Aliskiren Tablet, Film Coated
FDA Label NDC 66993-142

When pregnancy is detected, discontinue Aliskiren as soon as possible. (5.1, 8.1)

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1, 8.1)

Aliskiren is indicated for the treatment of hypertension in adults and children 6 years of age and older, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes. There are no controlled trials demonstrating risk reduction with Aliskiren.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality have also been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (e.g., patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

The usual recommended starting dose of 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 resulted in an increased rate of diarrhea. The antihypertensive effect of a given dose is substantially attained (85% to 90%) by 2 weeks.

Aliskiren is contraindicated in children less than 2 years of age [see Contraindications (4)].Aliskiren should not be used in children aged 2 to less than 6 years of age or in children who weigh less than 20 kg [see Use in Specific Populations (8.4) and Nonclinical Toxicology (13.2)]. See Table 1 for recommended dosage in pediatric patients 6 to 17 years of age.

For patients unable to swallow tablets, Aliskiren oral pellets can be used.

Aliskiren Oral Pellets are provided in a dispensing capsule. Do not swallow the capsules containing Aliskiren Oral Pellets. Do not empty the contents of the capsule directly into the mouth. Do not chew or crush the contents of the capsule.

Aliskiren Oral Pellets may be taken by opening the dispensing capsule, emptying the contents into a spoon and then administering by mouth, follow with milk (dairy or soy-based) or water immediately without chewing or crushing. Make sure that no pellets remain in the dispensing capsule.

Alternatively, Aliskiren Oral Pellets may be taken by carefully open the dispensing capsule and take the contents orally immediately after mixing with 1 or more teaspoons of vanilla pudding (milk or soy-based), vanilla ice cream (milk or soy- based), milk (dairy or soy-based), or water as a dosing vehicle. Dosing vehicles are limited to those specified. It is recommended that the contents of one dispensing capsule be taken with one teaspoon of dosing vehicle; however, more or less dosing vehicle may be administered, if desired. Do not chew or crush the contents of the capsules.

Patients should establish a routine pattern for taking Aliskiren with regard to meals. High-fat meals decrease absorption substantially [see Clinical Pharmacology (12.3)].

150 mg light pink biconvex round tablet, imprinted NVR/IL (Side 1/Side 2).

300 mg light red biconvex ovaloid round tablet, imprinted NVR/IU (Side 1/Side 2).

37.5 mg Aliskiren Oral Pellets in transparent, size-0 capsules.

Each size 0 capsule contains 12 white to yellowish round biconvex pellets. The capsule has red arrows pointing to the top and bottom of the capsule and is imprinted “NVR 12”.

Do not use aliskiren with ARBs or ACEIs in patients with diabetes [see Warnings and Precautions (5.2) and Clinical Studies (14.3)].

Aliskiren is contraindicated in patients with known hypersensitivity to any of the components [see Warnings and Precautions (5.3)].

Aliskiren is contraindicated in pediatric patients less than 2 years of age [see Use in Specific Populations (8.4)] and Nonclinical Toxicology (13.2)].

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Aliskiren as soon as possible [see Use in Specific Populations (8.1)].

Aliskiren is contraindicated in patients with diabetes who are receiving ARBs or ACEIs because of the increased risk of renal impairment, hyperkalemia, and hypotension. In general, avoid combined use of aliskiren with ACE inhibitors or ARBs, particularly in patients with creatinine clearance (CrCl) less than 60 mL/min [see Contraindications (4), Drug Interactions (7) and Clinical Studies (14.3)].

Hypersensitivity reactions such as anaphylactic reactions and angioedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported in patients treated with Aliskiren and has necessitated hospitalization and intubation. This may occur at any time during treatment and has occurred in patients with and without a history of angioedema with ACEIs or angiotensin receptor antagonists. Anaphylactic reactions have been reported from postmarketing experience with unknown frequency. If angioedema involves the throat, tongue, glottis or larynx, or if the patient has a history of upper respiratory surgery, airway obstruction may occur and be fatal. Patients who experience these effects, even without respiratory distress, require prolonged observation and appropriate monitoring measures since treatment with antihistamines and corticosteroids may not be sufficient to prevent respiratory involvement. Prompt administration of subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and measures to ensure a patent airway may be necessary.

