1.1 Hypertension

Candesartan cilexetil tablets are 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.

Candesartan cilexetil tablets may be used alone or in combination with other antihypertensive agents.

1.2 Heart Failure

Candesartan cilexetil tablets are 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 [see Drug Interactions (7.4)].

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 they are 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.

2.2 Pediatric Hypertension 1 to < 17 Years of Age

Candesartan cilexetil tablets 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 candesartan cilexetil tablets under close medical supervision and consider administration of a lower dose [see Warnings and Precautions (5.3)].

2.3 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.

5.1 Fetal Toxicity

Candesartan cilexetil 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 candesartan cilexetil tablets as soon as possible [see Use in Specific Populations (8.1)].

5.2 Morbidity in Infants

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

5.3 Hypotension

Candesartan cilexetil tablets 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 candesartan cilexetil tablets, diuretic or both, and volume repletion. Volume and/or salt depletion should be corrected before initiating therapy with candesartan cilexetil tablets.

In the CHARM program (heart failure patients), hypotension was reported in 18.8% of patients on candesartan cilexetil tablets versus 9.8% of patients on placebo. The incidence of hypotension leading to drug discontinuation in candesartan cilexetil tablet-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 candesartan cilexetil tablets versus 13.8% treated with placebo [see Drug Interactions (7.3)].

Monitoring of blood pressure is recommended during dose escalation and periodically thereafter.

5.4 Impaired Renal Function

Monitor renal function periodically in patients treated with candesartan cilexetil tablets. 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 candesartan cilexetil tablets. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on candesartan cilexetil tablets.

In the CHARM program (heart failure patients), the incidence of abnormal renal function (e.g., creatinine increase) was 12.5% in patients treated with candesartan cilexetil tablets versus 6.3% in patients treated with placebo. The incidence of abnormal renal function (e.g., creatinine increase) leading to drug discontinuation in candesartan cilexetil tablet-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 candesartan cilexetil tablets versus 9% in patients treated with placebo [see Drug Interactions (7.3)].

5.5 Hyperkalemia

Drugs that inhibit the renin-angiotensin system can cause hyperkalemia.

Concomitant use of candesartan cilexetil tablets with drugs that increase potassium levels may increase the risk of hyperkalemia [see Drug Interactions (7.1)].

Monitor serum potassium periodically.

In the CHARM program (heart failure patients), the incidence of hyperkalemia was 6.3% in patients treated with candesartan cilexetil tablets versus 2.1% in patients treated with placebo. The incidence of hyperkalemia leading to drug discontinuation in candesartan cilexetil tablet-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 candesartan cilexetil tablets versus 3.5% in patients treated with placebo [see Drug Interactions (7.1)].

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.

6.2 Postmarketing Experience

The following adverse reactions were identified during post-approval use of candesartan cilexetil tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following have been very rarely reported in post-marketing experience:

Digestive: Abnormal hepatic function and hepatitis.

Hematologic: Neutropenia, leukopenia, and agranulocytosis.

Immunologic: Angioedema.

Metabolic and Nutritional Disorders: Hyperkalemia, hyponatremia.

Respiratory System Disorders: Cough.

Skin and Appendages Disorders: Pruritus, rash and urticaria.

Rare reports of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

7.1 Agents Increasing Serum Potassium

Co-administration of candesartan cilexetil tablets 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.

7.2 Lithium

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

7.3 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.

7.4 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 candesartan cilexetil tablets with an ACE-inhibitor and a mineralocorticoid receptor antagonist is generally not recommended. Closely monitor blood pressure, renal function and electrolytes in patients on candesartan cilexetil tablets and other agents that affect the RAS.

Do not co-administer aliskiren with candesartan cilexetil tablets in patients with diabetes. Avoid use of aliskiren with candesartan cilexetil tablets in patients with renal impairment (GFR < 60 mL/min) [see Contraindications (4)].

8.1 Pregnancy

8.2 Lactation

It is not known whether candesartan is excreted in human milk, but candesartan has been shown to be present in rat milk. Because of the potential for serious adverse reactions in breastfed infants, advise a nursing woman that breastfeeding is not recommended during treatment with candesartan cilexetil tablets [see Warnings and Precautions (5.2)].

8.4 Pediatric Use

The antihypertensive effects of candesartan cilexetil tablets were evaluated in hypertensive children 1 to < 17 years of age in randomized, double-blind clinical studies [see Clinical Studies (14.1)]. The pharmacokinetics of candesartan cilexetil tablets have been evaluated in pediatric patients 1 to < 17 years of age [see Clinical Pharmacology (12.3)].

Children < 1 year of age must not receive candesartan cilexetil tablets for hypertension [see Warnings and Precautions (5.2)].

12.1 Mechanism of Action

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathways for angiotensin II synthesis.

