Product Monograph - Candesartan (Ranbaxy Pharmaceuticals Canada)
SUMMARY PRODUCT INFORMATION
Route of Administration | Dosage Form / Strength | All Nonmedicinal Ingredients |
| Oral | Tablets: 4 mg, 8 mg, 16 mg, and 32 mg | Carmellose calcium, ferric oxide red (except 4 mg tablets), hydroxypropyl cellulose-L, lactose monohydrate, macrogol 6000, magnesium stearate, and maize starch |
INDICATIONS AND CLINICAL USE
Candesartan (candesartan cilexetil) is indicated for:
Hypertension
- The treatment of mild to moderate essential hypertension.
- Candesartan may be used alone or concomitantly with thiazide diuretics.
- The safety and efficacy of concurrent use with calcium channel blockers and angiotensin converting enzyme inhibitors have not been established.
Heart Failure
- The treatment of NYHA Class II and III heart failure with ejection fraction ≤ 40% in addition to standard therapy, with or without an ACE inhibitor.
Geriatrics (> 65 years of age): 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.
Pediatrics (< 18 years of age): The safety and efficacy of candesartan cilexetil have not been established in children.
CONTRAINDICATIONS
Candesartan (candesartan cilexetil) is contraindicated in:
Patients who are hypersensitive to any component of this product (see DOSAGE FORMS,
COMPOSITION AND PACKAGING).
WARNINGS AND PRECAUTIONS
Serious Warnings and Precautions
When used in pregnancy, angiotensin receptor (AT1) blockers (ARBs) can cause injury or even death of the developing fetus. When pregnancy is detected, Candesartan should be discontinued as soon as possible (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).
Cardiovascular
Hypotension
Occasionally, symptomatic hypotension has occurred after administration of candesartan cilexetil. It is more likely to occur in patients who are volume-depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea or 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.
Patients with heart failure given candesartan cilexetil commonly have some reduction in blood pressure. Caution should be observed when initiating therapy.
The effect of candesartan cilexetil on the ability to drive and use machines has not been studied, but based on its pharmacodynamic properties candesartan cilexetil is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that dizziness or weariness may occur during treatment.
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.
Endocrine and Metabolism
Hyperkalemia
In heart failure patients treated with candesartan cilexetil, hyperkalemia may occur. During treatment with candesartan cilexetil in patients with heart failure, periodic monitoring of serum potassium is recommended, especially when taken concomitantly with ACE inhibitors and potassium-sparing diuretics such as spironolactone.
Renal
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 cilexetil should include appropriate assessment of renal function.
In heart failure patients, increases in serum creatinine may occur. Dosage reduction, and/or discontinuation of the diuretic, and/or candesartan cilexetil, and/or volume repletion may be required. Monitoring of serum creatinine is recommended during dose escalation and periodically thereafter.
Special Populations
Pregnant Women: drugs that act directly on the renin-angiotensin-aldosterone-system (RAAS) 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 ARBs is not recommended during pregnancy. Epidemiological evidence regarding the risk of teratogenicity following exposure to angiotensin converting enzyme inhibitors (another class of therapeutic products interfering with the RAAS) during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Given the current evidence available on the risk with ARBs, similar risks may exist for this class of drugs. Patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin receptor (AT1) blockers should be stopped immediately, and, if appropriate, alternative therapy should be started.
The use of ARBs during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
Infants with a history of in utero exposure to ARBs 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 or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit. Candesartan cilexetil is not removed from plasma by dialysis.
Animal data: oral doses ≥ 10 mg 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. Candesartan cilexetil 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 cilexetil/kg/day were administered to pregnant mice.
Nursing Women: it is not known whether candesartan is excreted in human milk, but significant levels have been found 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.
Pediatrics (< 18 years of age): the safety and efficacy of candesartan cilexetil have not been established in children.
Geriatrics (> 65 years of age): 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.
ADVERSE REACTIONS
Adverse Drug Reaction Overview
Hypertension
Candesartan cilexetil 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 cilexetil monotherapy and placebo, respectively.
