FDA label a742bba8-ee3a-4e5b-b670-ea31c4633b3e

WARNING: AVOID USE IN PREGNANCY When pregnancy is detected, discontinue Tekturna as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. [See Warnings and Precautions (5.1)] WARNING: AVOID USE IN PREGNANCY See full prescribing information for complete boxed warning When pregnancy is detected, discontinue Tekturna as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1)

5 WARNINGS AND PRECAUTIONS Avoid neonatal/fetal exposure (5.1) Head and neck angioedema. Discontinue use of Tekturna and monitor until signs and symptoms resolve (5.2) Hypotension in volume and/or salt depleted patients: Correct imbalances before initiating therapy with Tekturna (5.3) Patients with severe renal dysfunction: Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances (5.4) Hyperkalemia: Caution should be exercised when co-administered with ACEI, potassium-sparing diuretics, potassium supplements or other potassium containing salt substitutes (5.5) 5.1 Fetal/neonatal morbidity and mortality Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)] . In several dozen published cases, ACE inhibitor use during the second and third trimesters of pregnancy was associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. In addition, first trimester use of ACE inhibitors has been associated with birth defects in retrospective data. 5.2 Head and Neck Angioedema Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has 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 ACE inhibitors or angiotensin receptor antagonists. 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 since treatment with antihistamines and corticosteroids may not be sufficient to prevent respiratory involvement. Prompt administration of subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 ml) and measures to ensure a patent airway may be necessary. Discontinue Tekturna immediately in patients who develop angioedema, and do not readminister. 5.3 Hypotension An excessive fall in blood pressure was rarely seen (0.1%) in patients with uncomplicated hypertension treated with Tekturna alone in controlled trials and in <1% during combination therapy with other antihypertensive agents. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those receiving high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Tekturna. This condition should be corrected prior to administration of Tekturna, or the treatment should start under close medical supervision. If an excessive fall in blood pressure occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. 5.4 Impaired Renal Function Patients with greater than moderate renal dysfunction (creatinine 1.7 mg/dL for women and 2.0 mg/dL for men and/or estimated GFR <30 ml/min), a history of dialysis, nephrotic syndrome, or renovascular hypertension were excluded from clinical trials of Tekturna in hypertension. Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances particularly in patients with severe renal impairment. 5.5 Hyperkalemia Increases in serum potassium >5.5 mEq/L were infrequent with Tekturna alone (0.9% compared to 0.6% with placebo). However, when used in combination with an ACE inhibitor in a diabetic population, increases in serum potassium were more frequent (5.5%). Routine monitoring of electrolytes and renal function is indicated in this population. Concomitant use of Tekturna with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other drugs that increase potassium levels may lead to increases in serum potassium. 5.6 Renal Artery Stenosis No data are available on the use of Tekturna in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. 5.7 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 [ see Drug Interactions ( 7 ) ].

6 ADVERSE REACTIONS Most common adverse reaction: diarrhea (incidence 2.3%) (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. 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 vs. 3.5% of patients given placebo. 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 involved 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 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) increases in diarrhea rates were evident starting at a dose of 150 mg daily, with rates for these subgroups at 150 mg comparable to those seen at 300 mg for men or younger patients (all rates about 2.0-2.3%). Other GI symptoms included abdominal pain, dyspepsia, and gastroesophageal reflux, although increased rates for abdominal pain and dyspepsia were distinguished from placebo only at 600 mg daily. Diarrhea and other GI symptoms were typically mild and rarely led to discontinuation. Cough: Tekturna was associated with a slight increase in cough in the placebo-controlled studies (1.1% for any Tekturna use vs. 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 two 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 re-challenge. The following adverse events occurred in placebo-controlled clinical trials at an incidence of more than 1% of patients treated with Tekturna, but also occurred at about the same or greater incidence in patients receiving placebo: headache, nasopharyngitis, dizziness, fatigue, upper respiratory tract infection, back pain and cough. Other adverse effects with increased rates for Tekturna compared to placebo included rash (1% vs. 0.3%), elevated uric acid (0.4% vs. 0.1%), gout (0.2% vs. 0.1%) and renal stones (0.2% vs. 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. Clinical Laboratory Findings In controlled clinical trials, clinically relevant changes in standard laboratory parameters were rarely associated with the administration of Tekturna. In multiple-dose studies in hypertensive patients, Tekturna had no clinically important effects on total cholesterol, HDL, fasting triglycerides, fasting glucose, or uric acid. Blood Urea Nitrogen, Creatinine : Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 7% of patients with essential hypertension treated with Tekturna alone vs. 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 angiotensin receptor blockers and may be mediated by reduction of angiotensin II which stimulates erythropoetin 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, vs 0% for placebo). No patients discontinued therapy due to anemia. Serum Potassium : Increases in serum potassium >5.5 mEq/L were infrequent in patients with essential hypertension treated with Tekturna alone (0.9% compared to 0.6% with placebo). However, when used in combination with an angiotensin-converting enzyme inhibitor (ACEI) in a diabetic population increases in serum potassium were more frequent (5.5%) and routine monitoring of electrolytes and renal function is indicated in this population. Serum Uric Acid : Aliskiren monotherapy produced small median increases in serum uric acid levels (about 6 μmol/L) while HCTZ produced larger increases (about 30 μmol/L). The combination of aliskiren with HCTZ appears to be additive (about 40 μmol/L increase). The increases in uric acid appear to lead to slight increases in uric acid-related AEs: elevated uric acid (0.4% vs 0.1%), gout (0.2% vs. 0.1%), and renal stones (0.2% vs 0%). Creatine Kinase : Increases in creatine kinase of >300% were recorded in about 1% of aliskiren monotherapy patients vs. 0.5% of placebo patients. Five cases of creatine kinase rises, three leading to discontinuation and one 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 post-marketing 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: angioedema requiring airway management and hospitalization Peripheral edema Blood creatinine increased