DRUGS & SUPPLEMENTS
Recent Major Changes
Warnings and Precautions, Fetal Toxicity (5.1) 04/2012
WARNING: FETAL TOXICITY
WARNING: FETAL TOXICITY
See Full Prescribing Information for complete boxed warning.
1 INDICATIONS AND USAGE
Candelong is an angiotensin II receptor blocker indicated for:
Candelong is 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
Candelong 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 . Candelong also has an added effect on these outcomes when used with an ACE inhibitor.
2 DOSAGE AND ADMINISTRATION
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 Candelong is 16 mg once daily when it is used as monotherapy in patients who are not volume depleted. Candelong 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 Candelong.
No initial dosage adjustment is necessary for elderly patients, for patients with mildly impaired renal function, or for patients with mildly impaired hepatic function . In patients with moderate hepatic impairment, consideration should be given to initiation of Candelong at a lower dose . For patients with possible depletion of intravascular volume (eg, patients treated with diuretics, particularly those with impaired renal function), Candelong should be initiated under close medical supervision and consideration should be given to administration of a lower dose .
Candelong may be administered with or without food.
If blood pressure is not controlled by Candelong alone, a diuretic may be added. Candelong may be administered with other antihypertensive agents.
2.2 Pediatric Hypertension 1 to < 17 Years of age
Candelong 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, initiate Candelong under close medical supervision and consider administration of a lower dose .
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 .
An antihypertensive effect is usually present within 2 weeks, with full effect generally obtained within 4 weeks of treatment with Candelong.
Children < 1 year of age must not receive Candelong for hypertension.
All pediatric patients with a glomerular filtration rate less than 30 ml/min/1.73m2 should not receive Candelong since Candelong 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:
Candelong oral suspension can be prepared in concentrations within the range of 0.1 to 2.0 mg/mL. Typically, a concentration of 1 mg/mL will be suitable for the prescribed dose. Any strength of Candelong 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.
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.
3 DOSAGE FORMS and STRENGTHS
4 mg are white to off-white, circular/biconvex-shaped, non-film-coated scored tablets, coded ACF on one side and 004 on the other.
8 mg are light pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACG on one side and 008 on the other.
16 mg are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACH on one side and 016 on the other.
32 mg are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACL on one side and 032 on the other.
Tablets 4 mg, 8 mg, 16 mg, 32 mg (3).
Candelong is contraindicated in patients who are hypersensitive to any component of this product.
Known hypersensitivity to product components (4).
5 WARNINGS AND PRECAUTIONS
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 Candelong 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/m2 basis (comparison assumes human body weight of 50 kg). Candelong given to pregnant rabbits at an oral dose of 3 mg/kg/day (approximately 1.7 times the MRHD on a mg/m2 basis) caused maternal toxicity (decreased body weight and death) but, in surviving dams, had no adverse effects on fetal survival, fetal weight, or external, visceral, or skeletal development. No maternal toxicity or adverse effects on fetal development were observed when oral doses up to 1000 mg of candesartan cilexetil/kg/day (approximately 138 times the MRHD on a mg/m2 basis) were administered to pregnant mice.
5.2 Morbidity in Infants
Children < 1 year of age must not receive Candelong for hypertension. Drugs that act directly on the renin-angiotensin system can have effects on the development of immature kidneys.
In adult or children patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (eg, those being treated with diuretics), symptomatic hypotension may occur. These conditions should be corrected prior to administration of Candelong, or the treatment should start under close medical supervision.
If hypotension occurs, the patients should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment which usually can be continued without difficulty once the blood pressure has stabilized.
Caution should be observed when initiating therapy in patients with heart failure. Patients with heart failure given Candelong commonly have some reduction in blood pressure. In patients with symptomatic hypotension this may require temporarily reducing the dose of Candelong, or diuretic, or both, and volume repletion. In the CHARM program, hypotension was reported in 18.8% of patients on Candelong versus 9.8% of patients on placebo. The incidence of hypotension leading to drug discontinuation in ATACAND-treated patients was 4.1% compared with 2.0% in placebo-treated patients.
Monitoring of blood pressure is recommended during dose escalation and periodically thereafter.
