Candesartan: uses, appearance and warnings

Candesartan cilexetil tablets are an angiotensin II receptor blocker (ARB) indicated for: Treatment of hypertension in adults and children 1 year 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 ( 1.1 ). Treatment of heart failure (NYHA class II-IV); candesartan cilexetil 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 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 )] .

Tablets 4 mg, 8 mg, 16 mg, 32 mg ( 3 ). Candesartan cilexetil tablets USP, 4 mg are light pink, mottled, round, biconvex, uncoated scored tablets engraved with 'ZE' on one side and '58' on other side. Candesartan cilexetil tablets USP, 8 mg are pink, mottled, round, biconvex, uncoated tablets engraved with 'Z' & 'E' divided by score line on one side and '59' on other side. Candesartan cilexetil tablets USP, 16 mg are white, round, biconvex, uncoated tablets engraved with 'Z' & 'E' divided by score line on one side and '60' on other side. Candesartan cilexetil tablets USP, 32 mg are white to off-white, round, biconvex, uncoated tablets engraved with 'Z' & 'E' divided by score line on one side and '61' on other side.

Candesartan cilexetil tablets USP, 4 mg are light pink, mottled, round, biconvex, uncoated scored tablets engraved with 'ZE' on one side and '58' on other side and are supplied as follows: NDC 72578-157-06 in bottle of 30 tablets NDC 72578-157-16 in bottle of 90 tablets NDC 72578-157-05 in bottle of 500 tablets Candesartan cilexetil tablets USP, 8 mg are pink, mottled, round, biconvex, uncoated tablets engraved with 'Z' & 'E' divided by score line on one side and '59' on other side and are supplied as follows: NDC 72578-158-06 in bottle of 30 tablets with child-resistant closure NDC 72578-158-16 in bottle of 90 tablets with child-resistant closure Candesartan cilexetil tablets USP, 16 mg are white, round, biconvex, uncoated tablets engraved with 'Z' & 'E' divided by score line on one side and '60' on other side and are supplied as follows: NDC 72578-159-06 in bottle of 30 tablets with child-resistant closure NDC 72578-159-16 in bottle of 90 tablets with child-resistant closure Candesartan cilexetil tablets USP, 32 mg are white to off-white, round, biconvex, uncoated tablets engraved with 'Z' & 'E' divided by score line on one side and '61' on other side and are supplied as follows: NDC 72578-160-06 in bottle of 30 tablets with child-resistant closure NDC 72578-160-16 in bottle of 90 tablets with child-resistant closure Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted at 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Keep in a tightly closed container. Dispense in a tight, light-resistant container as defined in the USP.

Known hypersensitivity to product components ( 4 ). Do not coadminister aliskiren with candesartan cilexetil in patients with diabetes ( 4 ). Candesartan cilexetil is contraindicated in patients who are hypersensitive to candesartan. Do not coadminister aliskiren with candesartan cilexetil in patients with diabetes [see Drug Interactions ( 7.4 )].

Observe for signs and symptoms of hypotension ( 5.3 ). Monitor renal function ( 5.4 ) and potassium levels ( 5.5 ). 5.1 Fetal Toxicity Candesartan cilexetil 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 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 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 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, diuretic or both, and volume repletion. Volume and/or salt depletion should be corrected before initiating therapy with candesartan cilexetil. In the CHARM program (heart failure patients), hypotension was reported in 18.8% of patients on candesartan cilexetil versus 9.8% of patients on placebo. The incidence of hypotension leading to drug discontinuation in candesartan cilexetil-treated patients was 4.1% compared with 2% 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 versus 13.8% treated with placebo [see Drug Interactions ( 7.3 )] . 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 candesartan cilexetil, 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. 5.4 Impaired Renal Function Monitor renal function periodically in patients treated with candesartan cilexetil. 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. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on candesartan cilexetil. 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 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-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 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 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 versus 2.1% in patients treated with placebo. The incidence of hyperkalemia leading to drug discontinuation in candesartan cilexetil-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 versus 3.5% in patients treated with placebo [see Drug Interactions ( 7.1 )] .

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 Viona Pharmaceuticals Inc. at 1-888-304-5011 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. …

Lithium: Increases in serum lithium concentrations and toxicity ( 7 ). NSAIDs use may lead to increased risk of renal impairment and loss of antihypertensive effect ( 7 ). Combined inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia ( 7 ). 7.1 Agents Increasing Serum Potassium Coadministration of candesartan cilexetil 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. Monitor serum lithium levels. …