Avalide

1 INDICATIONS AND USAGE AVALIDE ® (irbesartan and hydrochlorothiazide) tablets are indicated for the treatment of hypertension. AVALIDE may be used in patients whose blood pressure is not adequately controlled on monotherapy. AVALIDE may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals. The choice of AVALIDE as initial therapy for hypertension should be based on an assessment of potential benefits and risks. Patients with stage 2 (moderate or severe) hypertension are at relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. The decision to use a combination as initial therapy should be individualized and may be shaped by considerations such as the baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared with monotherapy. Data from Studies V and VI [see Clinical Studies (14.2) ] provide estimates of the probability of reaching a blood pressure goal with AVALIDE compared to irbesartan or hydrochlorothiazide (HCTZ) monotherapy. The relationship between baseline blood pressure and achievement of a SeSBP <140 or <130 mmHg or SeDBP <90 or <80 mmHg in patients treated with AVALIDE compared to patients treated with irbesartan or HCTZ monotherapy are shown in Figures 1a through 2b. Figure 1a: Probability of Achieving SBP <140 mmHg in Patients from Initial Therapy Studies V (Week 8) and VI (Week 7) For all probability curves, patients without blood pressure measurements at Week 7 (Study VI) and Week 8 (Study V) were counted as not reaching goal (intent-to-treat analysis). Figure 1b: Probability of Achieving SBP <130 mmHg in Patients from Initial Therapy Studies V (Week 8) and VI (Week 7) Figure 2a: Probability of Achieving DBP <90 mmHg in Patients from Initial Therapy Studies V (Week 8) and VI (Week 7) Figure 2b: Probability of Achieving DBP <80 mmHg in Patients from Initial Therapy Studies V (Week 8) and VI (Week 7) The above graphs provide a rough approximation of the likelihood of reaching a targeted blood pressure goal (e.g., Week 8 sitting systolic blood pressure ≤140 mmHg) for the treatment groups. The curve of each treatment group in each study was estimated by logistic regression modeling from all available data of that treatment group. The estimated likelihood at the right tail of each curve is less reliable due to small numbers of subjects with high baseline blood pressures. For example, a patient with a blood pressure of 180/105 mmHg has about a 25% likelihood of achieving a goal of <140 mmHg (systolic) and 50% likelihood of achieving <90 mmHg (diastolic) on irbesartan alone (and lower still likelihoods on HCTZ alone). The likelihood of achieving these goals on AVALIDE rises to about 40% (systolic) or 70% (diastolic). AVALIDE is a combination of irbesartan, an angiotensin II receptor antagonist, and hydrochlorothiazide, a thiazide diuretic, indicated for hypertension: In patients not adequately controlled with monotherapy. ( 1 ) As initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals. ( 1 ) Figure 1a Figure 1b Figure 2a Figure 2b

2 DOSAGE AND ADMINISTRATION General Considerations Maximum effects within 2 to 4 weeks after dose change. ( 2.1 ) Renal impairment: Not recommended for patients with severe renal impairment (creatinine clearance 30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so AVALIDE is not recommended. Hepatic Impairment No dosage adjustment is necessary in patients with hepatic impairment. 2.2 Add-On Therapy In patients not controlled on monotherapy with irbesartan or hydrochlorothiazide, the recommended doses of AVALIDE, in order of increasing mean effect, are (irbesartan and hydrochlorothiazide) 150/12.5 mg, 300/12.5 mg, and 300/25 mg. The largest incremental effect will likely be in the transition from monotherapy to 150/12.5 mg. [See Clinical Studies (14.2) .] 2.3 Replacement Therapy AVALIDE may be substituted for the titrated components. 2.4 Initial Therapy The usual starting dose is AVALIDE 150/12.5 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of 300/25 mg once daily as needed to control blood pressure [see Clinical Studies (14.2) ] . AVALIDE is not recommended as initial therapy in patients with intravascular volume depletion [see Warnings and Precautions (5.2) ] .

3 DOSAGE FORMS AND STRENGTHS AVALIDE ® (irbesartan and hydrochlorothiazide) 150/12.5 mg and 300/12.5 mg film-coated tablets are peach, biconvex, and oval with a heart debossed on one side and "2875" or "2876" on the reverse side, respectively. 150 mg irbesartan/12.5 mg hydrochlorothiazide tablets ( 3 ) 300 mg irbesartan/12.5 mg hydrochlorothiazide tablets ( 3 )

4 CONTRAINDICATIONS AVALIDE is contraindicated in patients who are hypersensitive to any component of this product. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Do not coadminister aliskiren with AVALIDE in patients with diabetes [see Drug Interactions (7) ] . Hypersensitivity to any component of this product. ( 4 ) Anuria. ( 4 ) Hypersensitivity to sulfonamide-derived drugs. ( 4 ) Do not coadminister aliskiren with AVALIDE in patients with diabetes. ( 4 )

