ATACAND (candesartan cilexetil), a prodrug, is hydrolyzed to candesartan during absorption from the gastrointestinal tract. Candesartan is a selective AT 1 subtype angiotensin II receptor antagonist. Candesartan cilexetil, a nonpeptide, is chemically described as (±)-1-Hydroxyethyl 2-ethoxy-1-[ p-(o -1 H -tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester). Its empirical formula is C 33 H 34 N 6 O 6 , and its structural formula is: Candesartan cilexetil is a white to off-white powder with a molecular weight of 610.67. It is practically insoluble in water and sparingly soluble in methanol. Candesartan cilexetil is a racemic mixture containing one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group. Following oral administration, candesartan cilexetil undergoes hydrolysis at the ester link to form the active drug, candesartan, which is achiral. ATACAND is available for oral use as tablets containing either 4 mg, 8 mg, 16 mg, or 32 mg of candesartan cilexetil and the following inactive ingredients: hydroxypropyl cellulose, polyethylene glycol, lactose, corn starch, carboxymethylcellulose calcium, and magnesium stearate. Ferric oxide (reddish brown) is added to the 8-mg, 16-mg, and 32-mg tablets as a colorant. structural formula

ATACAND is an angiotensin II receptor blocker (ARB) indicated for: • Treatment of hypertension in adults and children 1 to < 17 years of age, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions . • Treatment of heart failure (NYHA class II-IV); ATACAND reduces cardiovascular death and heart failure hospitalization

Hypertension ATACAND is indicated for the treatment of hypertension in adults and in children 1 to <17 years of age, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. 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 one 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. ATACAND may be used alone or in combination with other antihypertensive agents

Heart Failure ATACAND is indicated for the treatment of heart failure (NYHA class II-IV) in adults with left ventricular systolic dysfunction (ejection fraction ≤ 40%) to reduce cardiovascular death and to reduce heart failure hospitalizations . ATACAND also has an added effect on these outcomes when used with an ACE inhibitor .

4 mg are white to off-white, circular/biconvex-shaped, non-film-coated scored tablets, coded ACF on one side and 004 on the other. 8 mg are light pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACG on one side and 008 on the other. 16 mg are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACH on one side and 016 on the other. 32 mg are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACL on one side and 032 on the other. Tablets 4 mg, 8 mg, 16 mg, 32 mg .

Starting Dose Target Dose Adult Hypertension 16 mg tablet once daily 8 – 32 mg tablet total daily dose Pediatric Hypertension (1 to < 6 years) 0.20 mg/kg oral suspension once daily 0.05 – 0.4 mg/kg oral suspension once daily or consider divided dose Pediatric Hypertension (6 to < 17 years) < 50 kg 4 – 8 mg tablet once daily >50 kg 8 – 16 mg tablet once daily < 50 kg 4 – 16 mg tablet once daily or consider divided dose > 50 kg 4 – 32 mg tablet once daily or consider divided dose Adult Heart Failure 4 mg tablet once daily 32 mg tablet once daily The target dose is 32 mg once daily, which is achieved by doubling the dose at approximately 2-week intervals, as tolerated by patient

Adult Hypertension Dosage must be individualized. Blood pressure response is dose related over the range of 2 to 32 mg. The usual recommended starting dose of ATACAND is 16 mg once daily when it is used as monotherapy in patients who are not volume depleted. ATACAND can be administered once or twice daily with total daily doses ranging from 8 mg to 32 mg. Larger doses do not appear to have a greater effect, and there is relatively little experience with such doses. Most of the antihypertensive effect is present within 2 weeks, and maximal blood pressure reduction is generally obtained within 4 to 6 weeks of treatment with ATACAND. Use in Hepatic Impairment: Initiate with 8 mg ATACAND in patients with moderate hepatic insufficiency. Dosing recommendations cannot be provided for patients with severe hepatic insufficiency . ATACAND may be administered with or without food. If blood pressure is not controlled by ATACAND alone, a diuretic may be added. ATACAND may be administered with other antihypertensive agents

Pediatric Hypertension 1 to < 17 Years of Age ATACAND may be administered once daily or divided into two equal doses. Adjust the dosage according to blood pressure response. For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), initiate ATACAND under close medical supervision and consider administration of a lower dose . Children 1 to < 6 years of age: The dose range is 0.05 to 0.4 mg/kg per day. The recommended starting dose is 0.20 mg/kg (oral suspension). Children 6 to < 17 years of age: For those less than 50 kg, the dose range is 2 to 16 mg per day. The recommended starting dose is 4 to 8 mg. For those greater than 50 kg, the dose range is 4 to 32 mg per day. The recommended starting dose is 8 to 16 mg. Doses above 0.4 mg/kg (1 to < 6 year olds) or 32 mg (6 to < 17 year olds) have not been studied in pediatric patients . An antihypertensive effect is usually present within 2 weeks, with full effect generally obtained within 4 weeks of treatment with ATACAND. Children < 1 year of age must not receive ATACAND for hypertension. All pediatric patients with a glomerular filtration rate less than 30 mL/min/1.73m 2 should not receive ATACAND since ATACAND has not been studied in this population . For children who cannot swallow tablets, an oral suspension may be substituted as described below: Preparation of Oral Suspension: ATACAND oral suspension can be prepared in concentrations within the range of 0.1 to 2.0 mg/mL. Typically, a concentration of 1 mg/mL will be suitable for the prescribed dose. Any strength of ATACAND tablets can be used in the preparation of the suspension. Follow the steps below for preparation of the suspension. The number of tablets and volume of vehicle specified below will yield 160 mL of a 1 mg/mL suspension. • Prepare the vehicle by adding equal volumes of Ora-Plus ® (80 mL) and Ora-Sweet SF ® (80 mL) or, alternatively, use Ora-Blend SF ® (160 mL). • Add a small amount of vehicle to the required number of ATACAND tablets (five 32 mg tablets) and grind into a smooth paste using a mortar and pestle. • Add the paste to a preparation vessel of suitable size. • Rinse the mortar and pestle clean using the vehicle and add this to the vessel. Repeat, if necessary. • Prepare the final volume by adding the remaining vehicle. • Mix thoroughly. • Dispense into suitably sized amber PET bottles. • Label with an expiry date of 100 days and include the following instructions: Store at room temperature (below 30°C/86°F). Use within 30 days after first opening. Do not use after the expiry date stated on the bottle. Do not freeze. Shake well before each use

