1-year clinical trial, 21 of 543 patients (3.9%) on an aliskiren regimen and 9/535 patients (1.7%) on an HCTZ regimen had >300% increases in creatine kinase. This increase was seen more often in men than in women. In another long term study almost no elevations in CKs were seen in patients (0.5%) on an aliskiren regimen vs. in 1.3% of the patients on a ramipril regimen.

nausea, dyspepsia, abdominal pain.

urinary tract infection.

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.

Rare cases of colonic cancer (0.05%) were reported in the clinical trials with Rasilez. The incidence is consistent with the expected prevalence rates of 0.1-0.3% in this patient population.

Rasilez use was associated with a slightly increased incidence of dry cough, but less so than with angiotensin converting enzyme inhibitor use. In controlled, short-term clinical trials the incidence of cough was similar in placebo (0.6%) and Rasilez (1.1%) patients.

In a short-term active controlled trial, peripheral edema occurred in 3.4% of patients treated with amlodipine 5 mg, 11.2% of patients treated with amlodipine 10 mg, and 2.1% of patients treated with the combination of amlodipine 5 mg and aliskiren 150 mg. In other controlled short-term clinical trials, the incidence of edema was similar in placebo (0.6%) and Rasilez-treated patients (0.8% to 1.0%) except at a dose of 600 mg (2.0%).

Other adverse events that occurred in short-term, controlled clinical trials of patients treated with Rasilez (>0.5% Rasilez patients) are listed below. It cannot be determined whether these events were causally related to Rasilez.

Rasilez has been evaluated for safety in more than 7440 patients, including at least 2580 treated for over 6 months, and at least 1730 for over 1 year. The incidence of adverse events showed no association with gender, age, body mass index, race, or ethnicity. Treatment with Rasilez was well tolerated with an overall incidence of adverse events similar to placebo up to 300 mg. Adverse events have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. In placebo-controlled clinical trials, discontinuation of therapy due to a clinical adverse event occurred in 2.2% of patients treated with Rasilez versus 3.5% of patients given placebo. In long-term active controlled clinical trials discontinuation of therapy due to an adverse event occurred in 5.4% of Rasilez treated patients versus 4.7% of ramipril treated patients and 7.3% of hydrochlorothiazide treated patients.

Angioedema, including edema of the larynx, 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. Patients should discontinue the treatment and should report immediately to the physician any signs suggesting allergic reactions, in particular, difficulties in breathing or swallowing, swelling of face, extremities, eyes, lips, tongue.

bronchitis, pharyngolaryngeal pain, epistaxis.

Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.8 g/L and 0.16 volume percent, respectively) were observed with Rasilez monotherapy. These decreases led to slight increases in the rate of anemia with aliskiren: 0.1% for any aliskiren use, 0.3% for aliskiren 600 mg o.d., vs. 0% for placebo). No patients discontinued therapy due to anemia. This effect is also seen with other agents acting on the renin-angiotensin system, such as angiotensin converting enzyme inhibitors and angiotensin receptor blockers, and may be mediated by reduction of angiotensin II which stimulates erythropoietin production via the AT₁ receptor.

In short-term placebo controlled clinical trials, increases in serum potassium were minor and infrequent in patients with essential hypertension treated with Rasilez alone (0.9% patients had serum potassium levels >5.5 mmol/L compared to 0.6% with placebo). However, when used in combination with an angiotensin converting enzyme 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.

In an active controlled, double-blind, 1-year clinical trial in patients with essential hypertension, increases in serum potassium (>5.5 mmol/L) occurred in 36/550 (6.5%) of patients on Rasilez compared to 20/535 (3.7%) on hydrochlorothiazide and decreases in serum potassium (<3.5 mmol/L) occurred in 5/550 (0.9%) patients on Rasilez compared to 96/535 (17.9%) on hydrochlorothiazide. In another active controlled, double-blind trial, increases in serum potassium (>5.5 mmol/L) occurred in 8/412 (1.9%) of Rasilez-treated patients compared to 4/417 (1.0%) on ramipril and decreases in potassium (<3.5 mmol/L) occurred in 22/412 (5.3%) on Rasilez compared to 19/417 (4.6%) on ramipril.