Hypotension may occur during major surgery and anesthesia in patients treated with angiotensin II receptor antagonists, including Candelong, 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 Hepatic Function
Based on pharmacokinetic data which demonstrate significant increases in candesartan AUC and Cmax in patients with moderate hepatic impairment, a lower initiating dose should be considered for patients with moderate hepatic impairment .
5.5 Renal Function Deterioration
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in some individuals treated with Candelong. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (eg, patients with severe heart failure), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results may be anticipated in patients treated with Candelong.
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of Candelong in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.
In heart failure patients treated with Candelong, increases in serum creatinine may occur. Dosage reduction or discontinuation of the diuretic or Candelong, and volume repletion may be required. In the CHARM program, the incidence of abnormal renal function (e.g., creatinine increase) was 12.5% in patients treated with Candelong versus 6.3% in patients treated with placebo. The incidence of abnormal renal function (eg, creatinine increase) leading to drug discontinuation in ATACAND-treated patients was 6.3% compared with 2.9% in placebo-treated patients. Evaluation of patients with heart failure should always include assessment of renal function and volume status. Monitoring of serum creatinine is recommended during dose escalation and periodically thereafter.
Pediatrics - Candelong has not been studied in children with estimated glomerular filtration rate < 30 mL/min/1.73m2.
In heart failure patients treated with Candelong, hyperkalemia may occur, especially when taken concomitantly with ACE inhibitors and potassium-sparing diuretics such as spironolactone. In the CHARM program, the incidence of hyperkalemia was 6.3% in patients treated with Candelong versus 2.1% in patients treated with placebo. The incidence of hyperkalemia leading to drug discontinuation in ATACAND-treated patients was 2.4% compared with 0.6% in placebo-treated patients. During treatment with Candelong in patients with heart failure, monitoring of serum potassium is recommended during dose escalation and periodically thereafter.
6 ADVERSE REACTIONS
To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1–800–236–9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Candelong has been evaluated for safety in more than 3600 patients/subjects, including more than 3200 patients treated for hypertension. About 600 of these patients were studied for at least 6 months and about 200 for at least 1 year. In general, treatment with Candelong was well tolerated. The overall incidence of adverse events reported with Candelong was similar to placebo.
The rate of withdrawals due to adverse events in all trials in patients (7510 total) was 3.3% (ie, 108 of 3260) of patients treated with Candelong as monotherapy and 3.5% (ie, 39 of 1106) of patients treated with placebo. In placebo-controlled trials, discontinuation of therapy due to clinical adverse events occurred in 2.4% (ie, 57 of 2350) of patients treated with Candelong and 3.4% (ie, 35 of 1027) of patients treated with placebo.
The most common reasons for discontinuation of therapy with Candelong were headache (0.6%) and dizziness (0.3%).
The adverse events that occurred in placebo-controlled clinical trials in at least 1% of patients treated with Candelong and at a higher incidence in Candelong (n = 2350) than placebo (n = 1027) patients included back pain (3% vs. 2%), dizziness (4% vs. 3%), upper respiratory tract infection (6% vs. 4%), pharyngitis (2% vs. 1%), and rhinitis (2% vs. 1%).
The following adverse events occurred in placebo-controlled clinical trials at a more than 1% rate but at about the same or greater incidence in patients receiving placebo compared to Candelong: fatigue, peripheral edema, chest pain, headache, bronchitis, coughing, sinusitis, nausea, abdominal pain, diarrhea, vomiting, arthralgia, albuminuria.
Other potentially important adverse events that have been reported, whether or not attributed to treatment, with an incidence of 0.5% or greater from the 3260 patients worldwide treated in clinical trials with Candelong are listed below. It cannot be determined whether these events were causally related to Candelong. Body as a Whole: asthenia, fever; Central and Peripheral Nervous System: paresthesia, vertigo; Gastrointestinal System Disorder: dyspepsia, gastroenteritis; Heart Rate and Rhythm Disorders: tachycardia, palpitation; Metabolic and Nutritional Disorders: creatine phosphokinase increased, hyperglycemia, hypertriglyceridemia, hyperuricemia; Musculoskeletal System Disorders: myalgia; Platelet/Bleeding-Clotting Disorders: epistaxis; Psychiatric Disorders: anxiety, depression, somnolence; Respiratory System Disorders: dyspnea; Skin and Appendages Disorders: rash, sweating increased; Urinary System Disorders: hematuria.