6 ADVERSE REACTIONS Most common adverse events (≥5% on AVALIDE and more often than on placebo) are dizziness, fatigue, and musculoskeletal pain. ( 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. Irbesartan and Hydrochlorothiazide AVALIDE tablets have been evaluated for safety in 1694 patients treated for essential hypertension in 6 clinical trials. In Studies I through IV with AVALIDE, no adverse events peculiar to this combination drug product have been observed. Adverse events have been limited to those that were reported previously with irbesartan or hydrochlorothiazide (HCTZ). The overall incidence of adverse events was similar with the combination and placebo. In general, treatment with AVALIDE was well tolerated. For the most part, adverse events have been mild and transient in nature and have not required discontinuation of therapy. In controlled clinical trials, discontinuation of AVALIDE therapy due to clinical adverse events was required in only 3.6%. This incidence was significantly less (p=0.023) than the 6.8% of patients treated with placebo who discontinued therapy. In these double-blind controlled clinical trials, the following adverse events reported with AVALIDE occurred in ≥1% of patients, and more often on the irbesartan and hydrochlorothiazide combination than on placebo, regardless of drug relationship: Irbesartan/HCTZ (n=898) (%) Placebo (n=236) (%) Irbesartan (n=400) (%) HCTZ (n=380) (%) Body as a Whole Chest Pain 2 1 2 2 Fatigue 6 3 4 3 Influenza 3 1 2 2 Cardiovascular Edema 3 3 2 2 Tachycardia 1 0 1 1 Gastrointestinal Abdominal Pain 2 1 2 2 Dyspepsia/heartburn 2 1 0 2 Nausea/vomiting 3 0 2 2 Immunology Allergy 1 0 1 1 Musculoskeletal Musculoskeletal Pain 6 5 6 10 Nervous System Dizziness 8 4 6 5 Dizziness Orthostatic 1 0 1 1 Renal/Genitourinary Abnormality Urination 2 1 1 2 The following adverse events were also reported at a rate of 1% or greater, but were as, or more, common in the placebo group: headache, sinus abnormality, cough, URI, pharyngitis, diarrhea, rhinitis, urinary tract infection, rash, anxiety/nervousness, and muscle cramp. Adverse events occurred at about the same rates in men and women, older and younger patients, and black and non-black patients. Adverse events in Studies V and VI were similar to those described above in Studies I through IV. Irbesartan Other adverse events that have been reported with irbesartan, without regard to causality, are listed below: Body as a Whole: fever, chills, orthostatic effects, facial edema, upper extremity edema Cardiovascular: flushing, hypertension, cardiac murmur, myocardial infarction, angina pectoris, hypotension, syncope, arrhythmic/conduction disorder, cardiorespiratory arrest, heart failure, hypertensive crisis Dermatologic: pruritus, dermatitis, ecchymosis, erythema face, urticaria Endocrine/Metabolic/Electrolyte Imbalances: sexual dysfunction, libido change, gout Gastrointestinal: diarrhea, constipation, gastroenteritis, flatulence, abdominal distention Musculoskeletal/Connective Tissue: musculoskeletal trauma, extremity swelling, muscle cramp, arthritis, muscle ache, musculoskeletal chest pain, joint stiffness, bursitis, muscle weakness Nervous System: anxiety/nervousness, sleep disturbance, numbness, somnolence, vertigo, emotional disturbance, depression, paresthesia, tremor, transient ischemic attack, cerebrovascular accident Renal/Genitourinary: prostate disorder Res …

7 DRUG INTERACTIONS NSAIDs and selective COX-2 inhibitors: Can reduce diuretic, natriuretic of diuretic, may lead to increased risk of renal impairment and reduced antihypertensive effect. Monitor renal function periodically. ( 7 ) Dual blockade of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia. ( 7 ) Antidiabetic drugs: Dosage adjustment of antidiabetic may be required. ( 7 ) Cholestyramine and colestipol: Reduced absorption of thiazides. ( 7 ) Lithium: Increases in serum lithium concentrations and lithium toxicity. ( 7 ) Carbamazepine: Increased risk of hyponatremia. ( 7 ) 7.1 Nonsteroidal Anti-inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) Irbesartan 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. Therefore, monitor renal function and blood pressure periodically in patients receiving irbesartan and NSAID therapy. Hydrochlorothiazide Administration of a nonsteroidal anti-inflammatory agent, including a selective COX-2 inhibitor can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Therefore, when AVALIDE (irbesartan and hydrochlorothiazide) tablets and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. 7.2 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. Closely monitor blood pressure, renal function, and electrolytes in patients on AVALIDE and other agents that affect the RAS. In most patients no benefit has been associated with using two RAS inhibitors concomitantly. In general, avoid combined use of RAS inhibitors. Do not coadminister aliskiren with AVALIDE in patients with diabetes. Avoid use of aliskiren with AVALIDE in patients with renal impairment (GFR <60 mL/min). 7.3 Agents Increasing Serum Potassium Coadministration of AVALIDE with other drugs that raise serum potassium levels may result in hyperkalemia, sometimes severe. Monitor serum potassium in such patients. 7.4 Antidiabetic Drugs (oral agents and insulin) Dosage adjustment of the antidiabetic drug may be required when coadministered with hydrochlorothiazide. 7.5 Cholestyramine and Colestipol Resins Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Stagger the dosage of hydrochlorothiazide and the resin such that AVALIDE is administered at least 4 hours before or 4 to 6 hours after the administration of the resin. 7.6 Lithium Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of irbesartan or thiazide diuretics. Monitor lithium levels in patients receiving AVALIDE and lithium. 7.7 Carbamazepine Concomitant use of carbamazepine and hydrochlorothiazide has been associated with the risk of symptomatic hyponatremia. Monitor electrolytes during concomitant use.

