EXCAN

Candesartan cilexetil, a prodrug, is hydrolyzed to candesartan during absorption from the gastrointestinal tract.

Candesartan is a selective

AT 1 subtype angiotensin II receptor antagonist.

Candesartan cilexetil, a nonpeptide, is chemically described as (±).

• Hydroxyethyl 2.

• [ p - ( o - 1 H - tetrazol - 5­ ylphenyl) benzyl].

• 7 -benzimidazolecarboxylate, cyclohexyl carbonate (ester).

Its empirical formula is

C 33 H 34 N 6 O 6, and its structural formula is Candesartan cilexetil, USP 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.

Candesartan cilexetil is available for oral use as tablet containing 32 mg of candesartan cilexetil, USP and the following inactive ingredients: mannitol, pullulan, carboxymethylcellulose calcium, corn starch, polyethylene glycol, hydroxypropyl cellulose, magnesium stearate and lactose monohydrate.

The 32 mg tablet contains iron oxide red as a colorant.

Candesartan cilexetil tablets are an angiotensin

II receptor blocker (ARB) indicated for: · Treatment of hypertension in adults and children 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. · Treatment of heart failure (NYHA class II-IV); candesartan cilexetil tablets reduces cardiovascular death and heart failure hospitalization 1.1 Hypertension Candesartan cilexetil tablets are indicated for the treatment of hypertension in adults and in children to <17 years of age, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions.

These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.

Many patients will require more than one drug to achieve blood pressure goals.

For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits.

The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit.

Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).

These considerations may guide selection of therapy.

Candesartan cilexetil tablets may be used alone or in combination with other antihypertensive agents. 1.2 Heart Failure Candesartan cilexetil tablets are indicated for the treatment of heart failure (NYHA class II-IV) in adults with left ventricular systolic dysfunction (ejection fraction ≤40%) to reduce cardiovascular death and to reduce heart failure hospitalizations.

Candesartan cilexetil tablets also have an added effect on these outcomes when used with an ACE inhibitor.

Lactation Anesthesia Obstructive Cardiomyopathy

Child between and 18 years Primary hyperaldosteronism Hypovolaemia Severe congestive heart failure Mild to moderate hepatic impairment Renal impairment Brain failure Surgical intervention Myocardial Ischemia Hemodialysis patient Aortic rectification Mitral shrinkage Subject over 75 years Black subject.

Mechanism of Action Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II).

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 AT 1 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

AT 2 receptor found in many tissues, but AT is not known to be associated with cardiovascular homeostasis.

Candesartan has much greater affinity (>10,000-fold) for the AT 1 receptor than for the AT 2 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. 12.2 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.

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 HbA 1c.

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

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 of 14 C-labeled candesartan cilexetil, approximately 33% of radioactivity is recovered in urine and approximately 67% in feces.

Following an intravenous dose of 14 C-labeled candesartan, approximately 59% of radioactivity is recovered in urine and approximately 36% in feces.

Biliary excretion contributes to the elimination of candesartan.

Candesartan cilexetil is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan, a selective AT1 subtype 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 to 4 hours.

Food with a high fat content does not affect the bioavailability of candesartan after candesartan cilexetil administration.

In children 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 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 max and 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.

Administering drugs that act directly on the renin-angiotensin system (RAS) can alter normal renal development.

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 max was 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.

There is no difference in the pharmacokinetics of candesartan between male and female subjects.

In hypertensive patients with renal insufficiency, serum concentrations of candesartan were elevated.

After repeated dosing, the AUC and C max were approximately doubled in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73m 2 ) 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, AUC 0-72h was 36% and 65% higher in mild and moderate renal impairment, respectively.

C max was 15% and 55% higher in mild and moderate renal impairment, respectively.

Candesartan cilexetil pharmacokinetics has not been determined in children with renal 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).

C max 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 cilexetil at a lower dose.

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.

Mechanism of action Angiotensin

II is the main vasoactive hormone in the renin-angiotensin-aldosterone system that plays a role in the physiopathology of hypertension, heart failure and other cardiovascular disorders.

It also participates in the pathogenesis of hypertrophy and damage of the target organs.

The major physiological effects of angiotensin

II such as vasoconstriction, aldosterone stimulation, regulation of hydrosodium homoeostasis and stimulation of cell growth are exercised via the receptor type 1 (AT1).