Other reported events seen less frequently included angina pectoris, myocardial infarction, and angioedema.
Adverse events occurred at about the same rates in men and women, older and younger patients, and black and non-black patients.
Among children in clinical studies, 1 in 93 children age 1 to < 6 and 3 in 240 age 6 to < 17 experienced worsening renal disease. The association between candesartan and exacerbation of the underlying condition could not be excluded.
The adverse event profile of Candelong in adult heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM program, comparing Candelong in total daily doses up to 32 mg once daily (n=3803) with placebo (n=3796), 21.0% of patients discontinued Candelong for adverse events vs. 16.1% of placebo patients.
6.2 Postmarketing Experience
The following adverse reactions were identified during post-approval use of Candelong. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following have been very rarely reported in post-marketing experience:
Digestive: Abnormal hepatic function and hepatitis.
Hematologic: Neutropenia, leukopenia, and agranulocytosis.
Metabolic and Nutritional Disorders: hyperkalemia, hyponatremia.
Renal: renal impairment, renal failure.
Skin and Appendages Disorders: Pruritus and urticaria.
Rare reports of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
6.3 Laboratory Test Findings
In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with the administration of Candelong.
Creatinine, Blood Urea Nitrogen
Minor increases in blood urea nitrogen (BUN) and serum creatinine were observed infrequently.
Hyperuricemia was rarely found (19 or 0.6% of 3260 patients treated with Candelong and 5 or 0.5% of 1106 patients treated with placebo).
Hemoglobin and Hematocrit
Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.2 grams/dL and 0.5 volume percent, respectively) were observed in patients treated with Candelong alone but were rarely of clinical importance. Anemia, leukopenia, and thrombocytopenia were associated with withdrawal of one patient each from clinical trials.
A small increase (mean increase of 0.1 mEq/L) was observed in patients treated with Candelong alone but was rarely of clinical importance. One patient from a congestive heart failure trial was withdrawn for hyperkalemia (serum potassium = 7.5 mEq/L). This patient was also receiving spironolactone.
Liver Function Tests
Elevations of liver enzymes and/or serum bilirubin were observed infrequently. Five patients assigned to Candelong in clinical trials were withdrawn because of abnormal liver chemistries. All had elevated transaminases. Two had mildly elevated total bilirubin, but one of these patients was diagnosed with Hepatitis A.
In the CHARM program, small increases in serum creatinine (mean increase 0.2 mg/dL in candesartan-treated patients and 0.1 mg/dL in placebo-treated patients) and serum potassium (mean increase 0.15 mEq/L in ATACAND-treated patients and 0.02 mEq/L in placebo-treated patients), and small decreases in hemoglobin (mean decrease 0.5 gm/dL in ATACAND-treated patients and 0.3 gm/dL in placebo-treated patients) and hematocrit (mean decrease 1.6% in ATACAND-treated patients and 0.9% in placebo-treated patients) were observed.
7 DRUG INTERACTIONS
No significant drug interactions have been reported in studies of Candelong given with other drugs such as glyburide, nifedipine, digoxin, warfarin, hydrochlorothiazide, and oral contraceptives in healthy volunteers, or given with enalapril to patients with heart failure (NYHA class II and III). 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.
The antihypertensive effect of angiotensin II receptor antagonists, including candesartan may be attenuated by NSAIDs including selective COX-2 inhibitors.
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 Candelong, so careful monitoring of serum lithium levels is recommended during concomitant use.
8 USE IN SPECIFIC POPULATIONS
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 Candelong 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 Candelong, 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 Candelong for hypotension, oliguria, and hyperkalemia. [see USE IN SPECIFIC POPULATIONS (8. 4) ]
8.2 Labor and Delivery
The effect of Candelong on labor and delivery in humans is unknown .
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 Candelong, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Neonates with a history of in utero exposure to Candelong:
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 Candelong were evaluated in hypertensive children 1 to < 17 years of age in randomized, double-blind clinical studies. The pharmacokinetics of Candelong have been evaluated in pediatric patients 1 to < 17 years of age .
Children < 1 year of age must not receive Candelong for hypertension .
8.5 Geriatric Use
Of the total number of subjects in clinical studies of Candelong, 21% (683/3260) were 65 and over, while 3% (87/3260) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger adult subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In a placebo-controlled trial of about 200 elderly hypertensive patients (ages 65 to 87 years), administration of Candelong was well tolerated and lowered blood pressure by about 12/6 mm Hg more than placebo.
