candesartan cilexetil 16 MG Oral Tablet
DRUG INTERACTIONS
7 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.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.
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, 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.In patients who are elderly, 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.The antihypertensive effect of angiotensin II receptor antagonists, including candesartan may be attenuated by NSAIDs including selective COX-2 inhibitors.
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.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.
Dual Blockade of the Renin-angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.
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 cilexetil in patients with diabetes.
Avoid use of aliskiren with candesartan cilexetil in patients with renal impairment (GFR <60 ml/min) [see CONTRAINDICATIONS (4) ].
Lithium: Reversible increases in serum lithium concentrations and toxicity ( 7).
NSAIDS use may lead to increased risk of renal impairment and loss of antihypertensive effect ( 7).
Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia ( 7).
OVERDOSAGE
10 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.
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.
DESCRIPTION
11 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 (±)2-Ethoxy-1-[[2’-(1 H-tetrazol-5-yl)[1,1’-biphenyl]-4-yl]methyl]-1 H-benzimidazole-7-carboxylic acid-1-[[cyclohexyloxy)carbonyl]oxy]ethyl ester.
Its molecular formula is C 33H 34N 6O 6, and its structural formula is: Candesartan cilexetil, USP is a white to off-white powder with a molecular weight of 610.66.
It is soluble in methylene chloride, slightly soluble in methanol and practically insoluble in water.
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 tablets containing either 4 mg, 8 mg, 16 mg, or 32 mg of candesartan cilexetil, USP and the following inactive ingredients: hydroxypropyl cellulose, lactose monohydrate, maize starch, carboxymethylcellulose calcium, glyceryl stearate and magnesium stearate.
The 8 mg, 16 mg, and 32 mg tablets contain red iron oxide as a colorant.
Structural formula
CLINICAL STUDIES
14 14.1 Hypertension Adult The antihypertensive effects of candesartan cilexetil were examined in 14 placebo-controlled trials of 4- to 12-weeks duration, primarily at daily doses of 2 to 32 mg per day in patients with baseline diastolic blood pressures of 95 to 114 mm Hg.
Most of the trials were of candesartan cilexetil as a single agent, but it was also studied as add-on to hydrochlorothiazide and amlodipine.
These studies included a total of 2350 patients randomized to one of several doses of candesartan cilexetil and 1027 to placebo.
Except for a study in diabetics, all studies showed significant effects, generally dose related, of 2 to 32 mg on trough (24 hour) systolic and diastolic pressures compared to placebo, with doses of 8 to 32 mg giving effects of about 8 to 12/4 to 8 mm Hg.
There were no exaggerated first-dose effects in these patients.
Most of the antihypertensive effect was seen within 2 weeks of initial dosing and the full effect in 4 weeks.
With once-daily dosing, blood pressure effect was maintained over 24 hours, with trough to peak ratios of blood pressure effect generally over 80%.
Candesartan cilexetil had an additional blood pressure lowering effect when added to hydrochlorothiazide.
The antihypertensive effects of candesartan cilexetil and losartan potassium at their highest recommended doses administered once-daily were compared in two randomized, double-blind trials.
In a total of 1268 patients with mild to moderate hypertension who were not receiving other antihypertensive therapy, candesartan cilexetil 32 mg lowered systolic and diastolic blood pressure by 2 to 3 mm Hg on average more than losartan potassium 100 mg, when measured at the time of either peak or trough effect.
The antihypertensive effects of twice daily dosing of either candesartan cilexetil or losartan potassium were not studied.
The antihypertensive effect was similar in men and women and in patients older and younger than 65.
Candesartan was effective in reducing blood pressure regardless of race, although the effect was somewhat less in blacks (usually a low-renin population).
This has been generally true for angiotensin II antagonists and ACE inhibitors.
In long-term studies of up to 1 year, the antihypertensive effectiveness of candesartan cilexetil was maintained, and there was no rebound after abrupt withdrawal.
There were no changes in the heart rate of patients treated with candesartan cilexetil in controlled trials.
Pediatric The antihypertensive effects of candesartan cilexetil were evaluated in hypertensive children 1 to < 6 years old and 6 to < 17 years of age in two randomized, double-blind multicenter, 4-week dose ranging studies.
There were 93 patients 1 to < 6 years of age, 74% of whom had renal disease, that were randomized to receive an oral dose of candesartan cilexetil suspension 0.05, 0.20 or 0.40 mg/kg once daily.
