Avapro

1 INDICATIONS AND USAGE AVAPRO is an angiotensin II receptor blocker (ARB) indicated for: Treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. ( 1.1 ) Treatment of diabetic nephropathy in hypertensive patients with type 2 diabetes, an elevated serum creatinine, and proteinuria. ( 1.2 ) 1.1 Hypertension AVAPRO ® is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular (CV) events, primarily strokes and myocardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. AVAPRO may be used alone or in combination with other antihypertensive agents. 1.2 Nephropathy in Type 2 Diabetic Patients AVAPRO is indicated for the treatment of diabetic nephropathy in patients with type 2 diabetes and hypertension, an elevated serum creatinine, and proteinuria (>300 mg/day). In this population, AVAPRO reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation) [see Clinical Studies (14.2) ] .

2 DOSAGE AND ADMINISTRATION Indication Dose Hypertension ( 2.2 ) 150 to 300 mg once daily Diabetic Nephropathy ( 2.3 ) 300 mg once daily 2.1 General Considerations AVAPRO may be administered with other antihypertensive agents and with or without food. 2.2 Hypertension The recommended initial dose of AVAPRO is 150 mg once daily. The dosage can be increased to a maximum dose of 300 mg once daily as needed to control blood pressure [see Clinical Studies (14.1) ] . 2.3 Nephropathy in Type 2 Diabetic Patients The recommended dose is 300 mg once daily [see Clinical Studies (14.2) ] . 2.4 Dose Adjustment in Volume and Salt-Depleted Patients The recommended initial dose is 75 mg once daily in patients with depletion of intravascular volume or salt (e.g., patients treated vigorously with diuretics or on hemodialysis) [see Warnings and Precautions (5.2) ] .

4 CONTRAINDICATIONS AVAPRO is contraindicated in patients who are hypersensitive to any component of this product. Do not coadminister aliskiren with AVAPRO in patients with diabetes. Hypersensitivity to any component of this product. ( 4 ) Coadministration with aliskiren in patients with diabetes. ( 4 )

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 AVAPRO 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 AVAPRO 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 AVAPRO. Correct volume or salt depletion prior to administration of AVAPRO 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 AVAPRO. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on AVAPRO [see Drug Interactions (7.3) ] .

7 DRUG INTERACTIONS Lithium: Risk of lithium toxicity. ( 7 ) Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and COX-2 inhibitors: Increased risk of renal impairment. Reduced antihypertensive effects. ( 7 ) Dual blockade of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia. ( 7 ) 7.1 Agents Increasing Serum Potassium Coadministration of AVAPRO with other drugs that raise serum potassium levels may result in hyperkalemia, sometimes severe. Monitor serum potassium in such patients. 7.2 Lithium Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of irbesartan and lithium. Monitor lithium levels in patients receiving irbesartan and lithium. 7.3 Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists (including irbesartan) may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving irbesartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including irbesartan, may be attenuated by NSAIDs including selective COX-2 inhibitors. 7.4 Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on AVAPRO and other agents that affect the RAS. Do not coadminister aliskiren with AVAPRO in patients with diabetes. Avoid use of aliskiren with AVAPRO in patients with renal impairment (GFR <60 mL/min).

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 sanofi-aventis U.S. LLC at 1-800-633-1610 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 AVAPRO has been evaluated for safety in more than 4300 patients with hypertension and about 5000 subjects overall. This experience includes 1303 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 AVAPRO (n=1965) 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 1.0–3.0 mg/dL), the percent of patients with potassium >6 mEq/L was 18.6% in the AVAPRO group versus 6.0% in the placebo group. Discontinuations due to hyperkalemia in the AVAPRO 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 AVAPRO 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 AVAPRO. 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. Blood and lymphatic system: Anemia, Thrombocytopenia Ear and labyrinth: Tinnitus Gastrointestinal: Intestinal angioedema Hepatobiliary: Hepatitis, Jaundice Immune system: Anaphylactic reaction including anaphylactic shock Investigations: Increased liver function tests, Increased CPK (Creatine Phosphokinase) Metabolism and nutrition: Hyperkalemia, Hypoglycemia in diabetic patients Skin and subcutaneous tissue: Urticaria, Angioedema (involving swelling of the face, lips, pharynx, and/or tongue)

8.1 Pregnancy Risk Summary AVAPRO 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 [see Clinical Considerations ] . Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. When pregnancy is detected, discontinue AVAPRO as soon as possible. All pregnancies have a background risk of birth defect, loss or other adverse outcomes regardless of drug exposure. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo-fetal risk Hypertension in pregnancy increases the maternal risk for preeclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and postpartum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/neonatal adverse reactions Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is observed, consider alternative treatment. Closely observe infants with histories of in utero exposure to AVAPRO for hypotension, oliguria, and hyperkalemia and other symptoms of renal impairment. In neonates with a history of in utero exposure to AVAPRO, if oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. Data Animal data Irbesartan crosses the placenta in rats and rabbits. In female rats given irbesartan prior to mating through gestation and lactation at oral doses of 50, 180, or 650 mg/kg/day (1.6 to 21.1 times the maximum recommended human dose (MRHD) based on body surface area), fetuses examined on Gestation Day 20 showed increased incidences of hydroureter and renal pelvic cavitation and/or absence of renal papilla in all irbesartan-treated groups. Subcutaneous edema also occurred in fetuses at maternal doses ≥180 mg/kg/day (5.8 times the MRHD). These anomalies occurred when female rats received irbesartan from prior to mating through Day 20 of gestation but were not observed in pups postnatally in the same study, or when irbesartan was given to pregnant rats only during organogenesis (Gestation Day 6 through Gestation Day 15) at oral doses from 50 to 450 mg/kg/day (up to 14.6 times the MRHD). In addition, no adverse effects on kidney development were observed in pups from dams given irbesartan from Gestation Day 15 through Lactation Day 24 at doses of 50, 180, or 650 mg/kg/day (up to 21.1 times the MRHD). The observed effects are believed to be late gestational effects of the drug. Pregnant rabbits given oral doses of irbesartan of 30 mg/kg/day (1.9 times the MRHD based on body surface area) experienced a high rate of maternal mortality and abortion. Surviving females had a slight increase in early resorptions and a corresponding decrease in live fetuses. Radioactivity was present in the rat and rabbit fetuses during late gestation following oral doses of radiolabeled irbesartan.