Of the 7599 patients with heart failure in the CHARM program, 4343 (57%) were age 65 years or older and 1736 (23%) were 75 years or older. In patients ≥ 75 years of age, the incidence of drug discontinuations due to adverse events was higher for those treated with Candelong or placebo compared with patients <75 years of age. In these patients, the most common adverse events leading to drug discontinuation at an incidence of at least 3%, and more frequent with Candelong than placebo, were abnormal renal function (7.9% vs. 4.0%), hypotension (5.2% vs. 3.2%) and hyperkalemia (4.2% vs. 0.9%). In addition to monitoring of serum creatinine, potassium, and blood pressure during dose escalation and periodically thereafter, greater sensitivity of some older individuals with heart failure must be considered.
No lethality was observed in acute toxicity studies in mice, rats, and dogs given single oral doses of up to 2000 mg/kg of Candelong. 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 Candelong 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.
Candelong (candesartan cilexetil), a prodrug, is hydrolyzed to candesartan during absorption from the gastrointestinal tract. Candesartan is a selective AT1 subtype angiotensin II receptor antagonist.
Candelong, a nonpeptide, is chemically described as (±)-1-Hydroxyethyl 2-ethoxy-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester).
Its empirical formula is C33H34N6O6, and its structural formula is:
Candelong 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. Candelong is a racemic mixture containing one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group. Following oral administration, Candelong undergoes hydrolysis at the ester link to form the active drug, candesartan, which is achiral.
Candelong is available for oral use as tablets containing either 4 mg, 8 mg, 16 mg, or 32 mg of Candelong and the following inactive ingredients: hydroxypropyl cellulose, polyethylene glycol, lactose, corn starch, carboxymethylcellulose calcium, and magnesium stearate. Ferric oxide (reddish brown) is added to the 8-mg, 16-mg, and 32-mg tablets as a colorant.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme. Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathways for angiotensin II synthesis.
There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Candesartan has much greater affinity (>10,000-fold) for the AT1 receptor than for the AT2 receptor.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because candesartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of candesartan on blood pressure.
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 Candelong, 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 Candelong to healthy subjects, hypertensive, and heart failure patients. ACE activity was not altered in healthy subjects after repeated Candelong administration. The once-daily administration of up to 16 mg of Candelong to healthy subjects did not influence plasma aldosterone concentrations, but a decrease in the plasma concentration of aldosterone was observed when 32 mg of Candelong was administered to hypertensive patients. In spite of the effect of Candelong 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 HbA1c.
In heart failure patients, candesartan ≥ 8 mg resulted in decreases in systemic vascular resistance and pulmonary capillary wedge pressure.
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.
Metabolism and Excretion
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 14C-labeled Candelong, approximately 33% of radioactivity is recovered in urine and approximately 67% in feces. Following an intravenous dose of 14C-labeled candesartan, approximately 59% of radioactivity is recovered in urine and approximately 36% in feces. Biliary excretion contributes to the elimination of candesartan.
Candelong 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 Candelong. Candesartan and its inactive metabolite do not accumulate in serum upon repeated once-daily dosing.
Following administration of Candelong, the absolute bioavailability of candesartan was estimated to be 15%. After tablet ingestion, the peak serum concentration (Cmax) is reached after 3 to 4 hours. Food with a high fat content does not affect the bioavailability of candesartan after Candelong administration.
In children 1 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 1 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 (Cmax and AUC) were not modified by age, sex or body weight.
Candelong pharmacokinetics have not been investigated in pediatric patients less than 1 year of age.
From the dose-ranging studies of Candelong, 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 Candelong. Administering drugs that act directly on the renin-angiotensin system (RAS) can alter normal renal development.
Geriatric and Sex
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 (Cmax 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 Cmax were approximately doubled in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73m2) compared to patients with normal kidney function. The pharmacokinetics of candesartan in hypertensive patients undergoing hemodialysis are similar to those in hypertensive patients with severe renal impairment. Candesartan cannot be removed by hemodialysis. No initial dosage adjustment is necessary in patients with renal insufficiency.
