ARB

1 INDICATIONS AND USAGE Candesartan Cilexetil Tablets are an angiotensin II receptor blocker (ARB) indicated for: Treatment of hypertension in adults and children 1 to < 17 years of age (1.1) . Treatment of heart failure (NYHA class II-IV); candesartan cilexetil tablets reduces cardiovascular death and heart failure hospitalization (1.2) . 1.1 Hypertension Candesartan cilexetil tablets are indicated for the treatment of hypertension in adults and children 1 to < 17 years of age. It may be used alone or in combination with other antihypertensive agents. 1.2 Heart Failure Candesartan cilexetil tablets 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 [see CLINICAL STUDIES (14.2) ]. Candesartan cilexetil tablets also have an added effect on these outcomes when used with an ACE inhibitor.

2 DOSAGE AND ADMINISTRATION Starting Dose Dose Range Target Maintenance Dose Adult Hypertension ( 2.1 ) 16 mg tablet once daily 8 to32 mg tablet total daily dose – Pediatric Hypertension (1 to < 6 years) ( 2.2 ) 0.20 mg/kg oral suspension once daily 0.05 to 0.4 mg/kg oral suspension once daily or consider divided dose – Pediatric Hypertension (6 to < 17 years) ( 2.2 ) < 50 kg 4 to 8 mg tablet once daily > 50 kg 8 to 16 mg tablet once daily < 50 kg 4 to 16 mg tablet once daily or consider divided dose > 50 kg 4 to 32 mg tablet once daily or consider divided dose – Adult Heart Failure ( 2.3 ) 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 2.1 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 candesartan cilexetil tablets is 16 mg once daily when it is used as monotherapy in patients who are not volume depleted. Candesartan cilexetil tablets 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 candesartan cilexetil tablets. Use in Hepatic Impairment: Initiate with 8 mg candesartan cilexetil tablets in patients with moderate hepatic insufficiency. Dosing recommendations cannot be provided for patients with severe hepatic insufficiency [see CLINICAL PHARMACOLOGY (12.3) ]. Candesartan cilexetil tablets may be administered with or without food. If blood pressure is not controlled by candesartan cilexetil tablets alone, a diuretic may be added. Candesartan cilexetil tablets may be administered with other antihypertensive agents.…

12.2 Pharmacodynamics Candesartan inhibits the pressor effects of angiotensin II infusion in a dose-dependent manner. After 1 week of once daily dosing with 8 mg of candesartan cilexetil, the pressor effect was inhibited by approximately 90% at peak with approximately 50% inhibition persisting for 24 hours. Plasma concentrations of angiotensin I and angiotensin II, and plasma renin activity (PRA), increased in a dose-dependent manner after single and repeated administration of candesartan cilexetil to healthy subjects, hypertensive, and heart failure patients. ACE activity was not altered in healthy subjects after repeated candesartan cilexetil administration. The once-daily administration of up to 16 mg of candesartan cilexetil to healthy subjects did not influence plasma aldosterone concentrations, but a decrease in the plasma concentration of aldosterone was observed when 32 mg of candesartan cilexetil was administered to hypertensive patients. In spite of the effect of candesartan cilexetil on aldosterone secretion, very little effect on serum potassium was observed. Hypertension Adults In multiple-dose studies with hypertensive patients, there were no clinically significant changes in metabolic function, including serum levels of total cholesterol, triglycerides, glucose, or uric acid. In a 12-week study of 161 patients with non-insulin-dependent (type 2) diabetes mellitus and hypertension, there was no change in the level of HbA 1c . Heart Failure In heart failure patients, candesartan ≥8 mg resulted in decreases in systemic vascular resistance and pulmonary capillary wedge pressure.

6 ADVERSE REACTIONS Most common adverse reactions which caused adult patients to discontinue therapy for: Hypertension were headache (0.6%) and dizziness (0.3%) (6.1) . Heart Failure were hypotension (4.1%) (5.3) , abnormal renal function (6.3%) (5.4) , and hyperkalemia (2.4%) (5.5) . To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc., at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adult Hypertension Candesartan cilexetil has been evaluated for safety in more than 3600 patients/subjects, including more than 3200 patients treated for hypertension. About 600 of these patients were studied for at least 6 months and about 200 for at least 1 year. In general, treatment with candesartan cilexetil was well tolerated. The overall incidence of adverse events reported with candesartan cilexetil was similar to placebo. The rate of withdrawals due to adverse events in all trials in patients (7510 total) was 3.3% (i.e., 108 of 3260) of patients treated with candesartan cilexetil as monotherapy and 3.5% (i.e., 39 of 1106) of patients treated with placebo. In placebo-controlled trials, discontinuation of therapy due to clinical adverse events occurred in 2.4% (i.e., 57 of 2350) of patients treated with candesartan cilexetil and 3.4% (ie., 35 of 1027) of patients treated with placebo. The most common reasons for discontinuation of therapy with candesartan cilexetil were headache (0.6%) and dizziness (0.3%). The adverse events that occurred in placebo-controlled clinical trials in at least 1% of patients treated with candesartan cilexetil and at a higher incidence in candesartan cilexetil (n = 2350) than placebo (n = 1027) patients included back pain (3% vs.…

4 CONTRAINDICATIONS Candesartan cilexetil tablets are contraindicated in patients who are hypersensitive to candesartan.Candesartan cilexetil tablets are contraindicated in patients who are hypersensitive to candesartan. Do not co-administer aliskiren with cansedartancilexetil tablets in patients with diabetes [see DRUG INTERACTIONS (7) ]. Known hypersensitivity to product components (4) . Do not co-administer aliskiren with candesartan cilexetil tablets in patients with diabetes (4) .

5 WARNINGS AND PRECAUTIONS Observe for signs and symptoms of hypotension (5.3) . Monitor renal function (5.4) and potassium levels (5.5) . 5.1 Fetal Toxicity Pregnancy Category D 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 candesartan cilexetil as soon as possible [see USE IN SPECIFIC POPULATIONS (8.1) ]. Oral doses ≥10 mg of candesartan cilexetil/kg/day administered to pregnant rats during late gestation and continued through lactation were associated with reduced survival and an increased incidence of hydronephrosis in the offspring. The 10-mg/kg/day dose in rats is approximately 2.8 times the maximum recommended daily human dose (MRHD) of 32 mg on a mg/m basis (comparison assumes human body weight of 50 kg). Candesartan cilexetil given to pregnant rabbits at an oral dose of 3 mg/kg/day (approximately 1.7 times the MRHD on a mg/m basis) caused maternal toxicity (decreased body weight and death) but, in surviving dams, had no adverse effects on fetal survival, fetal weight, or external, visceral, or skeletal development. No maternal toxicity or adverse effects on fetal development were observed when oral doses up to 1000 mg of candesartan cilexetil/kg/day (approximately 138 times the MRHD on a mg/m basis) were administered to pregnant mice. Oral doses ≥10 mg of candesartan cilexetil/kg/day administered to pregnant rats during late gestation and continued through lactation were associated with reduced survival and an increased incidence of hydronephrosis in the offspring. The 10-mg/kg/day dose in rats is approximately 2.8 times the maximum recommended daily human dose (MRHD) of 32…

7 DRUG INTERACTIONS Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effects on P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected.Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effects on P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected. 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.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.The antihypertensive effect of angiotensin II receptor antagonists, including candesartan may be attenuated by NSAIDs including selective COX-2 inhibitors. Lithium Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with…