Aliskiren

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue Aliskiren 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 Aliskiren 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. ( 5.6 ) 5.1 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 Aliskiren as soon as possible [see Use in Specific Populations ( 8.1 )]. 5.2 Renal Impairment/Hyperkalemia/Hypotension when Aliskiren is Given in Combination with ARBs or ACEIs Aliskiren 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 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 Aliskiren 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 Aliskiren immediately in patients who develop anaphylactic reactions or angioedema, and do not readminister [see Dosage and Administration ( 2.1 ) and Contraindications ( 4 )]. 5.4 Hypotension Symptomatic hypotension may occur after initiation of treatment with Aliskiren 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 Aliskiren, 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 Aliskiren. 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 Cyclooxygenase- 2 inhibitors (COX-2 inhibitors), therapy may be at particular risk for developing acute renal failure on Aliskiren [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7 ), Use in Specific Populations ( 8.6 ), and Clinical Studies ( 14.3 )] . Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function. 5.6 Hyperkalemia 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 ( 14.3 )] , NSAIDs, or potassium supplements or potassium sparing diuretics. 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 Noden Pharma USA 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 Aliskiren 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 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 ( 14.3 )]. Angioedema: 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-control study with Aliskiren 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: 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 2.0% 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: 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. Seizures: Single episodes of tonic-clonic seizures with loss of consciousness were reported in 2 patients treated with Aliskiren 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). Aliskiren was discontinued and there was no rechallenge. Other adverse effects with increased rates for Aliskiren 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 Aliskiren in patients with hypertension not concomitantly treated with an ARB or ACEI. In multiple- dose studies in hypertensive patients, Aliskiren 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 Aliskiren 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