Atacand®

Candesartan Cilexetil

Angiotensin II AT1 Receptor Blocker

AstraZeneca

http://www.astrazeneca-us.com/default.asp

Atacand Monograph PDF download here.

 

CPS:PIS_m070350

Date of Preparation: August 11, 2000

Date of Revision: April 27, 2004

 

 

Pharmacology

Candesartan antagonizes angiotensin II by blocking the angiotensin type one (AT₁) receptor. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system with effects that include vasoconstriction, stimulation of aldosterone secretion and renal reabsorption of sodium.

     ATACAND, a prodrug, is rapidly converted to the active drug, candesartan, during absorption from the gastrointestinal tract.

     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 it plays no known role in cardiovascular homeostasis to date. Candesartan has a much greater affinity (>10 000-fold) for the AT₁ receptor than for the AT₂ receptor. The strong bond between candesartan and the AT₁ receptor is a result of tight binding to and slow dissociation from the receptor.

     Candesartan does not inhibit angiotensin converting enzyme (ACE), also known as kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin, nor does it bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

 

Pharmacokinetics

Candesartan cilexetil is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan. Candesartan is mainly excreted unchanged in urine and feces (via bile). It undergoes minor hepatic metabolism by O-deethylation to an inactive metabolite. In vitro studies indicate that cytochrome P450 isoenzyme CYP 2C9 is involved in the biotransformation of candesartan to its inactive metabolite. Based on in vitro data, no interaction would be expected to occur in vivo with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. 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. Candesartan and its inactive metabolite do not accumulate in serum upon repeated once-daily dosing.

     Following oral administration of candesartan cilexetil as a tablet, the absolute bioavailability of candesartan was estimated to be approximately 15%. After tablet ingestion, the peak serum concentration (C_max) is reached after 3 to 4 hours. Food does not affect the bioavailability of candesartan after candesartan cilexetil administration.

     Total plasma clearance of candesartan is 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg. When candesartan cilexetil is administered orally, about 26% of the dose is excreted as candesartan in urine. Following an oral dose of ¹⁴C-labeled candesartan cilexetil, approximately 33% of radioactivity is recovered in urine and approximately 67% in feces. Following an i.v. 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.

     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 does cross the blood-brain barrier. It has also been demonstrated in rats that candesartan passes across the placental barrier and is distributed in the fetus.

     The plasma concentration of candesartan was higher in the elderly (≥ 65 years) (C_max was approximately 50% higher, and AUC was approximately 80% higher) compared to younger subjects administered the same dose. The pharmacokinetics of candesartan were linear in the elderly, and candesartan and its inactive metabolite did not accumulate in the serum of these subjects upon repeated, once-daily administration.

     No gender-related differences in the pharmacokinetics of candesartan have been observed.

     In patients with mild to moderate renal impairment (Cl_creat 31 to 60 mL/min/1.73m²), C_max and AUC of candesartan increased by 40 to 60% and 50 to 90%, respectively, but t_1/2 was not altered, compared to patients with normal renal function (Cl_creat >60 mL/min/1.73m²) during repeated dosing. There was no drug accumulation in plasma in patients with mild to moderate renal impairment. The increases in C_max and AUC in patients with severe renal impairment (Cl_creat 15 to 30 mL/min/1.73m²) were 40 to 60% and 110%, respectively. The terminal t_1/2 of candesartan was approximately doubled in patients with severe renal impairment, and these changes resulted in some accumulation in plasma. The pharmacokinetics of candesartan in patients undergoing hemodialysis were similar to those in patients with severe renal impairment (see Dosage, Impaired Renal Function).

     In patients with mild to moderate hepatic impairment, there was an increase in the AUC of candesartan of approximately 20%. There was no drug accumulation in plasma in these patients. In patients with severe hepatic impairment, the C_max and AUC increased up to 5 times in a very small group administered a single dose of 16 mg candesartan (see Dosage, Impaired Hepatic Function).

Pharmacodynamics: Candesartan inhibits the pressor effects of angiotensin II infusion in a dose-dependent manner. After 1 week of once-daily dosing of 8 mg candesartan, the pressor effect was inhibited by approximately 90% at peak (4 to 8 hours after dosing) with approximately 50% inhibition persisting at 24 hours.

     Plasma concentrations of angiotensin I, angiotensin II, and plasma renin activity, increased in a dose-dependent manner after single and repeated administration of candesartan to healthy subjects and hypertensive patients. A decrease in the plasma concentration of aldosterone was observed when 32 mg of candesartan cilexetil was administered to hypertensive patients.

