WARNING: FETAL TOXICITY • When pregnancy is detected, discontinue ATACAND as soon as possible [see Warnings and Precautions (5.1) ]. • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.2) ] WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning. • When pregnancy is detected, discontinue ATACAND as soon as possible. (5.1) • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1)
1 INDICATIONS AND USAGE 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 (1.1). •Treatment of heart failure (NYHA class II-IV); ATACAND reduces cardiovascular death and heart failure hospitalization (1.2). 1.1 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. 1.2 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 [see Clinical Studies (14.2) ]. ATACAND also has an added effect on these outcomes when used with an ACE inhibitor [see Drug Interactions (7.4) ].
| || Starting Dose || Target Dose |
| Adult Hypertension (2.1) || 16 mg tablet once daily || 8 – 32 mg tablet total daily dose |
| Pediatric Hypertension (1 to < 6 years) (2.2) || 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) (2.2) || < 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 (2.3) || 4 mg tablet once daily || 32 mg tablet once dailyThe target dose is 32 mg once daily, which is achieved by doubling the dose at approximately 2-week intervals, as tolerated by patient |
3 DOSAGE FORMS AND STRENGTHS 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 (3).
4 CONTRAINDICATIONS ATACAND is contraindicated in patients who are hypersensitive to candesartan. Do not co-administer aliskiren with ATACAND in patients with diabetes [see Drug Interactions (7.4) ]. Known hypersensitivity to product components (4). Do not co-administer aliskiren with ATACAND 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 ATACAND 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/m2 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/m2 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/m2 basis) were administered to pregnant mice. 5.2 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. 5.3 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 [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 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. 5.4 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 [see Drug Interactions (7.3) ]. 5.5 Hyperkalemia Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Concomitant use of ATACAND with drugs that may increase potassium levels may increase the risk of hyperkalemia [see Drug Interactions (7) ].. 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 [see Drug Interactions (7.1) ].
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 AstraZeneca at 1–800–236–9933 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 ATACAND 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 ATACAND was well tolerated. The overall incidence of adverse events reported with ATACAND 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 ATACAND 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 ATACAND and 3.4% (i.e., 35 of 1027) of patients treated with placebo. The most common reasons for discontinuation of therapy with ATACAND 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 ATACAND and at a higher incidence in candesartan cilexetil (n = 2350) than placebo (n = 1027) patients included back pain (3% vs. 2%), dizziness (4% vs. 3%), upper respiratory tract infection (6% vs. 4%), pharyngitis (2% vs. 1%), and rhinitis (2% vs. 1%). Pediatric Hypertension Among children in clinical studies, 1 in 93 children age 1 to < 6 and 3 in 240 age 6 to < 17 experienced worsening renal disease. The association between candesartan and exacerbation of the underlying condition could not be excluded. Heart Failure The adverse event profile of ATACAND in adult heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM program, comparing ATACAND in total daily doses up to 32 mg once daily (n=3803) with placebo (n=3796), 21.0% of patients discontinued ATACAND for adverse events vs. 16.1% of placebo patients. 6.2 Postmarketing Experience The following adverse reactions were identified during post-approval use of ATACAND. 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 DRUG INTERACTIONS •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 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. 7.2 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. 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 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) [see Contraindications (4) ].
8 USE IN SPECIFIC POPULATIONS • Nursing Mothers: Either nursing or drug should be discontinued (8.3). • Pediatrics: Children < 1 year of age must not receive ATACAND for hypertension (5.2). Inhibitors of the renin-angiotensin system can cause renal abnormalities in neonatal animals (12.3). 8.1 Pregnancy 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 ATACAND as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. 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. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue ATACAND, unless it is considered lifesaving for the mother. 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 ATACAND for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4) ]. 8.2 Labor and Delivery The effect of ATACAND on labor and delivery in humans is unknown [ see Warnings and Precautions (5.1) ]. 8.3 Nursing Mothers 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 adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue ATACAND, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Neonates with a history of in utero exposure to ATACAND: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. The antihypertensive effects of ATACAND 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 ATACAND 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 ATACAND for hypertension [see Warnings and Precautions (5.2) ].