Aliskiren Hemifumarate

1 INDICATIONS AND USAGE Tekturna is a renin inhibitor (RI) 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, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. ( 1.1 ) 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 DOSAGE AND ADMINISTRATION Starting dose (adults and pediatric patients): 150 mg once daily with a routine pattern with regard to meals. If blood pressure remains uncontrolled titrate up to 300 mg daily. ( 2.1 ) Majority of effect of given dose attained in 2 weeks. ( 2.1 ) 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 )].

6 ADVERSE REACTIONS Most common adverse reaction: diarrhea (incidence 2.3%) ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact LXO US Inc. at 1-844-800-8007 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Most common adverse reaction: diarrhea (incidence 2.3%) ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact LXO US Inc. at 1-844-800-8007 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Adult Hypertension Data described below reflect the evaluation of the safety of Tekturna 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 Tekturna 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 [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 ), and Clinical Studies ( 14.3 )]. Angioedema: Two cases of angioedema with respiratory symptoms were reported with Tekturna 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 Tekturna 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 Tekturna compared with 0.5% with placebo. In a long-term active-control study with Tekturna and hydrochlorothiazide (HCTZ) arms, the incidence of edema involving the face, hand or whole body was 0.4% in both treatment arms [see Warnings and Precautions ( 5.2 )]. Gastrointestinal: Tekturna 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: Tekturna was associated with a slight increase in cough in the placebo-controlled studies (1.1% for any Tekturna use versus 0.6% for placebo). In active-controlled trials with ACE inhibitor (ramipril, lisinopril) arms, the rates of cough for the Tekturna 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 Tekturna 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). Tekturna was discontinued and there was no rechallenge. Other adverse effects with increased rates for Tekturna 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 [see Clinical Studies ( 14.4 )] . 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 Tekturna in patients with hypertension not concomitantly treated with an ARB or ACEI. In multiple- dose studies in hypertensive patients, Tekturna 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 Tekturna alone versus 6% on placebo [see Warnings and Precautions ( 5.2 )] . 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) [see Contraindications ( 4 ) and Warnings and Precautions ( 5.6 )] . 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. 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

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. 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 C max 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. Drug Interactions The effect of coadministered drugs on the pharmacokinetics of aliskiren and vice versa, were studied in several single- and multiple-dose studies. Pharmacokinetic measures indicating the magnitude of these interactions are presented in Figure 1 (impact of coadministered drugs on aliskiren) and Figure 2 (impact of aliskiren on coadministered drugs). Figure 1: The Impact of Coadministered Drugs on the Pharmacokinetics of Aliskiren *Ketoconazole: A 400 mg once daily dose was not studied, but would be expected to increase aliskiren blood levels further. **Ramipril, valsartan, irbesartan: In general, avoid combined use of aliskiren with ACE inhibitors or ARBs, particularly in patients with CrCl less than 60 mL/min [see Drug Interactions ( 7 )]. Warfarin: There was no clinically significant effect of a single dose of warfarin 25 mg on the pharmacokinetics of aliskiren. Figure 2: The Impact of Aliskiren on the Pharmacokinetics of Coadministered Drugs *Furosemide: Patients receiving furosemide could find its effects diminished after starting aliskiren. In patients with heart failure, coadministration of aliskiren (300 mg/day) reduced plasma AUC and C max of oral furosemide (60 mg/day) by 17% and 27%, respectively, and reduced 24-hour urinary furosemide excretion by 29%. This change in exposure did not result in statistically significant difference in total urine volume and urinary sodium excretion over 24 hours. However, a transient decrease in urinary sodium excretion and urine volume effects up to 12 hours were observed when furosemide was coadministered with aliskiren 300 mg/day. **Ramipril, valsartan: In general, avoid combined use of aliskiren with ACE inhibitors or ARBs, particularly in patients with CrCl less than 60 mL/min [see Drug Interactions ( 7 )]. Figure 1 Figure 2 Specific Populations Renally Impaired Patients: Aliskiren was evaluated in adult patients with varying degrees of renal insufficiency. The rate and extent of exposure (AUC and C max ) of aliskiren in subjects with renal impairment did not show a consistent correlation with the severity of renal impairment. Adjustment of the starting dose is not required in these patients [see Warnings and Precautions ( 5.2 )] . The pharmacokinetics of aliskiren following administration of a single oral dose of 300 mg was evaluated in adult patients with End Stage Renal Disease (ESRD) undergoing hemodialysis. When compared to matched healthy subjects, changes in the rate and extent of aliskiren exposure (C max and AUC) in ESRD patients undergoing hemodialysis were not clinically significant. Timing of hemodialysis did not significantly alter the pharmacokinetics of aliskiren in ESRD patients. Therefore, no dose adjustment is warranted in ESRD patients receiving hemodialysis. Hepatically Impaired Patients: 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. Pediatric Patients: The pharmacokinetics of aliskiren were evaluated in an 8-day pharmacokinetic study in 39 pediatric patients with hypertension 6 years to 17 years of age. Aliskiren was given as daily doses of 2 mg/kg (0.67 times the lowest approved recommended dosage in a 50 kg pediatric patient) or 6 mg/kg (the highest recommended approved dosage in a 50 kg pediatric patient), administered as mini-tablets (3.125 mg oral pellets). The pharmacokinetic parameters of aliskiren were similar to those in adults, and the results of this study do not suggest that age or gender have any significant effect on aliskiren systemic exposure in patients 6 years to 17 years of age. Exposure decreased with increase in body weight. In an 8-week randomized double blind study with aliskiren monotherapy in 267 pediatric patients with hypertension 6 years to 17 years of age [see Clinical Studies ( 14.4 )] , fasting trough aliskiren concentrations at Day 28 demonstrated similar drug trough exposure levels to those observed in other trials using similar aliskiren doses in both adults and pediatric patients. Geriatric Patients: Exposure (measured by AUC) is increased in elderly patients 65 years and older. Adjustment of the starting dose is not required in these patients. Racial or Ethnic Groups : The pharmacokinetic differences between blacks, Caucasians, and Japanese are minimal.