The following potentially serious adverse reactions have been reported rarely with candesartan cilexetil in controlled clinical trials: syncope, hypotension.
Heart Failure
The adverse event profile of candesartan cilexetil in heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM Alternative and CHARM-Added studies comparing candesartan cilexetil in total daily doses up to 32 mg once daily to placebo, 23.2 % of candesartan cilexetil and 18.4% of placebo patients discontinued the treatment due to adverse events.
Severe adverse reactions most commonly seen in CHARM-Alternative and CHARM Added were hypotension, hyperkalemia and renal impairment.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Hypertension
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 events reported with candesartan cilexetil occurred in ≥ 1% of patients, regardless of drug relationship:
Table 1 Adverse events that occurred in ≥ 1% of patients, regardless of drug relationship
Candesartan Cilexetil 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.
Heart Failure
In these trials, the following adverse events reported with candesartan cilexetil occurred in ≥ 1% of patients and with higher frequency than placebo, regardless of drug relationship.
Table 2 Adverse events reported in CHARM-Alternative and CHARM-Added and occurring with frequency of ≥ 1% regardless of drug relationship
Candesartan Cilexetil
n=2289
Placebo n=2287
(%) (%) Body as a Whole Fatigue 1.4 0.9 Cardiovascular Disorders Hypotension 20.9 11.0 Syncope 3.3 3.2 Coronary artery disorder 4.2 3.5 Cardiac arrest 1.3 1.1 Blood disorders Anemia 2.8 2.3 Gastro-Intestinal System disorders Diarrhea 2.4 1.1 Gastroenteritis 1.1 0.7 Liver and Biliary System Disorders Cholelithiasis 1.1 0.9 Metabolic and Nutritional Disorders Hyperkalemia 7.6 2.6 Dehydration 2.5 1.3 Nonprotein nitrogen increased 1.3 0.3 Uremia 1.1 0.5 Gout 1.0 0.9 Musculo-Skeletal System Disorders Arthrosis 1.2 1.0 Nervous System Disorders Dizziness 3.4 2.1 Headache 1.0 0.7 Urinary System Disorders Renal function abnormal 14.3 7.2 Renal failure acute 3.0 1.8
Less Common Clinical Trial Adverse Drug Reactions (< 1%)
Hypertension
The following adverse events were reported at an incidence of < 1% in controlled clinical trials (in more than one 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, hyperkalemia, hyponatremia.
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.
Heart Failure
The following listed adverse events occurred in less than 1% of candesartan cilexetil treated patients but in at least 2 patients and with more frequent occurrence in the candesartan cilexetil group than in the placebo group (CHARM-Alternative and CHARM-Added).
Skin and Appendages Disorders: rash, pruritus, angioedema.
Liver and Biliary System Disorders: hepatic function abnormal.
White Cell and Resistance Disorders: granulocytopenia, leukopenia.
Abnormal Hematologic and Clinical Chemistry Findings
Laboratory Test Findings
Hypertension
In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of candesartan cilexetil.
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 cilexetil 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 cilexetil 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 cilexetil 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 cilexetil and 0.5% of patients treated with placebo).
Heart Failure
Increases in serum creatinine, potassium and urea, and decreases in hemoglobin and hematocrit were observed.
Post-Market Adverse Drug Reactions
Angioedema, (involving swelling of the face, lips and/or tongue), has been reported rarely in patients treated with candesartan cilexetil.
In other post-marketing experience, renal impairment, including renal failure in elderly susceptible patients, has been observed (see WARNINGS AND PRECAUTIONS, Renal, Renal Impairment for definition of susceptible patients).
Very rare cases of abnormal hepatic function or hepatitis have also been reported.
Other adverse events reported for candesartan cilexetil where a causal relationship could not be established include very rare cases of leukopenia, neutropenia and agranulocytosis. Cases of muscle pain, muscle weakness, myositis and rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
DRUG INTERACTIONS
Overview
Warfarin
When candesartan cilexetil 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 Cmax values for digoxin compared to digoxin alone. Similarly, combination treatment had no effect on AUC or Cmax values for candesartan compared to candesartan cilexetil alone.
