FDA label 3a41bc46-8bba-4c61-9299-3108f05a0d4d

WARNING: AVOID USE IN PREG NANCY When pregnancy is detected, discontinue Tekturna HCT as soon as possible. D rugs 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 When pregnancy is detected, discontinue Tekturna HCT as soon as possible. D rugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1)

5 WARNINGS AND PRECAUTIONS Head and Neck Angioedema: Discontinue Tekturna HCT and monitor until signs and symptoms resolve. (5.2) Hypotension in Volume- or Salt-Depleted Patients: Correct imbalances before initiating therapy with Tekturna HCT. (5.3) Patients with Severe Renal Impairment: Not recommended if GFR <30 mL/min. (5.4) Patients with Hepatic Impairment: Titrate slowly. (5.5) Hypersensitivity Reactions: May occur from HCTZ component (5.6) 5.1 Fetal/Neonatal Morbidity and Mortality Tekturna HCT can cause fetal harm when administered to a pregnant woman. 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. 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, apprise the patient of the potential hazard to the fetus. [ see Use in Specific Populations (8.1)] In several dozen published cases, ACE inhibitors 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. Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and possible other adverse reactions that have occurred in adults. 5.2 Head and Neck Angioedema Aliskiren 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 patient airway may be necessary. Discontinue Tekturna immediately in patients who develop angioedema, and do not readminister. 5. 3 Hypotension in Volume- and/or Salt-Depleted Patients An excessive fall in blood pressure (hypotension) was rarely seen (<1%) in patients with uncomplicated hypertension treated with Tekturna HCT in controlled trials. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. Correct these conditions prior to administration of Tekturna HCT, or the treatment should start under close medical supervision. If an excessive fall in blood pressure occurs, place the patient 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 Patients with Severe Renal Impairment Tekturna HCT In patients with severe renal impairment (GFR <30 mL/min), loop diuretics are preferred to thiazides, so Tekturna HCT is not recommended. H ydrochlorothiazide Uptitrate slowly;in patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function. 5. 5 Patients with Hepatic Impairment Hydrochlorothiazide Uptitrate slowly; minor alterations of fluid and electrolyte balance may precipitate hepatic coma. 5. 6 Hypersensitivity Reaction s Hydrochlorothiazide Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. 5. 7 Systemic Lupus Erythematosus Hydrochlorothiazide Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. 5. 8 Lithium Interaction Hydrochlorothiazide Lithium generally should not be given with thiazides [ see Drug Interaction (7) ] . 5. 9 Serum Electrolyte Abnormalitie s Tekturna HCT In the short-term controlled trials of various doses of Tekturna HCT the incidence of hypertensive patients who developed hypokalemia (serum potassium <3.5 mEq/L) was 2.2%; the incidence of hyperkalemia (serum potassium >5.5 mEq/L) was 0.8%. No patients discontinued due to increase or decrease of serum potassium. Periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. The intervals should be based on the history of electrolyte abnormalities in patients with aliskiren or hydrochlorothiazide monotherapy. Based on experience with the use of other substances that affect the renin-angiotensin system (RAS), concomitant use of Tekturna HCT with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other drugs that increase potassium levels may lead to increases in serum potassium. 5.10 Renal Artery Stenosis No data are available on the use of Tekturna HCT in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. 5.11 Cyclosporine Aliskiren When aliskiren was given with cyclosporine, the blood concentrations of aliskiren were significantly increased. Concomitant use of aliskiren with cyclosporine is not recommended [see Drug Interactions (7)] .