Minor increases in blood urea nitrogen (BUN) were observed in less than 7% of patients with essential hypertension treated with Rasilez alone vs. 6% on placebo. Rasilez alone increased creatinine slightly (by ~1 μmol/L), but this effect increased (to 2.4 μmol/L) with co-administration of HCTZ.

In an active controlled, double-blind 1-year clinical trial, 13.4% of Rasilez-treated patients compared to 15.8% of hydrochlorothiazide-treated patients experienced >50% increases in blood urea nitrogen (BUN). In another active controlled, double-blind trial, >50% increases in BUN occurred in 15.5% of Rasilez-treated patients and 16.0% of ramipril-treated patients. Increases in serum creatinine (>50%) were less frequent, occurring in 2.7% of Rasilez-treated patients in the one-year study compared to 1.1% of patients treated with hydrochlorothiazide, and 1.7% of Rasilez-treated patients and 1.4% of ramipril-treated patients in the other trial.

Safety and efficacy in children and adolescents have not been established. Rasilez should not be given to this patient population.

Of the total number of patients receiving Rasilez in clinical studies, 1275 (19 %) were 65 years or older and 231 (3.4%) were 75 years or older. No differences were observed in safety and efficacy of Rasilez in older patients compared to those under age 65.

Each light-red, biconvex, ovaloid, film-coated tablet, imprinted NVR on one side and IU on the other side, contains: aliskiren 300 mg (as aliskiren fumarate). Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, hypromellose, iron oxide colorants, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc and titanium dioxide. Blister packages (4 strips of 7 tablets).

Each light-pink, biconvex, round, film-coated tablet, imprinted NVR on one side and IL on the other side, contains: aliskiren 150 mg (as aliskiren fumarate). Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, hypromellose, iron oxide colorants, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc and titanium dioxide. Blister packages (4 strips of 7 tablets).

Of the total number of patients receiving Rasilez in clinical studies, 1275 (19 %) were 65 years or older and 231 (3.4%) were 75 years or older. No clinically significant differences were observed in safety and efficacy of Rasilez in older patients compared to those under age 65.

In the event of severe and persistent diarrhea, Rasilez therapy should be stopped (see Adverse Reactions, Clinical Trial Adverse Drug Reactions).

Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to drugs that act on the renin-angiotensin system, and they should also be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.

No data are available on the effects of Rasilez on renal function in patients with uni-or bilateral renal artery stenosis.

Symptomatic hypotension 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%). Aliskiren-induced hypotension is more likely to occur in patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (possibly as a result of treatment with a diuretic), patients on dialysis or with fluid loss through diarrhea or vomiting. This condition should be corrected prior to administration of Rasilez, or the treatment should start under close medical supervision.

If symptomatic hypotension 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. However, lower doses of Rasilez and/or reduced concomitant diuretic therapy should be considered when symptoms re-occur.

The safety and effectiveness of Rasilez in children and adolescents have not been established.

The concomitant use of aliskiren with cyclosporine, a highly potent P glycoprotein inhibitor, is not recommended (see Drug Interactions, Drug-Drug Interactions).

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, Rasilez 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 during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient 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 lifesaving 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.

There is no clinical experience with the use of Rasilez in pregnant women. 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. Aliskiren is not removed by hemodialysis.

Reproductive toxicity studies did not reveal any evidence of embryofetal toxicity or teratogenicity at oral doses up to 600 mg/kg/day in rats or 100 mg/kg/day in rabbits. Aliskiren was present in the placenta, amniotic fluid and fetuses of pregnant rabbits. In rats, there were no adverse effects on fertility or early embryonic development or reproductive performance of the F1 generation.

Patients with greater than moderate renal dysfunction (creatinine ≥150 μmol/L for women and ≥176.8 μmol/L for men and/or eGFR <30 mL/min), a history of dialysis, nephrotic syndrome, or renovascular hypertension were excluded from clinical trials of Rasilez. Caution should be exercised, due to the limited availability 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.

It is not known whether Rasilez is excreted in human milk. Rasilez was excreted 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.

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

The potential of aliskiren to affect cardiac conduction and repolarisation was studied in a randomized, double-blind, placebo and active-controlled (moxifloxacin), repeat dosing, parallel group study, conducted for 7 days in 283 subjects. Twelve lead Holter ECGs were monitored over the entire dosing interval. No effect of aliskiren on the QT interval was seen.

