1.1 Hypertension

Tekturna is indicated for the treatment of hypertension in adults and in pediatric patients weighing 50 kg or greater who are at least 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 Tekturna.

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.

2.1 Recommended Dosage

In adult patients and in pediatric patients weighing 50 kg or greater who are at least 6 years of age, the recommended starting dose of Tekturna is 150 mg once daily. In patients whose blood pressure is not adequately controlled, the daily dose may be increased to 300 mg once daily. 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 dosage is substantially attained (85% to 90%) by 2 weeks.

2.2 Relationship to Meals

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

5.1 Fetal Toxicity

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 Tekturna as soon as possible [see Use in Specific Populations ( 8.1)].

5.2 Renal Impairment/Hyperkalemia/Hypotension when Tekturna is Given in Combination with ARBs or ACEIs

Tekturna 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 Tekturna 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)] .

5.3 Anaphylactic Reactions and Head and Neck Angioedema

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

5.4 Hypotension

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

5.5 Impaired Renal Function

Monitor renal function periodically in patients treated with Tekturna. 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 Tekturna [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.

5.6 Hyperkalemia

Monitor serum potassium periodically in patients receiving Tekturna. 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.

5.7 Cyclosporine or Itraconazole

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

6.1 Clinical Trials Experience

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.

6.2 Postmarketing Experience

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

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Tekturna is contraindicated in patients less than 2 years of age [see Contraindications ( 4)].

Tekturna is indicated for treatment of hypertension in pediatric patients 6 years of age and older weighing 50 kg or more. The safety and effectiveness of aliskiren have been established in pediatric patients 6 years of age and older weighing 20 kg or more, but Tekturna is not approved in patients 6 years of age and older weighing 20 kg to less than 50 kg because of the lack of an appropriate dosage form. Use of Tekturna in pediatric patients 6 years and older is supported by evidence from a pharmacokinetic trial and two randomized, double-blind clinical trials in pediatric patients with hypertension 6 years to 17 years of age weighing 20 kg or more [see Clinical Pharmacology ( 12.3), Clinical Studies ( 14.4) ].

The safety and effectiveness of Tekturna have not been established in pediatric patients younger than 6 years of age and patients less than 20 kg. Avoid use in patients 2 years to less than 6 years and patients weighing less than 20 kg due to the limited information about aliskiren metabolism and exposures in this age group. No data are available in pediatric patients weighing less than 20 kg or in pediatric patients with a glomerular filtration rate <30 mL/min/1.73 m 2.

8.5 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. 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.

8.6 Renal Impairment

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

12.1 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 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.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

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.

13.1 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 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 Tekturna/60 kg on a mg/m 2 basis.)

13.2 Animal Toxicology and/or Pharmacology

14.1 Aliskiren Monotherapy

The antihypertensive effects of Tekturna 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.

The studies included approximately 2,730 patients given doses of 75 mg (0.5 times the lowest recommended dosage) to 600 mg (twice the highest recommended dosage) of aliskiren and 1,231 patients given placebo. The recommended dosage of Tekturna is either 150 or 300 mg once daily [see Dosage and Administration ( 2.1)]. 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 Tekturna or members of the direct renin inhibitors demonstrating reductions in cardiovascular risk in patients with hypertension.

14.2 Aliskiren in Combination with Other Antihypertensives

14.3 Aliskiren in Patients with Diabetes Treated with ARB or ACEI (ALTITUDE study)

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.

14.4 Pediatric Hypertension

The efficacy of aliskiren was evaluated in an 8-week randomized, double-blind trial in 267 pediatric patients with hypertension 6 years 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/1.73m 2 and < 2% had an estimated GFR < 60 mL/min/1.73m 2. 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. 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 patients 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.

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).

Information for Patients

Pregnancy: Advise female patients of child-bearing age about the consequences of exposure to Tekturna during pregnancy. Discuss treatment options with women planning to become pregnant. Advise patients to report pregnancies to their physicians as soon as possible.

Lactation: Advise nursing women that breastfeeding is not recommended during treatment with Tekturna [see Use in Specific Populations ( 8.2)].

Anaphylactic Reactions and Angioedema: Advise patients to immediately report any signs or symptoms suggesting a severe allergic reaction (difficulty breathing or swallowing, tightness of the chest, hives, general rash, swelling, itching, dizziness, vomiting, or abdominal pain) or 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 physicians.

Angioedema, including laryngeal edema, may occur at any time during treatment with Tekturna.

Symptomatic Hypotension: Advise patients that lightheadedness can occur, especially during the first days of Tekturna therapy, and that it should be reported to the prescribing physician. Advise patients that if syncope occurs, Tekturna should be discontinued until the physician has been consulted.

Caution patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.

Potassium Supplements: Advise patients receiving Tekturna not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.

Relationship to Meals: Advise patients to establish a routine pattern for taking Tekturna with regard to meals. High-fat meals decrease absorption substantially.