Candesartan

Candesartan
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

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Black Box Warning

WARNING: FETAL TOXICITY See full prescribing information for complete Boxed Warning. When pregnancy is detected, discontinue candesartan cilexetil as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Overview

Candesartan is an angiotensin II receptor blocker that is FDA approved for the {{{indicationType}}} of hypertension and heart failure. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension, backache, dizziness, pharyngitis, rhinitis and upper respiratory infection.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Hypertension

• Starting dosage:

• 16 mg/day, as monotherapy, in non-volume depleted patients.

• Use in hepatic impairment:

• Initiate with 8 mg/day. If blood pressure is not controlled by candesartan cilexetil alone, a diuretic may be added.
• Candesartan cilexetil may be administered with other antihypertensive agents.

Heart Failure

• Initial dosage:

• 4 mg/day

• Target dosage, achieved by doubling the dose at approximately 2-week intervals, as tolerated by the patient:

• 32 mg/day

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of candesartan cilexetil in adult patients.

Non–Guideline-Supported Use

Cerebrovascular accident

• Dosing Information

• (Dosage)

Diabetic nephropathy

• Dosing Information

• (Dosage)

Essential hypertension - Left ventricular hypertrophy

• Dosing Information

• (Dosage)

Kidney disease

• Dosing Information

• (Dosage)

Migraine

• Dosing Information

• (Dosage)

Transplantation

• Dosing Information

• (Dosage)

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Hypertension

• 1 to < 17 Years of age

Candesartan cilexetil may be administered once daily or divided into two equal doses.

• In children 1 - 6 years of age:

• Initial dosage:

• 0.20 mg/kg/day PO

• Further dosages:

• 0.05 to 0.4 mg/kg per day PO

• Children 6 - 17 years of age:

• Less than 50 kg

• Initial dosage:

• 4 to 8 mg/day PO

• Further dosages:

• 2 to 16 mg per day PO

• Greater than 50 kg

• Initial dosage:

• 8 to 16 mg/day PO

• Further dosages:

• 4 to 32 mg/day PO

• For patients who can not swallow a pill, follow the instructions 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:

• Prepare the vehicle by adding equal volumes of 1Ora-Plus® (80 mL) and 1Ora-Sweet SF® (80 mL) or, alternatively, use, 1,2Ora-Blend SF® (160 mL).
• Add a small amount of vehicle to the required number of ATACAND 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.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of candesartan cilexetil in children.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non-Guideline-Supported Use of candesartan cilexetil in adult patients.

Contraindications

• Hypersensitivity to candesartan.
• Do not co-administer aliskiren with candesartan cilexetil in diabetic patients.

Warnings

WARNING: FETAL TOXICITY See full prescribing information for complete Boxed Warning. When pregnancy is detected, discontinue candesartan cilexetil as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

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
• Death

• When pregnancy is detected, discontinue candesartan cilexetil as soon as possible.
• 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.

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.

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 2.0% 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 versus 13.8% treated with placebo.
• 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.

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.

Hyperkalemia

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

Adverse Reactions

Clinical Trials Experience

• Adult Hypertension:

• 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.
• 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% (ie, 108 of 3260) of patients treated with candesartan cilexetil as monotherapy and 3.5% (ie, 39 of 1106) of patients treated with placebo. In placebo-controlled trials, discontinuation of therapy due to clinical adverse events occurred in 2.4% (ie, 57 of 2350) of patients treated with candesartan cilexetil and 3.4% (ie, 35 of 1027) of patients treated with placebo.

• 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 candesartan cilexetil 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 candesartan cilexetil in total daily doses up to 32 mg once daily (n=3803) with placebo (n=3796), 21.0% of patients discontinued candesartan cilexetil for adverse events vs. 16.1% of placebo patients.

Central Nervous System

• Headache
• Dizziness
• Heart Failure

Respiratory

• Upper respiratory tract infection
• Pharyngitis
• Rhinitis

Miscellaneous

• Back pain

Postmarketing Experience

• The following adverse reactions were identified during post-approval use of candesartan cilexetil. 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.
• Rare reports of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

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

Digestive

• Abnormal hepatic function
• Hepatitis

Hematologic

• Neutropenia
• Leukopenia
• Agranulocytosis

Immunologic

• Angioedema

Metabolic and Nutritional Disorders

• Hyperkalemia
• Hyponatremia

Respiratory system disorders

• Cough

Skin and Appendages Disorders

• Pruritus
• Rash
• Urticaria

Drug Interactions

• Lithium
• NSAIDS
• Dual inhibition of the renin-angiotensin system

Lithium

• Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors, and with some angiotensin II receptor antagonists.
• An increase in serum lithium concentration has been reported during concomitant administration of lithium with candesartan cilexetil.
• Monitor serum lithium levels.

NSAIDS

• Including Selective Cyclooxygenase-2 Inhibitors (COX-2 inhibitors).
• In elderly patients, 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.

Dual inhibition of the renin-angiotensin system

• 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.
• Closely monitor blood pressure, renal function and electrolytes in patients on candesartan cilexetil and other agents that affect the RAS.
• Do not co-administer aliskiren with candesartan celexetil in patients with diabetes.
• Avoid use of aliskiren with candesartan celexetil in patients with renal impairment (GFR <60 ml/min).