6 ADVERSE REACTIONS The most common adverse reactions (incidence ≥1.5% and more common than with placebo) are: dizziness and diarrhea. (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 Studies Experience The following serious adverse reactions are discussed in greater detail in other sections of the label: Risk of fetal/neonatal morbidity and mortality [ s ee Warnings and Precautions (5.1)] Head and neck angioedema [ s ee Warnings and Precautions (5.2)] Hypotension in volume- and/or salt-depleted patients [ s ee Warnings and Precautions (5.3)] 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. Tekturna HCT Tekturna HCT has been evaluated for safety in more than 2,700 patients, including over 700 treated for 6 months and 190 for over 1 year. In placebo-controlled clinical trials, discontinuation of therapy due to a clinical adverse event (including uncontrolled hypertension) occurred in 2.7% of patients treated with Tekturna HCT versus 3.6% of patients given placebo. Adverse events in placebo-controlled trials that occurred in at least 1% of patients treated with Tekturna HCT and at a higher incidence than placebo included dizziness (2.3% vs. 1%), influenza (2.3% vs. 1.6%), diarrhea (1.6% vs. 0.5%), cough (1.3% vs. 0.5%), vertigo (1.2% vs. 0.5%), asthenia (1.2% vs. 0%), and arthralgia (1% vs. 0.5%). A liskiren Aliskiren has been evaluated for safety in 6,460 patients, including 1,740 treated for longer than 6 months, and 1,250 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 aliskiren, versus 3.5% of patients given placebo. Two cases of angioedema with respiratory symptoms were reported with aliskiren 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 aliskiren 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 aliskiren compared with 0.5% with placebo. In a long-term active-controlled study with aliskiren and HCTZ arms, the incidence of edema involving the face, hands, or whole body was 0.4% in both treatment arms. Aliskiren 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% 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. Aliskiren was associated with a slight increase in cough in the placebo-controlled studies (1.1% for any aliskiren use vs. 0.6% for placebo). In active-controlled trials with ACE inhibitor (ramipril, lisinopril) arms, the rates of cough for the aliskiren arms were about one-third to one-half the rates in the ACE inhibitor arms. Other adverse reactions with increased rates for aliskiren 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%). Single episodes of tonic-clonic seizures with loss of consciousness were reported in two patients treated with aliskiren in the clinical trials. One patient had 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. Aliskiren was discontinued and there was no rechallenge in either case. The following adverse events occurred in placebo-controlled clinical trials at an incidence of more than 1% of patients treated with aliskiren, 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. No clinically meaningful changes in vital signs or in ECG (including QTc interval) were observed in patients treated with aliskiren. H ydrochlorothiazide Other adverse reactions that have been reported with hydrochlorothiazide, without regard to causality, are listed below: B ody As A Whole: weakness Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia; Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions Metabolic: hyperglycemia, glycosuria, hyperuricemia Musculoskeletal: muscle spasm Nervous System/Psychiatric: restlessness Renal: renal failure, renal dysfunction, interstitial nephritis Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis Special Senses: transient blurred vision, xanthopsia 6.2 Clinical Laboratory Test Abnormalities In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Tekturna HCT. B lood Urea N itrogen (BUN)/Creatinine: Elevations (greater than 50% increase) in BUN and creatinine occurred in 11.8% and 0.9%, respectively, of patients taking Tekturna HCT, and 7% and 1.1%, respectively, of patients given placebo in short-term controlled clinical trials. No patients were discontinued due to an increase in either BUN or creatinine. H emoglobin and Hematocrit: A greater than 20% decrease in hemoglobin and hematocrit were observed in <0.1% and 0.1%, respectively, of patients treated with Tekturna HCT, compared with 0% in placebo-treated patients. No patients were discontinued due to anemia. L iver Function T ests: Occasional elevations (greater than 150%) in ALT (SGPT) were observed in 1.2% of patients treated with Tekturna HCT, compared with 0% in placebo-treated patients. No patients were discontinued due to abnormal liver function tests. S erum Uric Acid: Uric acid related abnormalities were more commonly observed in patients treated with Tekturna HCT, compared with placebo; 2.2% versus 0% had a uric acid increase >50% from baseline; gout and renal stones were less commonly observed. S erum Electrolytes: [ See Warnings and Precautions (5. 8 ) .] 6.3 Post- M arketing 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 reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity: angioedema requiring airway management and hospitalization Peripheral edema