In heart failure patients with renal impairment, AUC0-72h was 36% and 65% higher in mild and moderate renal impairment, respectively. Cmax was 15% and 55% higher in mild and moderate renal impairment, respectively.
Candelong pharmacokinetics have 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 Candelong. The increase in AUC for candesartan was 30% in patients with mild hepatic impairment (Child-Pugh A) and 145% in patients with moderate hepatic impairment (Child-Pugh B). The increase in Cmax for candesartan was 56% in patients with mild hepatic impairment and 73% in patients with moderate hepatic impairment. The pharmacokinetics after Candelong 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 Candelong at a lower dose.
The pharmacokinetics of candesartan were linear in patients with heart failure (NYHA class II and III) after Candelong 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 [see DOSAGE AND ADMINISTRATION (2.3) ].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
There was no evidence of carcinogenicity when Candelong was orally administered to mice and rats for up to 104 weeks at doses up to 100 and 1000 mg/kg/day, respectively. Rats received the drug by gavage, whereas mice received the drug by dietary administration. These (maximally-tolerated) doses of Candelong provided systemic exposures to candesartan (AUCs) that were, in mice, approximately 7 times and, in rats, more than 70 times the exposure in man at the maximum recommended daily human dose (32 mg).
Candesartan and its O-deethyl metabolite tested positive for genotoxicity in the in vitro Chinese hamster lung (CHL) chromosomal aberration assay. Neither compound tested positive in the Ames microbial mutagenesis assay or the in vitro mouse lymphoma cell assay. Candesartan (but not its O-deethyl metabolite) was also evaluated in vivo in the mouse micronucleus test and in vitro in the Chinese hamster ovary (CHO) gene mutation assay, in both cases with negative results. Candelong was evaluated in the Ames test, the in vitro mouse lymphoma cell and rat hepatocyte unscheduled DNA synthesis assays and the in vivo mouse micronucleus test, in each case with negative results. Candelong was not evaluated in the CHL chromosomal aberration or CHO gene mutation assay.
Fertility and reproductive performance were not affected in studies with male and female rats given oral doses of up to 300 mg/kg/day (83 times the maximum daily human dose of 32 mg on a body surface area basis).
14 CLINICAL STUDIES
The antihypertensive effects of Candelong 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 Candelong 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 Candelong 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 systolic and diastolic pressures compared to placebo, with doses of 8 to 32 mg giving effects of about 8-12/4-8 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%. Candelong had an additional blood pressure lowering effect when added to hydrochlorothiazide.
The antihypertensive effects of Candelong 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, Candelong 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 Candelong 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 Candelong was maintained, and there was no rebound after abrupt withdrawal.
There were no changes in the heart rate of patients treated with Candelong in controlled trials.
The antihypertensive effects of Candelong 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 Candelong 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 6.0/5.2 to 12.0/11.1 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 Candelong in a ratio of 1: 2: 2: 2. For children who weighed < 50 kg the doses of Candelong were 2, 8, or 16 mg once daily. For those > 50 kg the Candelong 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 4.9/3.0 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 - 6 years old to determine whether Blacks respond differently than other patients to Candelong.
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 Candelong (initially 4-8 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 Candelong 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 Candelong (p<0.001), with both components contributing to the overall effect (Table 1).
In CHARM–Added, 2548 subjects receiving an ACE inhibitor were randomized to Candelong 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 Candelong 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 Candelong (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 Candelong.
In these two studies, the benefit of Candelong in reducing the risk of CV death or heart failure hospitalization (18% p<0.001) was evident in major subgroups, 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
16 HOW SUPPLIED/STORAGE AND HANDLING
No. 3782 - Tablets Candelong, 4 mg, are white to off-white, circular/biconvex-shaped, non-film-coated scored tablets, coded ACF on one side and 004 on the other. They are supplied as follows:
NDC 0186-0004-31 unit of use bottles of 30.
No. 3780 - Tablets Candelong, 8 mg, are light pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACG on one side and 008 on the other. They are supplied as follows:
NDC 0186-0008-31 unit of use bottles of 30.
No. 3781 - Tablets Candelong, 16 mg, are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACH on one side and 016 on the other. They are supplied as follows:
NDC 0186-0016-31 unit of use bottles of 30
NDC 0186-0016-54 unit of use bottles of 90
NDC 0186-0016-28 unit dose packages of 100.