There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Candesartan has much greater affinity (> 10,000-fold) for the AT1 receptor than for the AT2 receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because candesartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of candesartan on blood pressure.

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.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no evidence of carcinogenicity when candesartan cilexetil was orally administered to mice and rats for up to 104 weeks at doses up to 100 and 1000 mg/kg/day, respectively. Rats received the drug by gavage, whereas mice received the drug by dietary administration. These (maximally-tolerated) doses of candesartan cilexetil provided systemic exposures to candesartan (AUCs) that were, in mice, approximately 7 times and, in rats, more than 70 times the exposure in man at the maximum recommended daily human dose (32 mg).

Candesartan and its O-deethyl metabolite tested positive for genotoxicity in the in vitro Chinese hamster lung (CHL) chromosomal aberration assay. Neither compound tested positive in the Ames microbial mutagenesis assay or the in vitro mouse lymphoma cell assay. Candesartan (but not its O-deethyl metabolite) was also evaluated in vivo in the mouse micronucleus test and in vitro in the Chinese hamster ovary (CHO) gene mutation assay, in both cases with negative results. Candesartan cilexetil was evaluated in the Ames test, the in vitro mouse lymphoma cell and rat hepatocyte unscheduled DNA synthesis assays and the in vivo mouse micronucleus test, in each case with negative results. Candesartan cilexetil was not evaluated in the CHL chromosomal aberration or CHO gene mutation assay.

Fertility and reproductive performance were not affected in studies with male and female rats given oral doses of up to 300 mg/kg/day (83 times the maximum daily human dose of 32 mg on a body surface area basis).

14.1 Hypertension

14.2 Heart Failure

Candesartan was studied in two heart failure outcome studies: 1. The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity trial in patients intolerant of ACE inhibitors (CHARM–Alternative), 2. CHARM–Added in patients already receiving ACE inhibitors. Both studies were international double-blind, placebo-controlled trials in patients with NYHA class II-IV heart failure and LVEF ≤ 40%. In both trials, patients were randomized to placebo or candesartan cilexetil tablets (initially 4-8 mg once daily, titrated as tolerated to 32 mg once daily) and followed for up to 4 years. Patients with serum creatinine ≥ 3 mg/dL, serum potassium ≥ 5.5 mEq/L, symptomatic hypotension or known bilateral renal artery stenosis were excluded. The primary end point in both trials was time to either cardiovascular death or hospitalization for heart failure.

CHARM–Alternative included 2028 subjects not receiving an ACE inhibitor due to intolerance. The mean age was 67 years and 32% were female, 48% were NYHA II, 49% were NYHA III, 4% were NYHA IV, and the mean ejection fraction was 30%. Sixty-two percent had a history of myocardial infarction, 50% had a history of hypertension, and 27% had diabetes. Concomitant drugs at baseline were diuretics (85%), digoxin (46%), beta-blockers (55%), and spironolactone (24%). The mean daily dose of candesartan cilexetil tablets was approximately 23 mg and 59% of subjects on treatment received 32 mg once daily.

After a median follow-up of 34 months, there was a 23% reduction in the risk of cardiovascular death or heart failure hospitalization on candesartan cilexetil tablets (p < 0.001), with both components contributing to the overall effect (Table 1).

In CHARM–Added, 2548 subjects receiving an ACE inhibitor were randomized to candesartan cilexetil tablets or placebo. The specific ACE inhibitor and dose were at the discretion of the investigators, who were encouraged to titrate patients to doses known to be effective in clinical outcome trials, subject to patient tolerability. Forced titration to maximum tolerated doses of ACE inhibitor was not required.

The mean age was 64 years and 21% were female, 24% were NYHA II, 73% were NYHA III, 3% were NYHA IV, and the mean ejection fraction was 28%. Fifty-six percent had a history of myocardial infarction, 48% had a history of hypertension, and 30% had diabetes. Concomitant drugs at baseline in addition to ACE inhibitors were diuretics (90%), digoxin (58%), beta-blockers (55%), and spironolactone (17%). The mean daily dose of candesartan cilexetil tablets was approximately 24 mg and 61% of subjects on treatment received 32 mg once daily.

After a median follow-up of 41 months, there was a 15% reduction in the risk of cardiovascular death or heart failure hospitalization on candesartan cilexetil tablets (p = 0.011), with both components contributing to the overall effect (Table 2). There was no evident relationship between dose of ACE inhibitor and the benefit of candesartan cilexetil tablets.

In these two studies, the benefit of candesartan cilexetil tablets in reducing the risk of CV death or heart failure hospitalization (18% p < 0.001) was evident in major subgroups (see Figure), and in patients on other combinations of cardiovascular and heart failure treatments, including ACE inhibitors and beta-blockers.

Figure. CV Death or Heart Failure Hospitalization in Subgroups – LV Systolic Dysfunction Trials