8 USE IN SPECIFIC POPULATIONS Lactation: Potential for adverse effects in infant. ( 8.2 ) 8.1 Pregnancy Risk Summary AVALIDE 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 AVALIDE 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. 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. Closely observe infants with histories of in utero exposure to AVALIDE for hypotension, oliguria, and hyperkalemia and other symptoms of renal impairment. In neonates with a history of in utero exposure to AVALIDE, 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. Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults [see Warnings and Precautions (5.1) ] . 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 …

12.1 Mechanism of Action Irbesartan Angiotensin II is a potent vasoconstrictor formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the RAS and also stimulates aldosterone synthesis and secretion by adrenal cortex, cardiac contraction, renal resorption of sodium, activity of the sympathetic nervous system, and smooth muscle cell growth. Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively binding to the AT 1 angiotensin II receptor. There is also an AT 2 receptor in many tissues, but it is not involved in cardiovascular homeostasis. Irbesartan is a specific competitive antagonist of AT 1 receptors with a much greater affinity (more than 8500-fold) for the AT 1 receptor than for the AT 2 receptor, and no agonist activity. Blockade of the AT 1 receptor removes the negative feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II do not overcome the effects of irbesartan on blood pressure. Irbesartan does not inhibit ACE or renin or affect other hormone receptors or ion channels known to be involved in the cardiovascular regulation of blood pressure and sodium homeostasis. Because irbesartan does not inhibit ACE, it does not affect the response to bradykinin; whether this has clinical relevance is not known. Hydrochlorothiazide Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is not fully understood.

11 DESCRIPTION AVALIDE (irbesartan and hydrochlorothiazide) tablets are a combination of an angiotensin II receptor antagonist (AT 1 subtype), irbesartan, and a thiazide diuretic, hydrochlorothiazide (HCTZ). Irbesartan is a non-peptide compound, chemically described as a 2-butyl-3-[ p -( o -1 H -tetrazol-5-ylphenyl) benzyl]-1,3-diazaspiro[4.4]non-1-en-4-one. Its empirical formula is C 25 H 28 N 6 O, and its structural formula is: Irbesartan is a white to off-white crystalline powder with a molecular weight of 428.5. It is a nonpolar compound with a partition coefficient (octanol/water) of 10.1 at pH of 7.4. Irbesartan is slightly soluble in alcohol and methylene chloride and practically insoluble in water. Hydrochlorothiazide is 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C 7 H 8 ClN 3 O 4 S 2 and its structural formula is: Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.7. Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution. AVALIDE is available for oral administration in film-coated tablets containing either 150 mg or 300 mg of irbesartan combined with 12.5 mg of hydrochlorothiazide. All dosage strengths contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hypromellose, magnesium stearate, silicon dioxide, ferric oxide red, ferric oxide yellow, polyethylene glycol, titanium dioxide, and carnauba wax. Chemical Structure Chemical Structure

10 OVERDOSAGE Irbesartan No data are available in regard to overdosage in humans. However, daily doses of 900 mg for 8 weeks were well tolerated. The most likely manifestations of overdosage are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. Irbesartan is not removed by hemodialysis. To obtain up-to-date information about the treatment of overdosage, a good resource is a certified regional Poison Control Center. Telephone numbers of certified Poison Control Centers are listed in the Physicians' Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug interactions, drug-drug interactions, and unusual drug kinetics in the patient. Laboratory determinations of serum levels of irbesartan are not widely available, and such determinations have, in any event, no established role in the management of irbesartan overdose. Acute oral toxicity studies with irbesartan in mice and rats indicated acute lethal doses were in excess of 2000 mg/kg, about 25-fold and 50-fold the MRHD (300 mg) based on body surface area. Hydrochlorothiazide The most common signs and symptoms of overdose observed in humans are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The oral LD 50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied AVALIDE ® (irbesartan and hydrochlorothiazide) film-coated tablets have markings on both sides and are available in the strengths and packages listed in the following table: Tablet Strength (irbesartan and hydrochlorothiazide) Film-Coated Tablet Color/Shape Tablet Markings Package Size NDC Code 150 mg and 12.5 mg peach, biconvex, oval-shaped heart debossed on one side and "2875" on the reverse Bottles of 30 0024-5855-30 300 mg and 12.5 mg peach, biconvex, oval-shaped heart debossed on one side and "2876" on the reverse Bottles of 30 0024-5856-30 16.2 Storage Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F) [see USP Controlled Room Temperature].