The primary method of analysis was slope of the change in systolic blood pressure (SBP) as a function of dose.
Since there was no placebo group, the change from baseline likely overestimates the true magnitude of blood pressure effect.
Nevertheless, SBP and diastolic blood pressure (DBP) decreased 6/5.2 to 12/11.1 mmHg from baseline across the three doses of candesartan.
In children 6 to < 17 years, 240 patients were randomized to receive either placebo or low, medium, or high doses of candesartan cilexetil in a ratio of 1: 2: 2: 2.
For children who weighed < 50 kg the doses of candesartan cilexetil were 2, 8, or 16 mg once daily.
For those > 50 kg the candesartan cilexetil doses were 4, 16 or 32 mg once daily.
Those enrolled were 47% Black and 29% were female; mean age +/- SD was 12.9 +/- 2.6 years.
The placebo subtracted effect at trough for sitting systolic blood pressure/sitting diastolic blood pressure for the different doses were from 4.9/3 to 7.5/6.2 mmHg.
In children 6 to < 17 years there was a trend for a lesser blood pressure effect for Blacks compared to other patients.
There were too few individuals in the age group of 1 to 6 years old to determine whether Blacks respond differently than other patients to candesartan cilexetil.
14.2 Heart Failure Candesartan was studied in two heart failure outcome studies: 1.
The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity trial in patients intolerant of ACE inhibitors (CHARM–Alternative), 2.
CHARM–Added in patients already receiving ACE inhibitors.
Both studies were international double-blind, placebo-controlled trials in patients with NYHA class II – IV heart failure and LVEF ≤40%.
In both trials, patients were randomized to placebo or candesartan cilexetil (initially 4 to 8 mg once daily, titrated as tolerated to 32 mg once daily) and followed for up to 4 years.
Patients with serum creatinine > 3 mg/dL, serum potassium > 5.5 mEq/L, symptomatic hypotension or known bilateral renal artery stenosis were excluded.
The primary end point in both trials was time to either cardiovascular death or hospitalization for heart failure.
CHARM–Alternative included 2028 subjects not receiving an ACE inhibitor due to intolerance.
The mean age was 67 years and 32% were female, 48% were NYHA II, 49% were NYHA III, 4% were NYHA IV, and the mean ejection fraction was 30%.
Sixty-two percent had a history of myocardial infarction, 50% had a history of hypertension, and 27% had diabetes.
Concomitant drugs at baseline were diuretics (85%), digoxin (46%), beta-blockers (55%), and spironolactone (24%).
The mean daily dose of candesartan cilexetil was approximately 23 mg and 59% of subjects on treatment received 32 mg once daily.
After a median follow-up of 34 months, there was a 23% reduction in the risk of cardiovascular death or heart failure hospitalization on candesartan cilexetil (p<0.001), with both components contributing to the overall effect ( Table 1).
Table 1.
CHARM — Alternative: Primary Endpoint and its Components Endpoint (time to first event) Candesartan Cilexetil (n= 1013) Placebo (n=1015) Hazard Ratio (95% CI) p-value (logrank) CV death or heart failure hospitalization 334 406 0.77 (0.67 to 0.89) <0.001 CV death 219 252 0.85 (0.71 to 1.02) 0.072 Heart failure hospitalization 207 286 0.68 (0.57 to 0.81) <0.001 In CHARM–Added, 2548 subjects receiving an ACE inhibitor were randomized to candesartan cilexetil or placebo.
The specific ACE inhibitor and dose were at the discretion of the investigators, who were encouraged to titrate patients to doses known to be effective in clinical outcome trials, subject to patient tolerability.
Forced titration to maximum tolerated doses of ACE inhibitor was not required.
The mean age was 64 years and 21% were female, 24% were NYHA II, 73% were NYHA III, 3% were NYHA IV, and the mean ejection fraction was 28%.
Fifty-six percent had a history of myocardial infarction, 48% had a history of hypertension, and 30% had diabetes.
Concomitant drugs at baseline in addition to ACE inhibitors were diuretics (90%), digoxin (58%), beta-blockers (55%), and spironolactone (17%).
The mean daily dose of candesartan cilexetil was approximately 24 mg and 61% of subjects on treatment received 32 mg once daily.
After a median follow-up of 41 months, there was a 15% reduction in the risk of cardiovascular death or heart failure hospitalization on candesartan cilexetil (p=0.011), with both components contributing to the overall effect ( Table 2).
