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Candesartan (Systemic)


VA CLASSIFICATION
Primary: CV805
Secondary: CV409

Commonly used brand name(s): Atacand.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antihypertensive—

Indications

Accepted

Hypertension (treatment)—Candesartan is indicated for the treatment of hypertension {01}. It may be used alone or in combination with other antihypertensive medications {01}.
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Candesartan cilexetil: 610.67 {01}

Mechanism of action/Effect:

Candesartan is a nonpeptide angiotensin II antagonist that selectively blocks the binding of angiotensin II to the AT 1 receptors in tissues such as vascular smooth muscle and the adrenal gland {01}. In the renin-angiotensin system, angiotensin I is converted by angiotensin-converting enzyme (ACE) to form angiotensin II {01}. Angiotensin II stimulates the adrenal cortex to synthesize and secrete aldosterone, which decreases the excretion of sodium and increases the excretion of potassium {01}. Angiotensin II also acts as a vasoconstrictor in vascular smooth muscle {01}. By blocking the binding of angiotensin II to the AT 1 receptors, candesartan causes vasodilation and decreases the effects of aldosterone {01}. The negative feedback regulation of angiotensin II on renin secretion also is inhibited, resulting in a rise in plasma renin concentrations and a consequent rise in angiotensin II plasma concentrations; however, these effects do not counteract the blood pressure–lowering effect that occurs {01}.

Absorption:

Absolute bioavailability of candesartan from the administered prodrug, candesartan cilexetil, has been estimated to be about 15% {01}.

Food with a high fat content does not affect the bioavailability of candesartan from candesartan cilexetil (see Biotransformation section) {01}.

Distribution:

Vol D—0.13 L per kg (L/kg) {01}. Candesartan does not penetrate red blood cells {01}. In rats, distribution across the blood-brain barrier is poor {01}.

Protein binding:

Very high (> 99%) {01}.

Biotransformation:

During absorption from the gastrointestinal tract, candesartan cilexetil undergoes rapid and complete ester hydrolysis to form the active drug, candesartan {01}. Elimination of candesartan is primarily as unchanged drug in the urine and, by the biliary route, in the feces {01}. Minor hepatic metabolism of candesartan occurs by O-deethylation to form an inactive metabolite {01}.

Half-life:


Elimination:

Approximately 9 hours {01}.


Time to peak concentration:

3 to 4 hours {01}.

Elimination:


After oral administration—
        Renal—33% {01}.
        Fecal (biliary)—67% {01}.



After intravenous administration—
        Renal—59% {01}.
        Fecal (biliary)—36% {01}.



In dialysis—
        Candesartan is not removable by hemodialysis {01}.



Precautions to Consider

Carcinogenicity

No evidence of carcinogenicity was found when candesartan cilexetil was given to mice (via diet) or rats (via gavage) for up to 104 weeks in doses of up to 300 and 1000 mg per kg of body weight (mg/kg) per day, respectively {01}. These doses represent approximately 7 and more than 70 times the maximum recommended human daily dose (MRHDD) of 32 mg, respectively {01}.

Mutagenicity

Mutagenicity was not detected for candesartan cilexetil in the microbial mutagenesis, mammalian cell mutagenesis, in vivo chromosomal aberration, and rat unscheduled DNA synthesis assays {01}. Mutagenicity was also not detected for candesartan in the microbial mutagenesis, mammalian cell mutagenesis, and in vitro and in vivo chromosome aberration assays {01}.

Pregnancy/Reproduction
Fertility—
No impairment of fertility or reproductive performance was found in male or female rats given oral doses of up to 300 mg/kg per day {01}. This dose represents 83 times the MRHDD of 32 mg on a body surface area basis {01}.

Pregnancy—
Medications that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and mortality when administered to pregnant women during the second and third trimesters {01}. Candesartan should be discontinued as soon as possible when pregnancy is detected, unless no alternative therapy can be used {01}. In the latter instance, serial ultrasound examinations should be performed to assess the intra-amniotic environment {01}. If oligohydramnios is observed, candesartan should be discontinued unless it is considered lifesaving for the mother {01}. Perinatal diagnostic tests, such as contraction-stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate during the applicable week of pregnancy {01}. However, oligohydramnios may not appear until after the fetus has sustained irreversible damage {01}.

Fetal exposure to drugs that act directly on the renin-angiotensin system during the second and third trimesters can cause hypotension, reversible or irreversible renal failure, anuria, neonatal skull hypoplasia, and death in the fetus or neonate {01}. Maternal oligohydramnios, which may result from decreased fetal renal function, has been reported, and is associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development {01}. Other adverse effects that have been reported are prematurity, intrauterine growth retardation, and patent ductus arteriosus, although it is not clear how these effects are related to drug exposure {01}. When limited to the first trimester, exposure to this medication does not appear to be associated with these adverse effects {01}.

Infants exposed in utero to angiotensin II receptor antagonists should be closely observed for hypotension, oliguria, and hyperkalemia {01}. Oliguria should be treated with support of blood pressure and renal perfusion {01}. Dialysis or exchange transfusion may be necessary to reverse hypotension and/or substitute for disordered renal function {01}.

