Candesartan Cilexetil

Check Drug InteractionsCheck known drug interactions.

Candesartan Cilexetil Prescribing Information

•
When pregnancy is detected, discontinue candesartan cilexetil tablets as soon as possible
[see
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)]
.
and
8.1 Pregnancy
Risk Summary
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. 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.
When pregnancy is detected, discontinue candesartan cilexetil tablets as soon as possible.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
Disease-associated Maternal and/or Embryo/Fetal Risk
Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.
Pregnant women with chronic heart failure are at increased risk for preterm birth. Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester. Heart failure may worsen with pregnancy and may lead to maternal death. Closely monitor pregnant patients for destabilization of their heart failure.
Fetal/Neonatal Adverse Reactions
Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension and death. 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. 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. If oligohydramnios is observed, consider alternative drug treatment. Closely observe infants with histories of
in utero
exposure to candesartan for hypotension, oliguria, hyperkalemia or other symptoms of renal impairment
[see Use in Specific Populations (8.4)]
. In neonates with a history of
in utero
exposure to candesartan, if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function.
Animal Data
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/m²basis (comparison assumes human body weight of 50 kg). Candesartan cilexetil is toxic to rabbits. When given to pregnant rabbits at an oral dose of 3 mg/kg/day (approximately 1.7 times the MRHD on a mg/m²basis), candesartan cilexetil 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/m²basis) were administered to pregnant mice.
]
.
•
Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus
[see
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)]
.
and
8.1 Pregnancy
Risk Summary
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. 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.
When pregnancy is detected, discontinue candesartan cilexetil tablets as soon as possible.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
Disease-associated Maternal and/or Embryo/Fetal Risk
Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.
Pregnant women with chronic heart failure are at increased risk for preterm birth. Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester. Heart failure may worsen with pregnancy and may lead to maternal death. Closely monitor pregnant patients for destabilization of their heart failure.
Fetal/Neonatal Adverse Reactions
Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension and death. 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. 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. If oligohydramnios is observed, consider alternative drug treatment. Closely observe infants with histories of
in utero
exposure to candesartan for hypotension, oliguria, hyperkalemia or other symptoms of renal impairment
[see Use in Specific Populations (8.4)]
. In neonates with a history of
in utero
exposure to candesartan, if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function.
Animal Data
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/m²basis (comparison assumes human body weight of 50 kg). Candesartan cilexetil is toxic to rabbits. When given to pregnant rabbits at an oral dose of 3 mg/kg/day (approximately 1.7 times the MRHD on a mg/m²basis), candesartan cilexetil 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/m²basis) were administered to pregnant mice.
].

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, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions (
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.
).
•Treatment of heart failure (NYHA class II-IV); candesartan cilexetil tablets reduce cardiovascular death and heart failure hospitalization (
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)]
.
).

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 candesartan cilexetil 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.

)

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 candesartan cilexetil 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.

)

•
	Starting Dose	Target Dose
Adult Hypertension ( 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. 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. )	16 mg tablet once daily	8 – 32 mg tablet total daily dose
Pediatric Hypertension (1 to < 6 years) ( 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)] . 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 [see Clinical Studies (14.1)]. An antihypertensive effect is usually present within 2 weeks, with full effect generally obtained within 4 weeks of treatment with candesartan cilexetil tablets. Children < 1 year of age must not receive candesartan cilexetil tablets for hypertension. All pediatric patients with a glomerular filtration rate less than 30 mL/min/1.73m²should not receive candesartan cilexetil tablets since candesartan cilexetil tablets have not been studied in this population [see Use in Specific Populations (8.4)] . For children who cannot swallow tablets, an oral suspension may be substituted as described below: Preparation of Oral Suspension Candesartan cilexetil 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 candesartan cilexetil 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.
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 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)] . 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 [see Clinical Studies (14.1)]. An antihypertensive effect is usually present within 2 weeks, with full effect generally obtained within 4 weeks of treatment with candesartan cilexetil tablets. Children < 1 year of age must not receive candesartan cilexetil tablets for hypertension. All pediatric patients with a glomerular filtration rate less than 30 mL/min/1.73m²should not receive candesartan cilexetil tablets since candesartan cilexetil tablets have not been studied in this population [see Use in Specific Populations (8.4)] . For children who cannot swallow tablets, an oral suspension may be substituted as described below: Preparation of Oral Suspension Candesartan cilexetil 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 candesartan cilexetil 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.
	< 50 kg 4 – 8 mg tablet once daily	< 50 kg 4 – 16 mg tablet once daily or consider divided dose
> 50 kg 8 – 16 mg tablet once daily	> 50 kg 4 – 32 mg tablet once daily or consider divided dose
Adult Heart Failure ( 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. )	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.

Candesartan Cilexetil Tablets, USP are available containing 4 mg, 8 mg, 16 mg or 32 mg of candesartan cilexetil, USP.

•The 4 mg tablets are white to off-white, round, scored tablets debossed with
M
on the left side of the score and
C
on the right side of the score on one side of the tablet and
24
on the other side of the tablet.
•The 8 mg tablets are pink mottled, round, scored tablets debossed with
M
on the left side of the score and
C
on the right side of the score on one side of the tablet and
25
on the other side of the tablet.
•The 16 mg tablets are pink mottled, round, scored tablets debossed with
M
on the left side of the score and
C
on the right side of the score on one side of the tablet and
31
on the other side of the tablet.
•The 32 mg tablets are pink mottled, round, scored tablets debossed with
MC
above the score and
32
below the score on one side of the tablet and blank on the other side of the tablet.