There was no evident relationship between dose of ACE inhibitor and the benefit of candesartan cilexetil.
Table 2.
CHARM — Added: Primary Endpoint and its Components Endpoint (time to first event) Candesartan Cilexetil (n=1276) Placebo (n=1272) Hazard Ratio (95% CI) p-value (logrank) CV death or heart failure hospitalization 483 538 0.85 (0.75 to 0.96) 0.011 CV death 302 347 0.84 (0.72 to 0.98) 0.029 Heart failure hospitalization 309 356 0.83 (0.71 to 0.96) 0.014 In these two studies, the benefit of candesartan cilexetil in reducing the risk of CV death or heart failure hospitalization (18% p<0.001) was evident in major subgroups (see Figure), and in patients on other combinations of cardiovascular and heart failure treatments, including ACE inhibitors and beta-blockers.
Figure.
CV Death or Heart Failure Hospitalization in Subgroups – LV Systolic Dysfunction Trials Figure
HOW SUPPLIED
16 /STORAGE AND HANDLING Candesartan cilexetil tablets are available containing 16 mg of candesartan cilexetil, USP.
16 mg, pink, mottled round tablets debossed with M on left side of the score and C on right side of the score on one side of the tablet and 31 on the other side.
They are available as follows: Unit dose packages of 30 (5 x 6) NDC 68084-877-25 Storage Store at 20º to 25ºC (68º to 77ºF) [see USP Controlled Room Temperature].
FOR YOUR PROTECTION: Do not use if blister is torn or broken.
RECENT MAJOR CHANGES
Recent Major Changes Contraindications ( 4) 04/2013 Warnings and Precautions, Fetal Toxicity ( 5.1) 04/2012 Drug Interactions, Dual Blockade of the Renin-Angiotensin System ( 7) 04/2013
DOSAGE FORMS AND STRENGTHS
3 DOSAGE FORMS and STRENGTHS 4 mg, white to off-white, round tablets debossed with M on left side of the score and C on right side of the score on one side of the tablet and 24 on the other side.
8 mg, pink, round tablets debossed with M on left side of the score and C on right side of the score on one side of the tablet and 25 on the other side.
16 mg, pink, round tablets debossed with M on left side of the score and C on right side of the score on one side of the tablet and 31 on the other side.
32 mg, pink, round tablets debossed with MC above the score and 32 below the score on one side of the tablet and blank on the other side.
.
Tablets 4 mg, 8 mg, 16 mg, 32 mg (3).
MECHANISM OF ACTION
12.1 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 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 2 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.
INDICATIONS AND USAGE
1 Candesartan Cilexetil Tablets are an angiotensin II receptor blocker (ARB) indicated for: Treatment of hypertension in adults and children 1 to < 17 years of age (1.1).
Treatment of heart failure (NYHA class II-IV); candesartan cilexetil tablets reduces cardiovascular death and heart failure hospitalization (1.2).
1.1 Hypertension Candesartan cilexetil tablets are indicated for the treatment of hypertension in adults and children 1 to < 17 years of age.
It may be used alone or in combination with other antihypertensive agents.
1.2 Heart Failure Candesartan cilexetil tablets is indicated for the treatment of heart failure (NYHA class II-IV) in adults with left ventricular systolic dysfunction (ejection fraction ≤ 40%) to reduce cardiovascular death and to reduce heart failure hospitalizations [see CLINICAL STUDIES (14.2) ].
Candesartan cilexetil tablets also have an added effect on these outcomes when used with an ACE inhibitor.
PEDIATRIC USE
8.4 Pediatric Use Neonates with a history of in utero exposure to Candesartan Cilexetil 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 cilexetil were evaluated in hypertensive children 1 to < 17 years of age in randomized, double-blind clinical studies [see CLINICAL STUDIES (14.1) ].
The pharmacokinetics of candesartan cilexetil have been evaluated in pediatric patients 1 to < 17 years of age [see Pharmacokinetics (12.3) ].
Children < 1 year of age must not receive candesartan cilexetil for hypertension [see WARNINGS AND PRECAUTIONS (5.2)].
PREGNANCY
8.1 Pregnancy 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, and death.
When pregnancy is detected, discontinue candesartan cilexetil as soon as possible.
These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy.
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.
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 cilexetil, 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 cilexetil for hypotension, oliguria, and hyperkalemia.