     In hypertension, candesartan causes a dose-dependent reduction in arterial blood pressure. Systemic peripheral resistance is decreased, while heart rate, stroke volume and cardiac output are not significantly affected. No first dose hypotension was observed during controlled clinical trials with candesartan.

     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 greater than 80%. Candesartan had an additional blood pressure lowering effect when added to hydrochlorothiazide.

     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) than in Caucasians.

     In long-term studies of up to 1 year, the antihypertensive effectiveness of candesartan was maintained, and there was no rebound after abrupt withdrawal.

Comparative Effects: The antihypertensive efficacy of candesartan cilexetil and losartan potassium have been compared at their approved once daily maximum doses, 32 mg and 100 mg, respectively, in patients with mild to moderate essential hypertension. Candesartan cilexetil lowered systolic and diastolic blood pressure by 2 to 3 mm Hg on average more than losartan potassium when measured at the time of either peak or trough effect. Both agents were well tolerated.

     Candesartan also reduces urinary albumin excretion in patients with type II diabetes mellitus, hypertension and microalbuminuria. In a 12-week study of 161 mildly hypertensive patients with type II diabetes mellitus, candesartan 8 to 16 mg had no effect on mean HbA1c.

 

Indications

ATACAND (candesartan cilexetil) is indicated for the treatment of mild to moderate essential hypertension. ATACAND can be used as first-line treatment, as can beta-blockers, angiotensin converting enzyme inhibitors, calcium channel blockers, and diuretics, for the treatment of systolic-diastolic hypertension as well as isolated systolic hypertension.

     Candesartan may be used alone or concomitantly with thiazide diuretics.

     Candesartan has been used concomitantly with amlodipine, but the data on such use are limited.

     The safety and efficacy of concurrent use with (CCB) and angiotensin converting enzyme inhibitors (ACEI) have not been established.

 

Contraindications

In patients who are hypersensitive to any component of this product.

 

Warnings

Pregnancy

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, candesartan should be discontinued as soon as possible.

     The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.

     Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of candesartan as soon as possible.

     Rarely (probably less than 1 in every 1000 pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

     If oligohydramnios is observed, candesartan should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST) or biophysical profiling (BPP) may be appropriate, depending 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.

     Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion may be required as a means of reversing hypotension and/or substituting for impaired renal function. Candesartan is not removed from plasma by dialysis.

Animal Data: Oral doses ≥ 10 mg candesartan/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. Candesartan given to pregnant rabbits at an oral dose of 3 mg/kg/day 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 candesartan/kg/day were administered to pregnant mice.

Hypotension: Occasionally, symptomatic hypotension has occurred after administration of candesartan. It is more likely to occur in patients who are volume-depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, vomiting or undergoing surgery with anaesthesia. In these patients, because of the potential fall in blood pressure, therapy should be started under close medical supervision. Similar considerations apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident.

 

Precautions

Renal Impairment: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.

     Use of candesartan should include appropriate assessment of renal function.

Valvular Stenosis: There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

 

Lactation

It is not known whether candesartan is excreted in human milk, but it is excreted in the milk of lactating rats. Because many drugs are excreted in human milk, and because of their potential for affecting the nursing infant adversely, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

 

Children

The safety and efficacy of candesartan have not been established in children.

Geriatrics

No overall differences in safety or effectiveness were observed between these subjects and younger 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.

 

Drug Interactions

Diuretics: Patients on diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with candesartan. The possibility of symptomatic hypotension with the use of candesartan can be minimized by discontinuing the diuretic prior to initiation of treatment and/or lowering the initial dose of candesartan (see Warnings, Hypotension and Dosage). No drug interaction of clinical significance has been identified with thiazide diuretics in patients treated with up to 25 mg hydrochlorothiazide with 16 mg candesartan for 8 weeks.

Agents Increasing Serum Potassium: Since candesartan decreases the production of aldosterone, potassium-sparing diuretics or potassium supplements should be given only for documented hypokalemia and with frequent monitoring of serum potassium. Potassium-containing salt substitutes should also be used with caution.

Lithium Salts: As with other drugs which eliminate sodium, lithium clearance may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be administered.

Warfarin: When candesartan was administered at 16 mg once daily under steady-state conditions, no pharmacodynamic effect on prothrombin time was demonstrated in subjects stabilized on warfarin.