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): 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
• Death

• When pregnancy is detected, discontinue candesartan celexetil as soon as possible.
• These adverse outcomes are usually associated with use of similar drugs in the second and third trimester of pregnancy.
• Most epidemiological 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 candesartan celexetil, 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 candesartan celexetil for hypotension, oliguria, and hyperkalemia.

Pregnancy Category (AUS): D There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of candesartan celexetil in women who are pregnant.

Labor and Delivery

The effect of candesartan celexetil on labor and delivery in humans is unknown.

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 candesartan celexetil, taking into account the importance of the drug to the mother.

Pediatric Use

• Neonates with a history of in utero exposure to candesartan celexetil:

• 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 candesartan celexetil were evaluated in hypertensive children 1 to < 17 years of age in randomized, double-blind clinical studies. The pharmacokinetics of candesartan celexetil have been evaluated in pediatric patients 1 to < 17 years of age.
• Children < 1 year of age must not receive candesartan celexetil for hypertension.

Geriatic Use

There is no FDA guidance on the use of Candesartan in geriatric settings.

Gender

There is no FDA guidance on the use of Candesartan with respect to specific gender populations.

Race

There is no FDA guidance on the use of Candesartan with respect to specific racial populations.

Renal Impairment

• In hypertensive patients with renal insufficiency, serum concentrations of candesartan are elevated.
• After repeated dosing, the AUC and Cmax were noted to be 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.
• In heart failure patients with renal impairment, AUC0-72h was noted to be 36% and 65% higher in mild and moderate renal impairment, respectively. Cmax was 15% and 55% higher in mild and moderate renal impairment, respectively.

Hepatic Impairment

• 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 Cmax for 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 at a lower dose

Females of Reproductive Potential and Males

• 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).

Immunocompromised Patients

There is no FDA guidance one the use of Candesartan in patients who are immunocompromised.

Administration and Monitoring

Administration

Oral

Monitoring

Fetal Toxicity

• 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
• Death

• When pregnancy is detected, discontinue candesartan cilexetil as soon as possible.

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.

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

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.

Hyperkalemia

• Drugs that inhibit the renin-angiotensin system can cause hyperkalemia.
• Monitor serum potassium periodically.

IV Compatibility

There is limited information regarding the compatibility of candesartan cilexetil and IV administrations.

Overdosage

• No lethality was observed in acute toxicity studies in mice, rats, and dogs given single oral doses of up to 2000 mg/kg of candesartan cilexetil. In mice given single oral doses of the primary metabolite, candesartan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg.
• The most likely manifestation of overdosage with candesartan cilexetil would be:

• Hypotension
• Dizziness
• Tachycardia
• Bradycardia, could occur from parasympathetic (vagal) stimulation.

• If symptomatic hypotension should occur, supportive treatment should be instituted.
• Candesartan cannot be removed by hemodialysis.
• Treatment: To obtain up-to-date information about the treatment of overdose, consult your Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR).
• In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and altered pharmacokinetics in your patient.

Pharmacology

Candesartan
Systematic (IUPAC) name
2-ethoxy-1-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1H-1,3-benzodiazole-7-carboxylic acid
Identifiers
CAS number	139481-59-7
ATC code	C09CA06
PubChem	2541
DrugBank	DB00796
Chemical data
Formula	Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox
Mol. mass	440.45
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	15% (candesartan cilexetil)
Metabolism	Candesartan cilexetil: intestinal wall; candesartan: hepatic (CYP2C9)
Half life	9 hours
Excretion	Renal 33%, faecal 67%
Therapeutic considerations
Pregnancy cat.	D(AU)
Legal status	Template:Unicode Prescription only
Routes	oral

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.

Structure

• Candesartan cilexetil, a prodrug, is hydrolyzed to candesartan during absorption from the gastrointestinal tract.
• Candesartan is a selective AT1 subtype angiotensin II receptor antagonist.
• Candesartan cilexetil, a nonpeptide, is chemically described as (±)-1-Hydroxyethyl 2-ethoxy-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester).

Its empirical formula is C33H34N6O6, and its structural formula is:

This image is provided by the National Library of Medicine.

• Candesartan cilexetil is a white to off-white powder with a molecular weight of 610.67. It is practically insoluble in water and sparingly soluble in methanol. Candesartan cilexetil is a racemic mixture containing one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group. Following oral administration, candesartan cilexetil undergoes hydrolysis at the ester link to form the active drug, candesartan, which is achiral.

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 HbA1c.

Heart failure

• In heart failure patients, candesartan ≥ 8 mg resulted in decreases in systemic vascular resistance and pulmonary capillary wedge pressure.

Pharmacokinetics

(Description)

Nonclinical Toxicology

• 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).

Clinical Studies

Condition 1

(Description)

Condition 2

(Description)

Condition 3

(Description)

How Supplied

(Description)

Storage

There is limited information regarding Candesartan Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

(Patient Counseling Information)

Precautions with Alcohol

Alcohol-Candesartan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Candesartan Brand Names in the drug label.

Look-Alike Drug Names

• (Paired Confused Name 1a) — (Paired Confused Name 1b)
• (Paired Confused Name 2a) — (Paired Confused Name 2b)
• (Paired Confused Name 3a) — (Paired Confused Name 3b)

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.