Following oral administration, peak plasma concentrations of aliskiren are reached within 1-3 hours. The approximate bioavailability of aliskiren is 2.6%. Peak plasma concentrations (C_max) and exposure (AUC) are expected to increase 2.6-fold and 2.4-fold when doubling the dose of aliskiren. When taken with food with a high fat content, mean AUC and C_max of aliskiren are decreased by 71% and 85%, respectively, and t_max is delayed by 1 h. Steady state plasma concentrations are reached within 5 to 7 days after starting once daily administration, and steady state levels are approximately 2-fold greater than following a single dose.

There are presently no clinical outcome studies indicating beneficial effects of aliskiren in diabetic patients with nephropathy. Clinical data have shown that aliskiren reduces the urinary albumin to creatinine ratio (UACR) in these patients, but whether a reduction in this surrogate marker for nephropathy leads to improved cardio-renal outcomes has not been validated.

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. The mean elimination half-life is about 40 hours (range 34-41 hours).

Males have slightly lower AUC (24%) than females. This difference is not clinically significant.

Aliskiren is mainly eliminated as unchanged drug within feces. How much of the absorbed dose is metabolized is unknown. The enzyme responsible for this metabolism is CYP3A4.

In hypertensive patients, once-daily administration of Rasilez 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 trough to peak ratio for diastolic response of up to 98% for the 300 mg dose.

Treatment with aliskiren decreases plasma renin activity (PRA) and increases plasma renin concentration (PRC) in hypertensive patients. In clinical trials, PRA reductions ranged from approximately 50%-80%. PRA reductions occurred with aliskiren monotherapy or when aliskiren was combined with other antihypertensive drugs. There was no rebound increase in PRA or blood pressure either acutely or over a 4-week period after aliskiren discontinuation. There was a weak correlation between the magnitudes of PRC elevation and blood pressure reduction.

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

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).

The pharmacokinetics of aliskiren were studied in the elderly (≥65 years). The exposure (measured by AUC) and C_max of aliskiren is increased in elderly by 57% and 28%, respectively. Adjustment of the starting dose is not required in these patients (see Dosage and Administration).

Aliskiren has a novel mechanism of action which differs in pharmacologic action from the angiotensin converting enzyme inhibitors, angiotensin receptor blockers, aldosterone blockers, beta blockers, alpha blockers, diuretics and calcium channel blockers.

Aliskiren is an orally active, nonpeptide, highly specific and potent direct renin inhibitor. Aliskiren targets the renin angiotensin system (RAS) at its point of activation by binding to the renin enzyme, thereby blocking the conversion of angiotensinogen to angiotensin I (Ang I). Renin is secreted by the kidney in response to decreases in blood volume and renal perfusion. This response initiates a cycle that includes the renin angiotensin system (RAS) and a homeostatic feedback loop. 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. Chronic increases in Ang II result in the expression of markers and mediators of inflammation and fibrosis that are associated with end organ damage.

Aliskiren is a direct renin inhibitor that inhibits the production of Ang I, Ang II by acting at the point of activation of the renin cycle, inhibiting the conversion of angiotensinogen to Ang I and Ang II. This action suppresses the entire system, resulting in a reduction in plasma renin activity (PRA), Ang I, Ang II and aldosterone.

All agents that inhibit the RAS system suppress the negative feedback loop and lead to a compensatory rise in plasma renin concentration. When this rise occurs, it is accompanied by increased levels of PRA. However, treatment with aliskiren neutralizes the feedback loop effects. As a result, despite an elevation of the plasma renin concentration, PRA, Ang I and Ang II are all reduced, whether aliskiren is used as monotherapy or in combination with other antihypertensive agents.

The pharmacokinetics of aliskiren do not differ significantly among different races and ethnicities (Blacks, Caucasians, Hispanics, and Japanese).

The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renal insufficiency. Relative AUC and C_max of aliskiren in subjects with renal impairment ranged between 0.8- to 2-fold those observed in healthy subjects following single dose administration and at steady state. These observed changes, however, did not correlate with the severity of renal impairment. Consequently, adjustment of the starting dose is not required in patients with mild-to-severe renal impairment (see Dosage and Administration).

The pharmacokinetics of aliskiren were similar between type 2 diabetics and healthy volunteers.