No. 3791 - Tablets Candelong, 32 mg, are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACL on one side and 032 on the other. They are supplied as follows:
NDC 0186-0032-31 unit of use bottles of 30
NDC 0186-0032-54 unit of use bottles of 90
NDC 0186-0032-28 unit dose packages of 100.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) . Keep container tightly closed.
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling
Female patients of childbearing age should be told about the consequences of exposure to Candelong 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.
Manufactured under the license
from Takeda Pharmaceutical Company, Ltd.
by: AstraZeneca AB, S-151 85 Södertälje, Sweden
for: AstraZeneca LP, Wilmington, DE 19850
Candelong is a trademark of the AstraZeneca group of companies.
Read the Patient information that comes with Candelong before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about Candelong, ask your doctor or pharmacist.
What is the most important information I should know about Candelong?
Candelong can cause harm or death to an unborn baby. Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant. If you get pregnant while taking Candelong, tell your doctor right away.
What is Candelong?
Candelong is a prescription medicine called an angiotensin receptor blocker (ARB).
Candelong is used to:
Heart failure is a condition where the heart does not pump blood as well as it should.
Candelong must not be used in children less than 1 year of age for high blood pressure.
Who should not take Candelong?
Do not take Candelong if you:
What should I tell my doctor before taking Candelong?
Before you take Candelong, tell your doctor if you:
Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Candelong and other medicines may affect each other causing serious side effects. Candelong may affect the way other medicines work, and other medicines may affect how Candelong works.
Especially tell your doctor if you take:
Know the medicines you take. Keep a list of your medications with you to show your doctor and pharmacist when a new medication is prescribed. Talk to your doctor or pharmacist before you start taking any new medicine. Your doctor or pharmacist will know what medicines are safe to take together.
How should I take Candelong?
What should I avoid while taking Candelong?
Candelong can cause you to feel dizzy or tired. Do not drive, operate machinery, or do other dangerous activities until you know how Candelong affects you.
What are the possible side effects of Candelong?
Candelong may cause serious side effects, including:
If you feel dizzy or faint lie down and call your doctor right away.
Low blood pressure can also happen if you have major surgery or anesthesia. You will be monitored for this and treated if needed. See “What should I tell my doctor before taking Candelong?”
The most common side effects of Candelong are:
Tell your doctor or pharmacist about any side effect that bothers you or that does not go away.
These are not all the side effects of Candelong. Ask your doctor or pharmacist for more information.
Call your doctor for medical advice about side effects. You can report side effects to FDA at 1-800-FDA-1088.
How should I store Candelong?
Keep Candelong and all medicine out of the reach of children.
General information about Candelong.
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Candelong for a condition for which it was not prescribed. Do not give Candelong to other people, even if they have the same problem you have. It may harm them.
This leaflet summarizes the most important information about Candelong. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Candelong that is written for health professionals.
For more information, go to www.atacand-us.com or call 1 800-236-9933.
What are the ingredients in Candelong?
Active ingredient: Candelong.
Inactive ingredients in Candelong tablets and Candelong oral suspension are: hydroxypropyl cellulose, polyethylene glycol, lactose, corn starch, carboxymethylcellulose calcium, and magnesium stearate. Ferric oxide (reddish brown) is added to the 8-mg, 16-mg, and 32-mg tablets as a colorant.
In addition to the above, Candelong oral suspension also includes the following inactive ingredients: Ora Plus, Ora Sweet or Ora-Blend.
How does Candelong work?
Candelong is a type of medicine called angiotensin receptor blocker, which blocks the effect of the hormone angiotensin II, causing the blood vessels to relax. This helps lower blood pressure.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Manufactured under the license
from Takeda Pharmaceutical Company, Ltd.
by: AstraZeneca AB, S-151 85 Södertälje, Sweden
for: AstraZeneca LP, Wilmington, DE 19850
Candelong is a trademark of the AstraZeneca group of companies.
Issued: April 2012
©AstraZeneca 2010, 2012
structural formula figure 1 graph
Candelong pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Candelong available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Candelong destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Candelong Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Candelong pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Candelong?
Depending on the reaction of the Candelong after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Candelong not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Candelong addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
ReviewsDrugs.com conducted a study on Candelong, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Candelong consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
The information was verified by Dr. Arunabha Ray, MD Pharmacology