FDA label ed9274e4-086a-0713-e053-2a95a90ae88d

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue Tekturna HCT as soon as possible. ( 5.1 , 8.1 ) Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. ( 5.1 , 8.1 ) WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning. When pregnancy is detected, discontinue Tekturna HCT as soon as possible. ( 5.1 , 8.1 ) Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. ( 5.1 , 8.1 )

5 WARNINGS AND PRECAUTIONS Avoid concomitant use with ARBs or ACEIs particularly in patients with renal impairment [creatinine clearance (CrCl) <60 mL/min]. ( 5.2 , 5.4 ) Anaphylactic Reactions and Head and Neck Angioedema. ( 5.3 ) Hypotension: Correct imbalances in volume and/or salt-depleted patients. ( 5.4 ) Impaired Renal Function: Monitor serum creatinine periodically. ( 5.5 ) Hyperkalemia: Monitor potassium levels periodically. ( 5.8 ) Acute Myopia and Secondary Angle Closure Glaucoma. ( 5.10 ) 5.1 Fetal Toxicity Aliskiren 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 HCT as soon as possible [see Use in Specific Populations ( 8.1 )]. Hydrochlorothiazide 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 [see Use in Specific Populations ( 8.1 )]. 5.2 Renal Impairment/Hyperkalemia/Hypotension when Tekturna HCT is Given in Combination with ARBs or ACEIs Tekturna HCT 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 [see Contraindications ( 4 ), Drug Interactions ( 7 ) and Clinical Studies ( 14.3 )] . 5.3 Anaphylactic Reactions and Head and Neck Angioedema Aliskiren 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 HCT immediately in patients who develop anaphylactic reactions or angioedema, and do not readminister [see Contraindications ( 4 )] . 5.4 Hypotension Symptomatic hypotension may occur after initiation of treatment with Tekturna HCT in patients with marked volume depletion, patients with salt depletion, or with combined use of aliskiren and other agents acting on the renin-angiotensin-aldosterone system (RAAS). The volume or salt depletion should be corrected prior to administration of Tekturna HCT, 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 HCT. Changes in renal function, including acute renal failure, can be caused by drugs that affect the RAAS and by diuretics. 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 of developing acute renal failure on Tekturna HCT [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7 ), and Clinical Studies ( 14.4 )] . Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Tekturna HCT. 5.6 Hypersensitivity Reactions Hydrochlorothiazide (HCTZ) Hypersensitivity reactions to HCTZ 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 (HCTZ) Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. 5.8 Serum Electrolyte Abnormalities Tekturna HCT In the short-term controlled trials of various doses of Tekturna HCT, in patients with hypertension not concomitantly treated with an ARB or ACEI, the incidence of hypertensive patients who developed hypokalemia (serum potassium less than 3.5 mEq/L) was 2.2%; the incidence of hyperkalemia (serum potassium greater than 5.5 mEq/L) was 0.8%. No patients discontinued due to increase or decrease of serum potassium. Aliskiren Monitor serum potassium periodically in patients receiving aliskiren. 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 ( 14.4 )], NSAIDs, including selective Cyclooxygenase-2 inhibitors (COX-2 inhibitors), or potassium supplements or potassium-sparing diuretics. Hydrochlorothiazide (HCTZ) HCTZ can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. If hypokalemia is accompanied by clinical signs (e.g., muscular weakness, paresis, or ECG alterations), Tekturna HCT should be discontinued. Correction of hypokalemia and any coexisting hypomagnesemia is recommended prior to the initiation of thiazides. 5.9 Cyclosporine or Itraconazole Aliskiren 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 )] . 5.10 Acute Myopia and Secondary Angle-Closure Glaucoma HCTZ, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle- closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue HCTZ as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy. 5.11 Metabolic Disturbances Hydrochlorothiazide (HCTZ) HCTZ may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. HCTZ may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. HCTZ decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving Tekturna HCT.

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 Noden Pharma USA Inc. at 1-844-399-5701 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: 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. 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% versus 1%), influenza (2.3% versus 1.6%), diarrhea (1.6% versus 0.5%), cough (1.3% versus 0.5%), vertigo (1.2% versus 0.5%), asthenia (1.2% versus 0%), and arthralgia (1% versus 0.5%). Aliskiren 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. 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 ( 14.4 )]. 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 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% 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 versus 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% versus 0.3%) and renal stones (0.2% versus 0%). Single episodes of tonic-clonic seizures with loss of consciousness were reported in 2 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. No clinically meaningful changes in vital signs or in ECG (including QTc interval) were observed in patients treated with aliskiren. Hydrochlorothiazide (HCTZ) Other adverse reactions that have been reported with HCTZ, without regard to causality, are listed below: Body 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 Clinical Laboratory Test Abnormalities In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Tekturna HCT in patients with hypertension not concomitantly treated with an ARB or ACEI. Blood Urea Nitrogen (BUN)/Creatinine: In patients with hypertension not concomitantly treated with an ARB or ACEI, 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. Hemoglobin 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. Liver Function Tests: 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. 6.2 Post-Marketing Experience The following adverse reactions have been reported in aliskiren or hydrochlorothiazide 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. Aliskiren 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. Hydrochlorothiazide Acute renal failure, renal disorder, aplastic anemia, erythema mutliforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma, bone marrow failure, worsening of diabetes control, hypokalemia, blood lipids increased, hyponatremia, hypomagnesemia, hypercalcemia, hyperchloremic alkalosis, impotence, visual impairment. Pathological changes in the parathyroid gland of patients with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. If hypercalcemia occurs, further diagnostic evaluation is necessary. Non-melanoma Skin Cancer: Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.