Discontinue Aliskiren immediately in patients who develop anaphylactic reactions or angioedema, and do not readminister [see Dosage and Administration (2.1) and Contraindications (4)].

Symptomatic hypotension may occur after initiation of treatment with Aliskiren in patients with marked volume depletion, patients with salt depletion, or with combined use of aliskiren and other agents acting on the renin- angiotensin-aldosterone system (RAAS). The volume or salt depletion should be corrected prior to administration of Aliskiren, or the treatment should start under close medical supervision.

A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Monitor renal function periodically in patients treated with Aliskiren. Changes in renal function, including acute renal failure, can be caused by drugs that affect the RAAS. Patients whose renal function may depend in part on the activity of the RAAS (e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or patients receiving ARB, ACEI or nonsteroidal anti-inflammatory drug (NSAID), including selective Cyclooxygenase- 2 inhibitors (COX-2 inhibitors), therapy may be at particular risk for developing acute renal failure on Aliskiren [see Warnings and Precautions (5.2), Drug Interactions (7), Use in Specific Populations (8.6), and Clinical Studies (14.3)]. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function.

Monitor serum potassium periodically in patients receiving Aliskiren. Drugs that affect the RAAS can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes, combination use with ARBs or ACEIs [see Contraindications (4), Warnings and Precautions (5.2), and Clinical Studies (14.3)], NSAIDs, or potassium supplements or potassium sparing diuretics.

When aliskiren was given with cyclosporine or itraconazole, the blood concentrations of aliskiren were significantly increased. Avoid concomitant use of aliskiren with cyclosporine or itraconazole [see Drug Interactions (7)].

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Fetal Toxicity [see Warnings and Precautions (5.1)]
• Anaphylactic Reactions and Head and Neck Angioedema [see Warnings and Precautions (5.3)]
• Hypotension [see Warnings and Precautions (5.4)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse reactions have been reported in aliskiren postmarketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity: anaphylactic reactions and angioedema requiring airway management and hospitalization

Urticaria

Peripheral edema

Hepatic enzyme increase with clinical symptoms of hepatic dysfunction

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis

Pruritus

Erythema

Hyponatremia

Nausea, Vomiting

Cyclosporine: Avoid coadministration of cyclosporine with aliskiren [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)].

Itraconazole: Avoid coadministration of itraconazole with aliskiren [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)].

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) including selective Cyclooxygenase-2 inhibitors (COX-2 inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors with agents that affect the RAAS, including aliskiren, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving aliskiren and NSAID therapy.

The antihypertensive effect of aliskiren may be attenuated by NSAIDs.

Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS): The concomitant use of aliskiren with other agents acting on the RAAS such as ACEIs or ARBs is associated with an increased risk of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two drugs that inhibit the renin-angiotensin system do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of aliskiren with ACE inhibitors or ARBs, particularly in patients with CrCl less than 60 mL/min. Monitor blood pressure, renal function, and electrolytes in patients taking aliskiren and other agents that affect the RAAS [see Warnings and Precautions (5.4, 5.5, 5.6)].

The concomitant use of aliskiren with an ARB or an ACEI in diabetic patients is contraindicated [see Contraindications (4)].

Furosemide: Oral coadministration of aliskiren and furosemide reduced exposure to furosemide. Monitor diuretic effects when furosemide is coadministered with aliskiren.

There is no information regarding the presence of aliskiren in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including hypotension, hyperkalemia and renal impairment in nursing infants, advise a nursing woman that breastfeeding is not recommended during treatment with Aliskiren.

Safety and effectiveness have not been established in pediatric patients younger than 6 years.

The antihypertensive effects of Aliskiren have been evaluated in two randomized, double-blind clinical studies in pediatric patients 6 to 17 years of age [see Clinical Studies (14.4)]. The pharmacokinetics of Aliskiren have been evaluated in pediatric patients 6 to 17 years of age [see Pharmacokinetics, Special Populations, Pediatric (12.3)]. In this age group,the adverse event profile is expected to be similar to that in adults.

