CANDERAX PLUS

Candesartan is an angiotensin-receptor blocker (ARB) that may be used alone or with other agents to treat hypertension.

It is administered

Oral as the prodrug, candesartan cilexetil, which is rapidly converted to its active metabolite, candesartan, during absorption in the gastrointestinal tract.

Candesartan lowers blood pressure by antagonizing the renin-angiotensin-aldosterone system (RAAS); it competes with angiotensin II for binding to the type-1 angiotensin II receptor (AT1) subtype and prevents the blood pressure increasing effects of angiotensin II.

Unlike angiotensin-converting enzyme (ACE) inhibitors, ARBs do not have the adverse effect of dry cough.

Candesartan may be used to treat hypertension, isolated systolic hypertension, left ventricular hypertrophy and diabetic nephropathy.

It may also be used as an alternative agent for the treatment of heart failure, systolic dysfunction, myocardial infarction and coronary artery disease.

May be used as a first line agent to treat uncomplicated hypertension, isolated systolic hypertension and left ventricular hypertrophy.

May be used as a first line agent to delay progression of diabetic nephropathy.

Candesartan may be also used as a second line agent in the treatment of congestive heart failure, systolic dysfunction, myocardial infarction and coronary artery disease in those intolerant of ACE inhibitors.

Candesartan cilexetil is an

ARB prodrug that is rapidly converted to candesartan, its active metabolite, during absorption from the gastrointestinal tract.

Candesartan confers blood pressure lowering effects by antagonizing the hypertensive effects of angiotensin II via the RAAS.

RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance.

During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys.

Renin cleaves circulating angiotensinogen to angiotensin

I, which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II.

II increases blood pressure by increasing total peripheral resistance, increasing sodium and water reabsorption in the kidneys via aldosterone secretion, and altering cardiovascular structure.

II binds to two receptors: type-1 angiotensin II receptor (AT1) and type-2 angiotensin II receptor (AT2).

AT1 is a G-protein coupled receptor (GPCR) that mediates the vasoconstrictive and aldosterone-secreting effects of angiotensin II.

Studies performed in recent years suggest that AT2 antagonizes AT1-mediated effects and directly affects long-term blood pressure control by inducing vasorelaxation and increasing urinary sodium excretion.

Angiotensin receptor blockers (ARBs) are non-peptide competitive inhibitors of AT1.

ARBs block the ability of angiotensin

II to stimulate pressor and cell proliferative effects.

ACE inhibitors, ARBs do not affect bradykinin-induced vasodilation.

The overall effect of

ARBs is a decrease in blood pressure.

Following administration of the candesartan cilexetil prodrug, the absolute bioavailability of candesartan was estimated to be 15%.

Food with a high fat content has no effect on the bioavailability of candesartan from candesartan cilexetil.

The prodrug candesartan cilexetil undergoes rapid and complete ester hydrolysis in the intestinal wall to form the active drug, candesartan.

Elimination of candesartan is primarily as unchanged drug in the urine and, by the biliary route, in the feces.

Minor hepatic metabolism of candesartan (<20%) occurs by O-deethylation via cytochrome P450 2C9 to form an inactive metabolite.

Candesartan undergoes

N-glucuronidation in the tetrazole ring by uridine diphosphate glucuronosyltransferase 1A3 (UGT1A3).

O-glucuronidation may also occur. 75% of candesartan is excreted as unchanged drug in urine and feces.

Hover over products below to view reaction partners Candesartan cilexetil Candesartan Candesartan O-glucuronide Candesartan N2-glucuronide O-Deethylated candesartan.

When candesartan is administered

Oral, about 26% of the dose is excreted unchanged in urine.

Candesartan is mainly excreted unchanged in urine and feces (via bile).

Approximately 9 hours.

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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 or in rats given single oral doses of up to 2000 mg/kg of candesartan cilexetil in combination with 1000 mg/kg of hydrochlorothiazide.

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.

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.