•
Nursing Mothers:
Either nursing or drug should be discontinued (
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)]
.
).
•
Pediatrics:
Children < 1 year of age must not receive candesartan cilexetil tablets for hypertension (
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.
). Inhibitors of the renin-angiotensin system can cause renal abnormalities in neonatal animals (
12.3 Pharmacokinetics
Distribution
The volume of distribution of candesartan is 0.13 L/kg. Candesartan is highly bound to plasma proteins (> 99%) and does not penetrate red blood cells. The protein binding is constant at candesartan plasma concentrations well above the range achieved with recommended doses. In rats, it has been demonstrated that candesartan crosses the blood-brain barrier poorly, if at all. It has also been demonstrated in rats that candesartan passes across the placental barrier and is distributed in the fetus.
Metabolism and Excretion
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.
Total plasma clearance of candesartan is 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg. When candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Following an oral dose of¹⁴C-labeled candesartan cilexetil, approximately 33% of radioactivity is recovered in urine and approximately 67% in feces. Following an intravenous dose of¹⁴C-labeled candesartan, approximately 59% of radioactivity is recovered in urine and approximately 36% in feces. Biliary excretion contributes to the elimination of candesartan.
Adults
Candesartan cilexetil is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan, a selective AT₁subtype angiotensin II receptor antagonist. Candesartan is mainly excreted unchanged in urine and feces (via bile). It undergoes minor hepatic metabolism by O-deethylation to an inactive metabolite. The elimination half-life of candesartan is approximately 9 hours. After single and repeated administration, the pharmacokinetics of candesartan are linear for oral doses up to 32 mg of candesartan cilexetil. Candesartan and its inactive metabolite do not accumulate in serum upon repeated once-daily dosing.
Following administration of candesartan cilexetil, the absolute bioavailability of candesartan was estimated to be 15%. After tablet ingestion, the peak serum concentration (C_max) is reached after 3 to 4 hours. Food with a high fat content does not affect the bioavailability of candesartan after candesartan cilexetil administration.
Pediatrics
In children 1 to 17 years of age, plasma levels are greater than 10-fold higher at peak (approximately 4 hours) than 24 hours after a single dose.
Children 1 to < 6 years of age, given 0.2 mg/kg had exposure similar to adults given 8 mg.
Children > 6 years of age had exposure similar to adults given the same dose.
The pharmacokinetics (C_maxand AUC) were not modified by age, sex or body weight.
Candesartan cilexetil pharmacokinetics have not been investigated in pediatric patients less than 1 year of age.
From the dose-ranging studies of candesartan cilexetil, there was a dose related increase in plasma candesartan concentrations.
The renin-angiotensin system (RAS) plays a critical role in kidney development. RAS blockade has been shown to lead to abnormal kidney development in very young mice. Children < 1 year of age must not receive candesartan cilexetil tablets. Administering drugs that act directly on the renin-angiotensin system (RAS) can alter normal renal development.
Geriatric and Sex
The pharmacokinetics of candesartan have been studied in the elderly (≥ 65 years) and in both sexes. The plasma concentration of candesartan was higher in the elderly (C_maxwas approximately 50% higher, and AUC was approximately 80% higher) compared to younger subjects administered the same dose. The pharmacokinetics of candesartan were linear in the elderly, and candesartan and its inactive metabolite did not accumulate in the serum of these subjects upon repeated, once-daily administration. No initial dosage adjustment is necessary
[see Dosage and Administration (2.1)]
. There is no difference in the pharmacokinetics of candesartan between male and female subjects.
Renal Insufficiency
In hypertensive patients with renal insufficiency, serum concentrations of candesartan were elevated. After repeated dosing, the AUC and C_maxwere approximately doubled in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73m²) compared to patients with normal kidney function. The pharmacokinetics of candesartan in hypertensive patients undergoing hemodialysis are similar to those in hypertensive patients with severe renal impairment. Candesartan cannot be removed by hemodialysis. No initial dosage adjustment is necessary in patients with renal insufficiency
[see Dosage and Administration (2.1)]
.
In heart failure patients with renal impairment, AUC_0-72hwas 36% and 65% higher in mild and moderate renal impairment, respectively. C_maxwas 15% and 55% higher in mild and moderate renal impairment, respectively.
Pediatrics
Candesartan cilexetil tablet pharmacokinetics have not been determined in children with renal insufficiency.
Hepatic Insufficiency
The pharmacokinetics of candesartan were compared in patients with mild and moderate hepatic impairment to matched healthy volunteers following a single oral dose of 16 mg candesartan cilexetil. The increase in AUC for candesartan was 30% in patients with mild hepatic impairment (Child-Pugh A) and 145% in patients with moderate hepatic impairment (Child-Pugh B). The increase in C_maxfor candesartan was 56% in patients with mild hepatic impairment and 73% in patients with moderate hepatic impairment. The pharmacokinetics after candesartan cilexetil administration have not been investigated in patients with severe hepatic impairment. No initial dosage adjustment is necessary in patients with mild hepatic impairment. In hypertensive patients with moderate hepatic impairment, consideration should be given to initiation of candesartan cilexetil tablets at a lower dose
[see Dosage and Administration (2.1)]
.
Heart Failure
The pharmacokinetics of candesartan were linear in patients with heart failure (NYHA class II and III) after candesartan cilexetil doses of 4, 8, and 16 mg. After repeated dosing, the AUC was approximately doubled in these patients compared with healthy, younger patients. The pharmacokinetics in heart failure patients is similar to that in healthy elderly volunteers
[see Dosage and Administration (2.3)]
.
).

Candesartan cilexetil tablets are contraindicated in patients who are hypersensitive to candesartan.

Do not co-administer aliskiren with candesartan cilexetil tablets in patients with diabetes

[see

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)]

]

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