Adult Heart Failure The recommended initial dose for treating heart failure is 4 mg once daily. The target dose is 32 mg once daily, which is achieved by doubling the dose at approximately 2-week intervals, as tolerated by the patient.

• Observe for signs and symptoms of hypotension . • Monitor renal function and potassium levels

Fetal Toxicity ATACAND 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 ATACAND as soon as possible

Morbidity in Infants Children < 1 year of age must not receive ATACAND for hypertension. Drugs that act directly on the renin-angiotensin system (RAS) can have effects on the development of immature kidneys

Hypotension ATACAND can cause symptomatic hypotension. Symptomatic hypotension is most likely to occur in patients who have been volume and/or salt depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Patients with symptomatic hypotension may require temporarily reducing the dose of ATACAND, diuretic or both, and volume repletion. Volume and/or salt depletion should be corrected before initiating therapy with ATACAND. In the CHARM program (heart failure patients), hypotension was reported in 18.8% of patients on ATACAND versus 9.8% of patients on placebo. The incidence of hypotension leading to drug discontinuation in ATACAND-treated patients was 4.1% compared with 2.0% in placebo-treated patients. In the CHARM-Added program, where candesartan or placebo was given in addition to ACE inhibitors, hypotension was reported in 22.6% of patients treated with ATACAND versus 13.8% treated with placebo . Monitoring of blood pressure is recommended during dose escalation and periodically thereafter. Major Surgery/Anesthesia Hypotension may occur during major surgery and anesthesia in patients treated with angiotensin II receptor antagonists, including ATACAND, due to blockade of the renin-angiotensin system. Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors

Impaired Renal Function Monitor renal function periodically in patients treated with ATACAND. 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., patient with renal artery stenosis, chronic kidney disease, severe heart failure, or volume depletion) may be at particular risk of developing oliguria, progressive azotemia or acute renal failure when treated with ATACAND. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on ATACAND. In the CHARM program (heart failure patients), the incidence of abnormal renal function (e.g., creatinine increase) was 12.5% in patients treated with ATACAND versus 6.3% in patients treated with placebo. The incidence of abnormal renal function (e.g., creatinine increase) leading to drug discontinuation in ATACAND-treated patients was 6.3% compared with 2.9% in placebo-treated patients. In the CHARM-Added program, where candesartan or placebo was given in addition to ACE inhibitors, the incidence of abnormal renal function (e.g., creatinine increase) was 15% in patients treated with ATACAND versus 9% in patients treated with placebo

Hyperkalemia Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Concomitant use of ATACAND with drugs that increase potassium levels may increase the risk of hyperkalemia . Monitor serum potassium periodically. In the CHARM program (heart failure patients), the incidence of hyperkalemia was 6.3% in patients treated with ATACAND versus 2.1% in patients treated with placebo. The incidence of hyperkalemia leading to drug discontinuation in ATACAND-treated patients was 2.4% compared with 0.6% in placebo-treated patients. In the CHARM-Added program where candesartan or placebo was given in addition to ACE inhibitors, the incidence of hyperkalemia was 9.5% in patients treated with ATACAND versus 3.5% in patients treated with placebo .

• Lithium: Increases in serum lithium concentrations and toxicity . • NSAIDs use may lead to increased risk of renal impairment and loss of antihypertensive effect . • Combined inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia

Agents Increasing Serum Potassium Co-administration of ATACAND with potassium sparing diuretics, potassium supplements, potassium-containing salt substitutes or other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients

Lithium Increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including ATACAND. Monitor serum lithium levels

Non-Steroidal Anti-Inflammatory Agents 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, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including candesartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving candesartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including candesartan may be attenuated by NSAIDs including selective COX-2 inhibitors

Combination 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. Triple combination of ATACAND with an ACE-inhibitor and a mineralocorticoid receptor antagonist is generally not recommended. Closely monitor blood pressure, renal function and electrolytes in patients on ATACAND and other agents that affect the RAS. Do not co-administer aliskiren with ATACAND in patients with diabetes. Avoid use of aliskiren with ATACAND in patients with renal impairment (GFR <60 mL/min) .