Other
No significant drug interactions have been reported with glyburide, nifedipine or oral contraceptives co-administered with candesartan cilexetil to healthy volunteers. While there is no
clinically relevant interaction between candesartan and enalapril, patients with renal impairment showed a higher exposure to both drugs. This is consistent with known pharmacokinetics of these two compounds.
Drug-Drug Interactions
The drugs listed in Table 3 are based on either drug interaction case reports or studies or potential interactions due to the expected magnitude and seriousness of the interaction (i.e. those identified as contraindicated).
Table 3 Established or Potential Drug-Drug Interactions with Candesartan Cilexetil
| Drug/Drug Class | Effect | Clinical Comment |
| 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 cilexetil. | The possibility of symptomatic hypotension with the use of candesartan cilexetil can be minimized by discontinuing the diuretic prior to initiation of treatment and/or lowering the initial dose of candesartan cilexetil (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension and DOSAGE AND ADMINISTRATION). 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 cilexetil for 8 weeks. |
| Agents Increasing Serum Potassium | Candesartan cilexetil 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. | Serum lithium levels should be monitored carefully if lithium salts are to be administered. |
| Non-steroidal anti-inflammatory drugs (NSAIDs) | Attenuation of the antihypertensive effect may occur when simultaneously administering ARBs and NSAIDs; i.e. selective COX-2 inhibitors, acetylsalicylic acid and non-selective NSAIDs. As with angiotensin- converting enzyme (ACE) inhibitors, concomitant use of ARBs and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. | The combination ARBs and NSAIDs should be administered with caution, especially in older patients and in volume depleted patients. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy and periodically thereafter. |
Drug-Food Interactions
Candesartan may be taken with or without food (see DOSAGE AND ADMINISTRATION).
DOSAGE AND ADMINISTRATION
Dosing Considerations
The dosage of Candesartan must be individualized.
Recommended Dose and Dosage Adjustment
Candesartan should be taken once daily, at approximately the same time each day, with or without food.
Hypertension
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.
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, candesartan cilexetil may be used together with a thiazide diuretic (See DRUG INTERACTIONS, Drug-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 two to three days prior to the administration of Candesartan, to reduce the likelihood of hypotension (see WARNINGS AND PRECAUTIONS, Cardiovascular, 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.
Hepatic Impairment
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.
Renal Impairment
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.
Geriatrics (> 65 years of age)
No dosage adjustment is necessary for elderly patients. As greater sensitivity of some older patients cannot be ruled out, appropriate caution is recommended (see WARNINGS AND PRECAUTIONS, Geriatrics).
Pediatrics (< 18 years of age)
The safety and efficacy of candesartan cilexetil have not been established in children.
Heart Failure
The usual recommended initial dose for treating heart failure is 4 mg once daily. The target dose is 32 mg once daily which is achieved by doubling the dose at approximately 2 week intervals, as tolerated by the patient. candesartan cilexetil can be administered with other heart failure treatments including ACE inhibitors, beta-blockers, diuretics, digoxin, and/or spironolactone.
No initial dose adjustment is necessary for elderly patients or in patients with renal or hepatic impairment.
Missed Dose
If a patient misses a dose of Candesartan and remembers within 12 hours, the patient should take the dose as soon as possible and then go back to the regular schedule. If it is more than 12 hours after the patient remembers, they should not take the missed dose; the next dose should be taken on time.
A double dose of Candesartan should never be taken to make up for a missed dose.
OVERDOSAGE
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 cilexetil patient recovery was uneventful.
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 cilexetil is not removed from the plasma by hemodialysis.
| For management of a suspected drug overdose, contact your regional Poison Control Centre. |
ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action
Candesartan cilexetil 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.
Candesartan cilexetil, 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.
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 cilexetil, the pressor effect was inhibited by approximately 90% at peak (4-8 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 cilexetil to healthy subjects, hypertensive, and heart failure patients. A decrease in the plasma concentration of aldosterone was observed when 32 mg of candesartan cilexetil was administered to hypertensive patients.