Candesartan cilexetil is a prodrogue-reactive agent suitable for the oral administration.

It is rapidly transformed, after oral administration, the active principle of candesartan, by hydrolysis of a group ester during gastrointestin absorption.

Candesartan is an

ARIII, selective of the AT1 receptors, with a high concentration of the plasma II-enzyme and a possible-absorbntary-absorbntary of the canadycin no activity.

• Hyperkalaemia (Common)
• Hyponatremia (Very rare)
• Liver enzymes (increase) (Very rare)
• Neutropenia (Very rare)
• Blood globinaemia (decrease)
• Urticaria (Very rare)
• Rash (Very rare)
• Pruritus (Very rare)
• Fever (Common)
• Agranulocytosis (Very rare)
• Leucopenia (Very rare)
• Hepatitis (Very rare)
• Angioedema (Very rare)
• Vertigo (Common)
• Oropharyngeal pain (Very common)
• Feeling dizzy (Common)
• Rhinophyryngitis (Common)
• Sinus arrhythmia (Common)
• Hypotension (Common)
• Heart failure Intestinal angioedema (Very rare)
• Nausea (Very rare)
• Abnormal liver function (Very rare)
• Diarrhoea Muscle pain (Very rare)
• Joint pain (Very rare)
• Sleeping (Very rare)
• Headache (Common)
• Respiratory infection (Common)
• Cough (Very common)
• Upper respiratory tract infection (Very common)
• Renal impairment (Very rare)
• Renal impairment.

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, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation.

If symptomatic hypotension should occur, supportive treatment should be instituted.

Candesartan cannot be removed by hemodialysis.

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.

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.

Known hypersensitivity to product components.

Hypertension 16 mg tablet once daily to 32 mg tablet total daily dose Pediatric Hypertension (1 to ˂6 years) 0.2 mg/kg oral suspension once daily 0.05 to 0.4 mg/kg oral suspension once daily or consider divided dose Pediatric Hypertension (6 to ˂17 years) <50 kg to 8 mg tablet once daily >50 kg to 16 mg tablet once daily <50 kg to 16 mg tablet once daily or consider divided dose >50 kg to 32 mg tablet once daily or consider divided dose Adult Heart Failure 4 mg tablet 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 patient 2.1 Adult Hypertension Dosage must be individualized.

Blood pressure response is dose related over the range of to 32 mg. The usual recommended starting dose of candesartan cilexetil tablet is 16 mg once daily when it is 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 to 6 weeks of treatment with candesartan cilexetil tablets.

Initiate with 8 mg candesartan cilexetil tablets in patients with moderate hepatic insufficiency.

Dosing recommendations cannot be provided for patients with severe hepatic insufficiency.

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. 2.2 Pediatric Hypertension 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.

Children to <6 years of age: The dose range is 0.05 to 0.4 mg/kg per day. The recommended starting dose is 0.2 mg/kg (oral suspension).

Children to <17 years of age: For those less than 50 kg, the dose range is to 16 mg per day. The recommended starting dose is to 8 mg. For those greater than 50 kg, the dose range is to 32 mg per day. The recommended starting dose is 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.

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/1.73 m 2 should not receive candesartan cilexetil tablets since candesartan cilexetil tablets has not been studied in this population.

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 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. · 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. 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.

Candesartan cilexetil tablets

USP, 32 mg are light pink, round, biconvex, uncoated mottled tablets debossed with ‘L171’on one side and scoring on other side.

They are supplied as follows

NDC 62332-060-30 bottle of 30 tablets NDC 62332-060-90 bottle of 90 tablets NDC 62332-060-10 carton of 100 (10 x 10) unit dose tablets Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

Keep container tightly closed.

Candesartan cilexetil can cause fetal harm when administered to a pregnant woman.

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

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 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.

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 cilexetil for hypotension, oliguria, hyperkalemia or other symptoms of renal impairment.

In neonates with a history of in utero exposure to candesartan cilexetil, 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.

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/m 2 basis (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/m 2 basis), 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/m 2 basis) were administered to pregnant mice.

The antihypertensive effects of candesartan cilexetil were evaluated in hypertensive children to <17 years of age in randomized, double-blind clinical studies.

The pharmacokinetics of candesartan cilexetil have been evaluated in pediatric patients to <17 years of age.

Children <1 year of age must not receive candesartan cilexetil for hypertension.