Studies in pregnant rats given oral daily doses of ³ 10 mg per kg of candesartan during late gestation and continued through lactation resulted in reduced survival and an increase in the incidence of hydronephrosis in the offspring {01}. The 10-mg/kg dose represents 2.8 times the MRHDD of 32 mg on a mg/m 2 basis, assuming a 50-kg patient {01}.

Studies in pregnant rabbits given oral, maternally toxic (based on a reduction in body weight and death) daily doses of 3 mg/kg of candesartan resulted in no adverse effects on fetal survival, fetal weight, or external, visceral, or skeletal development in the offspring of surviving dams {01}. This dose represents approximately 1.7 times the MRHDD on a mg/m 2 basis {01}.

No maternal toxicity or adverse effects on fetal development were observed in pregnant mice given oral doses of up to 1000 mg/kg per day of candesartan {01}. This dose represents approximately 138 times the MRHDD on a mg/m 2 basis {01}.

FDA Pregnancy Category C (first trimester) {01}.

FDA Pregnancy Category D (second and third trimesters) {01}.

Breast-feeding

It is not known whether candesartan is distributed into human breast milk {01}. However, candesartan is distributed into the milk of lactating rats {01}. Because of the potential for adverse effects in the nursing infant, it is recommended that candesartan not be administered to mothers who are breast-feeding {01}.

Pediatrics

No information is available on the relationship of age to the effects of candesartan in pediatric patients. Safety and efficacy have not been established {01}.


Geriatrics


Use of candesartan in patients 65 years of age and older (21% of patients in clinical studies) has not demonstrated geriatrics-specific problems that would limit the usefulness of candesartan in the elderly {01}. However, in clinical studies, the peak plasma concentration (C max) and area under the plasma concentration–time curve (AUC) increased by 50 and 80%, respectively, when compared with those in younger patients {01}. In a placebo-controlled trial of about 200 elderly hypertensive patients, candesartan was well tolerated {01}.


Pharmacogenetics

Black patients have a somewhat smaller response to the blood pressure–lowering effects of candesartan {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Diuretics    (concurrent use with candesartan may have additive hypotensive effects {01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Blood urea nitrogen (BUN){01} and
Creatinine, serum{01}    (minor increases in concentrations have occurred infrequently in patients treated with candesartan {01})


Hematocrit{01} and
Hemoglobin{01}    (in clinical studies, small decreases in hemoglobin and hematocrit values of approximately 0.2 gram per dL and 0.5 volume %, respectively, occurred in patients treated with candesartan {01}; candesartan therapy was discontinued in three patients who experienced either anemia, leukopenia, or thrombocytopenia during these studies {01})


Liver function tests    (in clinical studies, elevations of liver enzymes and/or serum bilirubin occurred infrequently in candesartan-treated patients {01}; five patients discontinued candesartan because of abnormal liver function test values [all had elevated liver enzyme values and two had mildly elevated total bilirubin, although one (of the two) was diagnosed with Hepatitis A] {01})


Potassium, serum{01}    (in clinical studies, a mean increase of 0.1 mEq per L [mEq/L] occurred in patients treated with candesartan; one patient with congestive heart failure and concurrently receiving spironolactone was withdrawn from the trial for hyperkalemia [serum potassium of 7.5 mEq/L] {01})


Uric acid, serum{01}    (hyperuricemia occurred in 0.6% of patients treated with candesartan in clinical studies {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to candesartan
Risk-benefit should be considered when the following medical problems exist
» Congestive heart failure, severe    (therapy with angiotensin receptor antagonists in these patients, who may be especially susceptible to changes in the renin-angiotensin-aldosterone system, has been associated with oliguria, azotemia, acute renal failure, and/or death {01})


Dehydration (sodium or volume depletion, due to excessive perspiration, vomiting, diarrhea, prolonged diuretic therapy, dialysis, or dietary salt restriction{01} )    (a reduction in salt or fluid volume may increase the risk of symptomatic hypotension {01})


Hepatic function impairment, severe    (no information is available on the use of candesartan in patients with severe hepatic function impairment {01})


Renal artery stenosis, unilateral or bilateral{01} or
Renal function impairment{01}    (increases in candesartan serum concentrations have occurred in patients with renal function impairment {01}; in patients with severe renal function impairment [creatinine clearance < 30 mL per minute (mL/min) {01}], the area under the plasma concentration–time curve [AUC] and peak plasma concentration [C max] were approximately doubled during repeated dosing in clinical trials {01}. Increases in serum creatinine or blood urea nitrogen [BUN] have occurred in patients with unilateral or bilateral renal artery stenosis and treated with angiotensin-converting enzyme [ACE] inhibitors {01}; similar increases may also occur in patients treated with candesartan {01}. Changes in renal function as a result of therapy with angiotensin receptor–antagonists in patients susceptible to changes in the renin-angiotensin-aldosterone system [such as patients with severe congestive heart failure] have been associated with oliguria, progressive azotemia, acute renal failure, and/or death {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood pressure measurements{01}    (periodic monitoring is necessary for titration of dose according to the patient's response {01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Hyperuricemia or gout{01} (joint pain, lower back or side pain, swelling of feet or lower legs)
    
hypotension{01} (dizziness, lightheadedness, or fainting)—usually seen in volume- or salt-depleted patients{01}
    
leukopenia{01} (cough or hoarseness; chills or fever; lower back or side pain; painful or difficult urination)—usually asymptomatic
    
thrombocytopenia{01} (nosebleeds or bleeding gums)