Pharmacokinetics
Absorption: 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 (Cmax) is reached after 3-4 hours. Food does not affect the bioavailability of candesartan after candesartan cilexetil administration.
Distribution: the volume of distribution of candesartan is 0.13 L/kg. Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. The protein binding is constant at candesartan plasma concentrations well above the range achieved with recommended doses. In rats, it has been demonstrated that candesartan 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.
Metabolism: candesartan cilexetil is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan. 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.
Excretion: total plasma clearance of candesartan is 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg. Candesartan is mainly excreted unchanged in urine and feces (via bile). 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 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. 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.
Special Populations and Conditions
Geriatrics: the plasma concentration of candesartan was higher in the elderly (≥ 65 years) (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.
Gender: no gender-related differences in the pharmacokinetics of candesartan have been observed.
Hepatic Insufficiency: 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 moderate to severe hepatic impairment, the Cmax and AUC increased up to five times in a very small group administered a single dose of 16 mg candesartan (see DOSAGE AND ADMINISTRATION, Hepatic Impairment).
Renal Insufficiency: in patients with mild to moderate renal impairment (Clcreat 31-60 mL/min/1.73m2), Cmax and AUC of candesartan increased by 40-60% and 50-90%, respectively, but t1/2 was not altered, compared to patients with normal renal function (Clcreat >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 Cmax and AUC in patients with severe renal impairment (Clcreat 15-30 mL/min/1.73m2) were 40-60% and 110%, respectively. The terminal t½ 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 AND ADMINISTRATION, Renal Impairment).
STORAGE AND STABILITY
In well-closed containers at a temperature between 15°C-30°C.
DOSAGE FORMS, COMPOSITION AND PACKAGING
Dosage Forms
Candesartan is available in tablets of 4 mg, 8 mg, 16 mg, and 32 mg.
Composition
Each tablet contains candesartan cilexetil 4 mg, 8 mg, 16 mg, and 32 mg. Each tablet also contains the following non-medicinal ingredients: carmellose calcium, ferric oxide red (except 4 mg tablets), hydroxypropyl cellulose-L, lactose monohydrate, macrogol 6000, magnesium stearate, and maize starch.
Packaging
Candesartan 4 mg tablets are white colored, circular, biconvex tablets debossed with “R” on one side & “C” / “4” debossed on either side of the breakline on the other side. Available in blister packs of 30 tablets & bottle of 100 tablets.
Candesartan 8 mg tablets are pink colored, mottled, circular, biconvex tablets debossed with “CC8” on one side & “r” / “bx” debossed on either side of the breakline on the other side. Available in blister packs of 30 tablets & bottle of 100 tablets.
Candesartan 16 mg tablets are pink colored, mottled, circular, biconvex tablets debossed with “CC16” on one side & “r” / “bx” debossed on either side of the breakline on the other side. Available in blister packs of 30 tablets & bottle of 100 tablets.
Candesartan 32 mg tablets are pink colored, oval-shaped tablets debossed with “C” & “12” on either side of the breakline on one side and breakline on the other side. Available in blister packs of 30 tablets.
PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
Drug Substance
Proper Name: candesartan cilexetil
Chemical Name:
(±)-1-(Cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1Hbenzimidazole-7-carboxylate
Molecular Formula and Molecular Mass: C33H34N6O6
611 g/mol
Structural Formula:
Physicochemical Properties: Description:
Candesartan cilexetil is a white to off-white powder, freely soluble in chloroform, sparingly soluble in methanol, very slightly soluble in toluene and insoluble in water.
Melting Point:
163° C with decomposition.