Preclinical studies indicate a potential for substantial increase in exposure to aliskiren in pediatric patients [see Nonclinical Toxicology (13.2)]. Because of the findings in these studies, Aliskiren is contraindicated in children less than 2 years of age and should not be used in children 2 to less than 6 years of age.

No data are available in pediatric patients with a glomerular filtration rate <30 mL/min/1.73 m².

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. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Safety and effectiveness of Aliskiren in patients with severe renal impairment [creatinine clearance (CrCl) less than 30 mL/min] have not been established as these patients were excluded in clinical trials [see Clinical Studies (14)].

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

Aliskiren is poorly dialyzed. Therefore, hemodialysis is not adequate to treat aliskiren overexposure [see Clinical Pharmacology (12.3)].

Aliskiren contains aliskiren hemifumarate, adirect renin inhibitor. 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 and its structural formula is:

Structural Formula (Aliskiren Tablets 1)

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.

Aliskiren is available as film-coated tablets, which contains 165.75 mg or 331.5 mg aliskiren hemifumerate (equivalent to 150 mg or 300 mg aliskiren) and the following excipients: crospovidone; magnesium stearate; microcrystalline cellulose; povidone; silica, colloidal anhydrous; hypromellose; macrogol; talc; iron oxide, black (E 172); iron oxide, red (E 172); titanium dioxide (E 171).

Aliskiren is available as 37.5 mg pellets for oral administration which contains the following excipients: basic butylated methacrylate copolymer, colloidal silicon dioxide, crospovidone, povidone, dibutyl sebacate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulphate. Each oral pellet contains 3.125 mg of aliskiren, equivalent to 3.45 mg of aliskiren hemifumarate. Each 37.5 mg dose of oral pellets is equivalent to 41.44 mg of aliskiren hemifumarate. The oral pellets are provided in a hypromellose capsule dispensing aid. The hypromellose capsule shell is not intended for administration.

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 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 ACEIs 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.

In placebo-controlled clinical trials, PRA was decreased in a range of 50% to 80%. This reduction in PRA was 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 poorly absorbed (bioavailability about 2.5%) with an approximate accumulation half-life of 24 hours. Steady state blood levels are reached in about 7 to 8 days.

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 greater than or equal to 750 mg/kg/day in both species, with a colonic adenoma identified in 1 rat and a cecal adenocarcinoma identified in another, rare tumors in the strain of rat studied. On a systemic exposure (AUC_0-24hr) basis, 1500 mg/kg/day in the rat is about 4 times and in the mouse about 1.5 times the maximum recommended human dose (MRHD) (300 mg aliskiren/day). Mucosal hyperplasia in the cecum or colon of rats was also observed at 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 MRHD of 300 mg Aliskiren/60 kg on a mg/m² basis.)

The antihypertensive effects of Aliskiren have been demonstrated in 6 randomized, double-blind, placebo-controlled 8- week clinical trials in patients with mild-to-moderate hypertension. The placebo response and placebo-subtracted changes from baseline in seated trough cuff blood pressure are shown in Table 2.

^*p value less than 0.05 versus placebo by ANCOVA with Dunnett's procedure for multiple comparisons
^†p value less than 0.05 versus placebo by ANCOVA for the pairwise comparison.

The studies included approximately 2,730 patients given doses of 75 to 600 mg of aliskiren and 1,231 patients given placebo. As shown in Table 1, there is some increase in response with administered dose in all studies, with reasonable effects seen at 150mg to 300 mg, and no clear further increases at 600 mg. A substantial proportion (85% to 90%) of the blood pressure-lowering effect was observed within 2 weeks of treatment. Studies with ambulatory blood pressure monitoring showed reasonable control throughout the interdosing interval; the ratios of mean daytime to mean nighttime ambulatory BP range from 0.6 to 0.9.

Patients in the placebo-controlled trials continued open-label aliskiren for up to 1 year. A persistent blood pressure- lowering effect was demonstrated by a randomized withdrawal study (patients randomized to continue drug or placebo), which showed a statistically significant difference between patients kept on aliskiren and those randomized to placebo. With cessation of treatment, blood pressure gradually returned toward baseline levels over a period of several weeks.

There was no evidence of rebound hypertension after abrupt cessation of therapy.