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Back pain{01}
    
dizziness{01}
    
headache{01}
    
pharyngitis{01} (sore throat)
    
rhinitis{01} (stuffy nose)
    
upper respiratory tract infection{01} (coughing; ear congestion or pain; fever; head congestion; nasal congestion; runny nose; sneezing; sore throat)


Note: In clinical trials, the side effects that most often resulted in the discontinuation of candesartan were headache (incidence 0.6%) and dizziness (incidence 0.3%) {01}.





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and/or chronic
    
Bradycardia{01} (slow heartbeat)—as a result of parasympathetic (vagal) stimulation{01}
    
dizziness{01}
    
hypotension{01} (dizziness, lightheadedness, or fainting)
    
tachycardia{01} (fast heartbeat)


Treatment of overdose
Treatment should be symptomatic and supportive {01}.

Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Candesartan (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to candesartan

Pregnancy—Fetal and neonatal hypotension, skull hypoplasia, renal failure, and death have been reported; candesartan should be discontinued as soon as possible when pregnancy is detected





Breast-feeding—Candesartan is distributed into the milk of lactating rats; not recommended in mothers who are breast-feeding





Use in the elderly—Area under the plasma concentration–time curve (AUC) and peak plasma concentration (C max) may be increased
Pharmacogenetics—Black patients may have a somewhat smaller therapeutic response
Other medical problems, especially severe congestive heart failure

Proper use of this medication
» Compliance with therapy; taking medication at the same time each day to maintain the antihypertensive effect

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses

» Proper storage

Precautions while using this medication
Visiting the physician regularly to check progress

Notifying physician immediately if pregnancy is suspected

Not taking other medications without consulting the physician

Caution when driving or doing other things requiring alertness, because of possible dizziness

To prevent dehydration and hypotension, checking with physician if severe nausea, vomiting, or diarrhea occurs and continues

Caution when exercising or during exposure to hot weather, because of the risk of dehydration and hypotension due to reduced fluid volume


Side/adverse effects
Signs of potential side effects, especially hyperuricemia, hypotension, leukopenia, and thrombocytopenia


General Dosing Information
Dosage must be adjusted, on the basis of clinical response, to meet the individual requirements of each patient.

Diet/Nutrition
Candesartan may be taken with or without food {01}.

For treatment of adverse effects
Recommended treatment consists of the following:    • Treatment of symptomatic hypotension involves placing the patient in a supine position and, if needed, administering normal saline intravenously {01}.



Oral Dosage Forms

CANDESARTAN CILEXETIL TABLETS

Usual adult dose
Antihypertensive
Oral, initially 16 mg once a day, when used as monotherapy in patients who are not volume-depleted {01}. Candesartan may be administered once or twice daily with total daily doses ranging from 8 to 32 mg {01}. Larger doses do not appear to have a greater antihypertensive effect {01}. The antihypertensive effect is considerable within two weeks of candesartan therapy, and maximal antihypertensive effect usually is attained within four to six weeks of therapy {01}. If blood pressure is not controlled by candesartan alone, a diuretic may be added {01}.

Patients with volume depletion (e.g., from diuretic treatment) and/or renal function impairment should be closely monitored during initiation of therapy and may require a lower dose {01}.


Usual adult prescribing limits
32 mg per day {01}.

Usual pediatric dose
Safety and efficacy have not been established {01}.

Strength(s) usually available
U.S.—


4 mg (Rx) [Atacand (carboxymethylcellulose calcium) (corn starch) (hydroxypropyl cellulose) (lactose) (magnesium stearate) (polyethylene glycol)]


8 mg (Rx) [Atacand (carboxymethylcellulose calcium) (corn starch) (ferric oxide) (hydroxypropyl cellulose) (lactose) (magnesium stearate) (polyethylene glycol)]


16 mg (Rx) [Atacand (carboxymethylcellulose calcium) (corn starch) (ferric oxide) (hydroxypropyl cellulose) (lactose) (magnesium stearate) (polyethylene glycol)]


32 mg (Rx) [Atacand (carboxymethylcellulose calcium) (corn starch) (ferric oxide) (hydroxypropyl cellulose) (lactose) (magnesium stearate) (polyethylene glycol)]

Packaging and storage:
Store at 25 ºC (77 ºF) {01}. Fluctuations between 15 and 30 °C (59 and 86 °F) are acceptable {01}. Store in tight container {01}.

Auxiliary labeling:
   • Do not take other medicines without your doctor's advice.



Developed: 11/23/1998



References
  1. Candesartan package insert (Astra—US), New 6/98, Rec 9/98.
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