[see USE IN SPECIFIC POPULATIONS (8.4) ].
NUSRING MOTHERS
8.3 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 cilexetil, taking into account the importance of the drug to the mother.
BOXED WARNING
WARNING: FETAL TOXICITY When pregnancy is detected, discontinue candesartan cilexetil tablets as soon as possible.
(5.1) Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
(5.1) WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning.
When pregnancy is detected, discontinue candesartan cilexetil tablets as soon as possible.
(5.1) Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
(5.1)
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Observe for signs and symptoms of hypotension (5.3).
Monitor renal function (5.4) and potassium levels (5.5).
5.1 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 and death.
When pregnancy is detected, discontinue candesartan cilexetil as soon as possible [see USE IN SPECIFIC POPULATIONS (8.1) ].
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 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/m 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/m basis) were administered to pregnant mice.
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 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) 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.
5.2 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.
5.3 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, diatary 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% 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 [see DRUG INTERACTIONS (7) ].
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.
5.4 Impaired Renal Function Monitor renal function periodically in patients treated with candesartan cilexetil.
Changes in renal function including acute renal filure 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., patients with renal artery stenosis, chronic kidney diseas, 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 or abnormal renal function (e.g., creatinine increase) was 15% in patients treated with candesartan cilxetil versus 9% in patients treated with placebo [see DRUG INTERACTIONS (7) ].
5.5 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 [see DRUG INTERACTIONS ( 7 )].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information).
17.1 Pregnancy Female patients of childbearing age should be told about the consequences of exposure to Candesartan cilexetil tablets during pregnancy.
Discuss treatment options with women planning to become pregnant.
Patients should be asked to report pregnancies to their physicians as soon as possible.
DOSAGE AND ADMINISTRATION
2 Starting Dose Dose Range Target Maintenance Dose Adult Hypertension ( 2.1) 16 mg tablet once daily 8 to32 mg tablet total daily dose – Pediatric Hypertension (1 to < 6 years) ( 2.2) 0.20 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) ( 2.2) 50 kg 8 to 16 mg tablet once daily 50 kg 4 to 32 mg tablet once daily or consider divided dose – Adult Heart Failure ( 2.3) 4 mg tablet once daily 32 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 2 to 32 mg.
The usual recommended starting dose of candesartan cilexetil tablets 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 4 to 6 weeks of treatment with candesartan cilexetil tablets.
Use in Hepatic Impairment: Initiate with 8 mg candesartan cilexetil tablets in patients with moderate hepatic insufficiency.
Dosing recommendations cannot be provided for patients with severe hepatic insufficiency [see CLINICAL PHARMACOLOGY (12.3) ].
Candesartan cilexetil tablets may be administered with or without food.
If blood pressure is not controlled by candesartan cilexetil tablets alone, a diuretic may be added.
Candesartan cilexetil tablets may be administered with other antihypertensive agents.
2.2 Pediatric Hypertension 1 to < 17 Years of age Candesartan cilexetil tablets may be administered once daily or divided into two equal doses.
Adjust the dosage according to blood pressure response.
For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), initiate candesartan cilexetil tablets under close medical supervision and consider administration of a lower dose [see WARNINGS AND PRECAUTIONS (5.3) ].
Children 1 to < 6 years of age: The dose range is 0.05 to 0.4 mg/kg per day.
The recommended starting dose is 0.20 mg/kg (oral suspension).
Children 6 to < 17 years of age: For those less than 50 kg, the dose range is 2 to 16 mg per day.
The recommended starting dose is 4 to 8 mg.
For those greater than 50 kg, the dose range is 4 to 32 mg per day.
The recommended starting dose is 8 to 16 mg.
Doses above 0.4 mg/kg (1 to < 6 year olds) or 32 mg (6 to < 17 year olds) have not been studied in pediatric patients [see CLINICAL STUDIES (14.1)] .
An antihypertensive effect is usually present within 2 weeks, with full effect generally obtained within 4 weeks of treatment with candesartan cilexetil tablets.
Children < 1 year of age must not receive candesartan cilexetil tablets for hypertension.
All pediatric patients with a glomerular filtration rate less than 30 ml/min/1.73m 2 should not receive candesartan cilexetil tablets since candesartan cilexetil tablets have not been studied in this population [see SPECIAL POPULATIONS (8) ].
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 20º to 25ºC (68º to 77ºF).
[See USP Controlled Room Temperature].
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.