Aliskiren lowered blood pressure in all demographic subgroups, although black patients tended to have smaller reduction than Caucasians and Asians, as has been seen with ACEIs and ARBs.

There are no studies of Aliskiren or members of the direct renin inhibitors demonstrating reductions in cardiovascular risk in patients with hypertension.

Patients with diabetes with renal disease (defined either by the presence of albuminuria or reduced GFR) were randomized to aliskiren 300 mg daily (n=4296) or placebo (n=4310). All patients were receiving background therapy with an ARB or ACEI. The primary efficacy outcome was the time to the first event of the primary composite endpoint consisting of cardiovascular death, resuscitated sudden death, nonfatal myocardial infarction, nonfatal stroke, unplanned hospitalization for heart failure, onset of end stage renal disease, renal death, and doubling of serum creatinine concentration from baseline sustained for at least 1 month. After a median follow-up of about 32 months, the trial was terminated early for lack of efficacy. Higher risk of renal impairment, hypotension and hyperkalemia was observed in aliskiren compared to placebo-treated patients, as shown in Table 6.

The risk of stroke (3.4% aliskiren versus 2.7% placebo) and death (8.4% aliskiren versus 8.0% placebo) were also numerically higher in aliskiren treated patients.

The efficacy of aliskiren was evaluated in an 8-week randomized, double-blind trial in 267 pediatric hypertensive patients 6 to 17 years of age (Study CSPP100A2365; NCT01150357). The majority of patients (82%) had primary hypertension, 59% had a BMI ≥95^th percentile, 20% had an estimated GFR between 60 and 90 mL/min/1.73m² and < 2% had an estimated GFR < 60 mL/min/1.73m². The mean age was 11.8 years and 74% of patients were Caucasian. In the initial 4- week,dose-response phase of the trial patients were randomized to weight-based low, mid and high dosing groups as shown in the table 7 below. At the end of this phase, patients entered a 4-week randomized withdrawal phase in which they were re-randomized in each weight category in a 1:1 ratio to continue the same dose of aliskiren or take placebo.

During the initial dose-response phase, aliskiren reduced both systolic and diastolic blood pressure in a weight-based dose- dependent manner. Sitting systolic blood pressure, the trial's primary endpoint, was reduced by 4.8, 5.6 and 8.7 mmHg from baseline in the low, medium and high dose groups, respectively. In the randomized withdrawal phase , the mean difference between the high dose group of aliskiren and placebo in the mean change in sitting systolic blood pressure was -2.7 mmHg.

Following the 8-week trial, 208 subjects were enrolled in a 52-week extension trial in which patients were randomized in a 1:1 ratio (irrespective of whether they were on placebo or aliskiren at the end of the 8-week study) to receive either aliskiren or enalapril (CSPP100A2365E1; NCT01151410). The extension study included 3 dose levels based on weight; optional dose up-titrations were allowed during the study to control blood pressure as shown in table 8 below.

At the end of 52 weeks, reductions in blood pressure from baseline were similar in patients receiving aliskiren (7.6/3.9 mmHg) and enalapril (7.9/4.9 mmHg).

Aliskiren tablets are supplied as a light-pink, biconvex round tablet containing 150 mg of aliskiren, and as a light-red biconvex ovaloid tablet containing 300 mg of aliskiren. Tablets are imprinted with NVR on one side and IL, IU, on the other side of the 150 mg and 300 mg tablets, respectively.

All strengths are packaged in bottles as described below in Table 9.

Aliskiren Oral Pellets are supplied in size 0 capsules, each containing 12 white to yellowish round biconvex pellets. Each pellet contains 3.125 mg of aliskiren, equivalent to 3.453 mg of aliskiren hemifumarate. The capsule cap is transparent with a red arrow pointing to the top of the cap on the one side and imprinted “NVR 12” on the other side. The capsule body is transparent with a red arrow pointing to the bottom of the body of the capsule. Aliskiren 37.5 mg Oral pellets in capsules are packaged in child-resistant unit-dose blister packages (8 strips of 6 capsules).

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59 °F to 86°F) [See USP Controlled Room Temperature]. Protect from moisture.

Dispense blisters in original container.

Advise the patient to read the FDA-approved patient labeling (Patient Information) and Instructions for Use.