Irbesartan

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue irbesartan as soon as possible [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ]. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ]. WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning. When pregnancy is detected, discontinue irbesartan 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 Hypotension: Correct volume or salt depletion prior to administration. ( 5.2 ) Monitor renal function and serum potassium. ( 5.3 ) 5.1 Fetal Toxicity Irbesartan tablets can cause fetal harm when administered to a pregnant woman. 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 irbesartan as soon as possible [see Use in Specific Populations (8.1) ]. 5.2 Hypotension in Volume or Salt-Depleted Patients In patients with an activated renin-angiotensin system, such as volume or salt-depleted patients (e.g. those being treated with high doses of diuretics), symptomatic hypotension may occur after initialization of treatment with irbesartan. Correct volume or salt depletion prior to administration of irbesartan or use a lower starting dose [see Dosage and Administration (2.4) ]. 5.3 Impaired Renal Function Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe heart failure, or volume depletion) may be at particular risk of developing acute renal failure or death on irbesartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on irbesartan [see Drug Interactions (7.3) ].

6 ADVERSE REACTIONS The following important adverse reactions are described elsewhere in the labeling: Hypotension in Volume or Salt-depleted Patients [see Warnings and Precautions (5.2) ] Impaired Renal Function [see Warnings and Precautions (5.3) ] Nephropathy in type 2 diabetic patients: The most common adverse reactions which were more frequent than placebo were hyperkalemia, dizziness, orthostatic dizziness, and orthostatic hypotension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ScieGen Pharmaceuticals, Inc. at 1-855-724-3436 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 the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Hypertension Irbesartan has been evaluated for safety in more than 4,300 patients with hypertension and about 5,000 subjects overall. This experience includes 1,303 patients treated for over 6 months and 407 patients for 1 year or more. In placebo-controlled clinical trials, the following adverse reactions were reported in at least 1% of patients treated with irbesartan (n=1,965) and at a higher incidence versus placebo (n=641), excluding those too general to be informative and those not reasonably associated with the use of drug because they were associated with the condition being treated or are very common in the treated population, include: diarrhea (3% vs 2%), dyspepsia/heartburn (2% vs 1%), and fatigue (4% vs 3%). Irbesartan use was not associated with an increased incidence of dry cough, as is typically associated with ACE inhibitor use. In placebo-controlled studies, the incidence of cough in irbesartan-treated patients was 2.8% versus 2.7% in patients receiving placebo. Nephropathy in Type 2 Diabetic Patients Hyperkalemia: In the Irbesartan Diabetic Nephropathy Trial (IDNT) (proteinuria ≥900 mg/day, and serum creatinine ranging from 1.0 mg/dL to 3.0 mg/dL), the percent of patients with potassium >6 mEq/L was 18.6% in the irbesartan group versus 6.0% in the placebo group. Discontinuations due to hyperkalemia in the irbesartan group were 2.1% versus 0.4% in the placebo group. In IDNT, the adverse reactions were similar to those seen in patients with hypertension with the exception of an increased incidence of orthostatic symptoms which occurred more frequently in the irbesartan versus placebo group: dizziness (10.2% vs 6.0%), orthostatic dizziness (5.4% vs 2.7%) and orthostatic hypotension (5.4% vs 3.2%). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of irbesartan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a causal relationship to drug exposure. Urticaria; angioedema (involving swelling of the face, lips, pharynx, and/or tongue); anaphylactic reaction including anaphylactic shock; increased liver function tests; jaundice; hepatitis; hyperkalemia; thrombocytopenia; increased CPK; tinnitus.