Digoxin: Combination treatment with candesartan cilexetil and digoxin in healthy volunteers had no effect on AUC or C_max values for digoxin compared to digoxin alone. Similarly, combination treatment had no effect on AUC or C_max values for candesartan compared to candesartan cilexetil alone.

Other: No significant drug interactions have been reported with glyburide, nifedipine or oral contraceptives coadministered with candesartan to healthy volunteers.

 

Adverse Effects

Candesartan has been evaluated for safety in more than 8700 patients treated for hypertension, including 677 treated for six months or more, and 626 for about one year or more. Of these, 8694 were treated with candesartan cilexetil monotherapy in controlled clinical trials.

     In placebo-controlled clinical trials, discontinuation due to adverse events occurred in 2.9% and 2.7% of patients treated with candesartan monotherapy and placebo, respectively.

     The following potentially serious adverse reactions have been reported rarely with candesartan in controlled clinical trials: syncope, hypotension. In the double-blind, placebo-controlled trials, the overall incidence of adverse events showed no association with dose, age or gender. In these trials, the following adverse reactions reported with candesartan occurred in ≥ 1% of patients, regardless of drug relationship: see  Table 1.

CPS:Atacand_t1Click here for Table 1

Table 1: Atacand

Adverse Events

 

	Atacand  n=1388 (%)	Placebo n=573 (%)
Body as a Whole
Back Pain	3.2	0.9
Fatigue	1.5	1.6
Abdominal Pain	1.5	1.3
Peripheral Edema	1.0	0.7
Digestive
Nausea	1.9	1.3
Diarrhea	1.5	1.9
Vomiting	1.0	1.2
Nervous/Psychiatric
Headache	10.4	10.3
Dizziness	2.5	2.3
Respiratory
Upper Respiratory Infection	5.1	3.8
Coughing	1.6	1.1
Influenza-like Symptoms	1.5	0.8
Pharyngitis	1.1	0.4
Bronchitis	1.0	2.2
Rhinitis	1.0	0.4

 

     Clinical trials in which doses up to 32 mg were administered did not result in a significant increase in any of the adverse events listed above. In addition, the following adverse events were reported at an incidence of <1% in controlled clinical trials (in more than 1 patient, with higher frequency than placebo):

 

Body as a Whole

allergy, asthenia, pain, syncope.

 

Cardiovascular

angina pectoris, circulatory failure, flushing, hypotension, myocardial infarction, peripheral ischemia, thrombophlebitis.

 

Central and Peripheral Nervous System

hypertonia, hypoesthesia, paresthesia, vertigo.

 

Gastrointestinal

constipation, dyspepsia, dry mouth, toothache.

Hearing

tinnitus.

 

Metabolic and Nutritional

diabetes mellitus, hyperkalaemia, hyponatraemia.

 

Musculoskeletal

arthritis, arthropathy, myalgia, myopathy, skeletal pain, tendon disorder.

 

Blood

anemia, epistaxis.

Psychiatric

depression, impotence, neurosis.

Reproductive

menopausal symptoms.

Resistance Mechanism

otitis.

 

Respiratory

laryngitis.

 

Skin

eczema, pruritus, rash, skin disorder, sweating, (rarely) urticaria.

 

Urinary

abnormal urine, cystitis.

 

Vision

conjunctivitis.

     In studies using daily doses greater than 16 mg, the following adverse events were reported at a rate greater than 1% but at about the same or greater incidence in patients receiving placebo: chest pain, sinusitis, arthralgia and albuminuria. Other adverse events reported at an incidence of 0.5% or greater from more than 3200 patients treated worldwide include fever, gastroenteritis, tachycardia, palpitation, increased creatinine phosphokinase, hyperglycemia, hypertriglyceridemia, hyperuricemia, anxiety, somnolence, dyspnea and hematuria.

     Angioedema (involving swelling of the face, lips and/or tongue), has been reported rarely in patients treated with candesartan.

     In other post-marketing experience, renal impairment, including renal failure in elderly susceptible patients, has been observed (see Precautions for definition of susceptible patients). Very rare cases of abnormal hepatic function or hepatitis have also been reported. Other adverse events reported for ATACAND where a causal relationship could not be established include very rare cases of leukopenia, neutropenia and agranulocytosis.

Laboratory Test Findings: In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of candesartan.

Liver Function Tests: In controlled clinical trials, elevations of AST and ALT (>3 times the upper limit of normal) occurred in 0.3 and  0.5% of patients treated with candesartan monotherapy compared to 0.2 and 0.4% of patients receiving placebo.

