Enviange

Hypertension

Enviange 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 Enviange.

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.

Adult Hypertension

The usual recommended starting dose of Enviange 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.

Pediatric Hypertension 6 To 17 Years Of Age

Enviange is contraindicated in children less than 2 years of age.Enviange 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 Table 1 for recommended dosage in pediatric patients 6 to 17 years of age. Table 1: Recommended dosage in pediatric patients 6 to 17 years of age

Administration Of Enviange Oral Pellets

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

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

Enviange 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, Enviange 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.

Relationship To Meals

Patients should establish a routine pattern for taking Enviange with regard to meals. High-fat meals decrease absorption substantially.

Do not use aliskiren with ARBs or ACEIs in patients with diabetes. Enviange is contraindicated in patients with known hypersensitivity to any of the components.

Enviange is contraindicated in pediatric patients less than 2 years of age.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 Enviange as soon as possible.

Renal Impairment/Hyperkalemia/Hypotension When Enviange Is Given In Combination With ARBs Or ACEIs

Enviange 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.

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 Enviange 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 Enviange immediately in patients who develop anaphylactic reactions or angioedema, and do not readminister.

Hypotension

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

Impaired Renal Function

Monitor renal function periodically in patients treated with Enviange. 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 Cyclooxygenase2 inhibitors (COX-2 inhibitors), therapy may be at particular risk for developing acute renal failure on Enviange. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function.

Hyperkalemia

Monitor serum potassium periodically in patients receiving Enviange. 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 , NSAIDs, or potassium supplements or potassium sparing diuretics.

Cyclosporine Or Itraconazole

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.

Patient Counseling Information

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

Information For Patients

Pregnancy

Advise female patients of child-bearing age about the consequences of exposure to Enviange 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 Enviange.

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 Enviange.

Symptomatic Hypotension

Advise patients that lightheadedness can occur, especially during the first days of Enviange therapy, and that it should be reported to the prescribing physician. Advise patients that if syncope occurs, Enviange 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 Enviange 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 Enviange with regard to meals. High-fat meals decrease absorption substantially.

Administration Of Oral Pellets

Advise the patient or caregiver not to swallow capsules containing Enviange oral pellets. Review administration instructions for Oral Pellets with the patient or caregiver.

Nonclinical Toxicology

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 (AUC0-24hr) 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 13week 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 Enviange/60 kg on a mg/m² basis.)

Use In Specific Populations

Pregnancy

Risk Summary

Enviange can cause fetal harm when administered to a pregnant woman. 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. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. When pregnancy is detected, discontinue Enviange as soon as possible.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major malformations and miscarriage in clinically recognized pregnancies is 2-4%, and 1520%, respectively.

Clinical Considerations

Disease-Associated Maternal And/Or Embryo/Fetal Risk

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Fetal/Neonatal Adverse Reactions

Use of drugs that act on the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, oligohydramnios, fetal lung hypoplasia and skeletal deformations, including skull hypoplasia, hypotension, and death. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.

In patients taking Enviange during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Enviange for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occur in neonates with a history of in utero exposure to Enviange, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function.

Data

Animal Data

In developmental toxicity studies, pregnant rats and rabbits received oral aliskiren hemifumarate during organogenesis at doses up to 20 and 7 times the maximum recommended human dose (MRHD) based on body surface area (mg/m²), respectively, in rats and rabbits. (Actual animal doses were up to 600 mg/kg/day in rats and up to 100 mg/kg/day in rabbits.) No teratogenicity was observed; however, fetal birth weight was decreased in rabbits at doses 3.2 times the MRHD based on body surface area (mg/m²). Aliskiren was present in placentas, amniotic fluid and fetuses of pregnant rabbits.

Lactation

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 Enviange.

Pediatric Use

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

The antihypertensive effects of Enviange have been evaluated in two randomized, double-blind clinical studies in pediatric patients 6 to 17 years of age. The pharmacokinetics of Enviange have been evaluated in pediatric patients 6 to 17 years of age. 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. Because of the findings in these studies,Enviange 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.

Neonates With A History Of In Utero Exposure To Enviange

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

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.

Renal Impairment

Safety and effectiveness of Enviange 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.

Clinical Trials Experience

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

• Fetal Toxicity
• Anaphylactic Reactions and Head and Neck Angioedema
• Hypotension

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.

Adult Hypertension

Data described below reflect the evaluation of the safety of Enviange in more than 6,460 patients, including over 1,740 treated for longer than 6 months, and more than 1,250 patients 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 Enviange versus 3.5% of patients given placebo. These data do not include information from the ALTITUDE study which evaluated the use of aliskiren in combination with ARBs or ACEIs.

Angioedema

Two cases of angioedema with respiratory symptoms were reported with Enviange 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 Enviange 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 Enviange compared with 0.5% with placebo. In a long-term active-control study with Enviange and hydrochlorothiazide (HCTZ) arms, the incidence of edema involving the face, hand or whole body was 0.4% in both treatment arms.

Gastrointestinal

Enviange produces dose-related gastrointestinal (GI) adverse reactions. 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 years and older) 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% to 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.

Cough

Enviange was associated with a slight increase in cough in the placebo-controlled studies (1.1% for any Enviange use versus 0.6% for placebo). In active-controlled trials with ACE inhibitor (ramipril, lisinopril) arms, the rates of cough for the Enviange arms were about one-third to one-half the rates in the ACE inhibitor arms.

Seizures

Single episodes of tonic-clonic seizures with loss of consciousness were reported in 2 patients treated with Enviange 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). Enviange was discontinued and there was no rechallenge.

Other adverse effects with increased rates for Enviange compared to placebo included rash (1% versus 0.3%), elevated uric acid (0.4% versus 0.1%), gout (0.2% versus 0.1%) and renal stones (0.2% versus 0%).

Aliskiren's effect on ECG intervals was 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.

Pediatric Hypertension

Aliskiren has been evaluated for safety in 267 pediatric hypertensive patients 6 to 17 years of age; including 208 patients treated for 52 weeks. These studies did not reveal any unanticipated adverse reactions. Adverse reactions in pediatric patients 6 years of age and older are expected to be similar to those seen in adults.

Clinical Laboratory Findings

In controlled clinical trials, clinically relevant changes in standard laboratory parameters were rarely associated with the administration of Enviange in patients with hypertension not concomitantly treated with an ARB or ACEI. In multiple-dose studies in hypertensive patients, Enviange had no clinically important effects on total cholesterol, HDL, fasting triglycerides, or fasting glucose.

Blood Urea Nitrogen, Creatinine

In patients with hypertension not concomitantly treated with an ARB or ACEI, minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 7% of patients treated with Enviange alone versus 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 ARBs, 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, versus 0% for placebo). No patients discontinued therapy due to anemia.

Serum Potassium

In patients with hypertension not concomitantly treated with an ARB or ACEI, increases in serum potassium greater than 5.5 mEq/L were infrequent (0.9% compared to 0.6% with placebo).

Serum Uric Acid

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

Creatine Kinase

Increases in creatine kinase of greater than 300% were recorded in about 1% of aliskiren monotherapy patients versus 0.5% of placebo patients. Five cases of creatine kinase rises, 3 leading to discontinuation and 1 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.

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

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.

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.

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 CYP3A4. Aliskiren does not inhibit the CYP450 isoenzymes (CYP 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) or induce CYP3A4.

Transporters

Pgp (MDR1/Mdr1a/1b) was found to be the major efflux system involved in intestinal absorption and elimination via biliary excretion 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.