Serum Potassium: A small increase (mean increase of 0.1 mEq/L) was observed in hypertensive patients treated with candesartan alone but was rarely of clinical importance.

Creatinine, Blood Urea Nitrogen and Sodium: Minor increases in blood urea nitrogen (BUN) and serum creatinine were observed infrequently, as were decreases in sodium.

Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.2 g/dL and 0.5 volume %, respectively) were observed in patients treated with candesartan alone but were rarely of clinical importance. Anemia, leukopenia and thrombocytopenia were associated with withdrawal of one patient each from clinical trials.

Hyperuricemia: Hyperuricemia was rarely found (0.6% of patients treated with candesartan and 0.5% of patients treated with placebo.)

 

Overdose

 

 

Symptoms

Limited data are available in regard to overdosage in humans. The most likely manifestations of overdosage would be hypotension, dizziness and tachycardia; bradycardia could occur from reflex parasympathetic (vagal) stimulation. In case reports detailing overdosage (up to 672 mg candesartan) patient recovery was uneventful.

 

 

Treatment

If symptomatic hypotension should occur, supportive treatment should be instituted and vital signs monitored. The patient should be placed supine with the legs elevated. If this is not sufficient, plasma volume should be increased by infusion of, for example, isotonic saline solution. Sympathomimetic drugs may also be administered if the above-mentioned measures are not sufficient.

     Candesartan is not removed from the plasma by hemodialysis.

 

Dosage

The dosage must be individualized.

     Initiation of therapy requires consideration of recent antihypertensive treatment, the extent of blood pressure elevation, salt restriction, and other pertinent clinical factors. The dosage of other antihypertensive agents used with candesartan may need to be adjusted. Blood pressure response is dose related over the range of 4 to 32 mg.

     Candesartan should be taken once daily, at approximately the same time each day, with or without food.

     The recommended initial dose of candesartan is 16 mg, once daily when used as monotherapy. Total daily doses of candesartan should range from 8 to 32 mg.  Doses higher than 32 mg do not appear to have a greater effect on blood pressure reduction, and there is relatively little experience with such doses. Most of the antihypertensive effect is present within 2 weeks and the maximal blood pressure reduction is generally obtained within 4 weeks. For patients with possible depletion of intravascular volume (e.g. patients treated with diuretics, particularly those with impaired renal function) consideration should be given to administration of a lower dose. If blood pressure is not controlled by candesartan alone, a thiazide diuretic may be added (See Drug Interactions, Diuretics).

Concomitant Diuretic Therapy: In patients receiving diuretics, candesartan therapy should be initiated with caution, since these patients may be volume-depleted and thus more likely to experience hypotension following initiation of additional antihypertensive therapy. Whenever possible, all diuretics should be discontinued 2 to 3 days prior to the administration of candesartan, to reduce the likelihood of hypotension (see Warnings, Hypotension). If this is not possible because of the patient's condition, candesartan should be administered with caution and the blood pressure monitored closely. Thereafter, the dosage should be adjusted according to the individual response of the patient.

 

Geriatrics

No dosage adjustment is necessary for elderly patients.

Impaired Renal Function: No dosage adjustment is necessary in patients with mildly impaired renal function. In patients with moderately or severely impaired renal function, or in patients undergoing dialysis, a lower initial dose of 4 mg should be considered.

Impaired Hepatic Function: No dosage adjustment is necessary in patients with mild to moderate chronic liver disease. There is only limited experience available in patients with severe hepatic impairment and/or cholestasis. In patients with severely impaired hepatic function, a lower initial dose of 4 mg should be considered.

 

Children

The safety and efficacy of candesartan have not been established in children.

 

Supplied

8 mg

Each circular, biconvex, light pink tablet, with a score and marked  on one side and marked 008 on the other side, contains: candesartan cilexetil 8 mg. Nonmedicinal ingredients: calcium carboxymethylcellulose, cornstarch, hydroxypropyl cellulose, iron oxide, lactose, magnesium stearate and polyethylene glycol. Blister packs of 30. Bottles of 100.

16 mg

Each circular, biconvex, pink tablet, with a score and marked  on one side and marked 016 on the other side, contains: candesartan cilexetil 16 mg. Nonmedicinal ingredients: calcium carboxymethylcellulose, cornstarch, hydroxypropyl cellulose, iron oxide, lactose, magnesium stearate and polyethylene glycol. Blister packs of 30. Bottles of 100.

     Store at 15 to 30°C.