Partition Coefficient
| pH of Aqueous Layer | Partition Coefficient (K at 20°C) | |
| Ethyl Ether | 1-Octanol | |
| 1.1 | > 1000 | > 1000 |
| 6.9 | > 1000 | > 1000 |
| 8.9 | 141 | > 1000 |
K = Concentration of Candesartan Cilexetil in the organic layer
Concentration of Candesartan Cilexetil in the aqueous layer
CLINICAL TRIALS
A double blinded, randomized, two-sequence, two-treatment, two-period, single oral dose, crossover bioequivalence study of Candesartan (candesartan cilexetil) 16 mg tablets (Ranbaxy Pharmaceuticals Canada Inc.) and PRATACAND® (candesartan cilexetil) 16 mg tablets (AstraZeneca Canada Inc.) was performed in 48 healthy, adult, human male subjects under fasting conditions. The data from 43 subjects is summarized in the following table.
SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA
Candesartan (1 x 16 mg) From Measured Data Geometric Mean Arithmetic Mean (CV%) | ||||
| Parameter | Test* | Reference† | Ratio of Geometric Means (%) | 90% Confidence Interval (%) |
AUCT (µg•hr/mL) | 2107.84 2166.22 (23.0) | 2215.30 2299.28 (26.5) | 95.10 | 89.74 - 100.84 |
AUCI (µg•hr/mL) | 2169.02 2228.05 (22.8) | 2257.60 2344.39 (26.7) | 96.00 | 90.46 - 101.97 |
Cmax (µg/mL) | 166.60 175.38 (33.3) | 198.26 206.46 (28.2) | 84.30 | 78.28 - 90.84 |
| Tmax (h)§ | 4.33 (2.33 – 10.00) | 4.33 (2.00 – 10.00) | ||
| T½ (h) € | 8.62 (23.5) | 8.24 (15.6) | ||
*Candesartan (candesartan cilexetil) 16 mg Tablets (Ranbaxy Pharmaceuticals Canada Inc.). †PRATACAND® (candesartan cilexetil) 16 mg tablets (AstraZeneca Canada Inc.) were purchased in Canada. §Expressed as the median (range) only.
€Expressed as the arithmetic mean (CV %) only.
Hypertension
Candesartan cilexetil 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 cilexetil.
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 cilexetil 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 cilexetil was maintained, and there was no rebound after abrupt withdrawal.
Candesartan cilexetil 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 cilexetil 8 to 16 mg had no effect on mean A1c.
Comparative Effects
The antihypertensive efficacy of candesartan cilexetil and losartan potassium have been compared at their 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.
Heart Failure
In heart failure patients, candesartan cilexetil administration resulted in a dose-related increase in plasma renin activity and angiotensin II concentration, and a decrease in aldosterone levels.
The effects of candesartan cilexetil on mortality and hospitalization due to Congestive Heart Failure (CHF) were evaluated in two studies, CHARM-Alternative and CHARM-Added. These were multinational, placebo controlled, double blind studies in patients with New York Heart Association (NYHA) functional class II to class IV CHF. Class IV CHF was a baseline characteristic for only 3% of the patient population within each of these studies. CHARM-Alternative (n=2,028) included patients with LVEF ≤ 40% not treated with ACE inhibitors because of intolerance. CHARM-Added (n=2,548) was carried out in patients with LVEF ≤ 40% tolerant of ACE inhibitors and treated with ACE inhibitors. In these studies patients were randomised to receive either placebo or candesartan cilexetil in addition to standard therapy. Candesartan cilexetil was titrated from 4 mg or 8 mg once daily to 32 mg once daily (mean 23 mg) or the highest tolerated dose. Patients were followed for up to 4 years, with a median of 40 months. Standard therapy included diuretics, β-blockers, ACE inhibitors, digoxin and spironolactone.
The primary composite endpoint of cardiovascular mortality or first CHF hospitalisation was significantly reduced with candesartan cilexetil in comparison with placebo in CHARM Alternative (hazard ratio (HR) 0.77, 95% CI 0.67-0.89, p<0.001) and in CHARM-Added (HR 0.85, 95% CI 0.75-0.96, p=0.011). This corresponds to a relative risk reduction of 23% and 15% respectively.
Table 4 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) | Relative Risk Reduction | Absolute Risk Reduction |
| CV death or CHF hospitalisation | 334 | 406 | 0.77 (0.67-0.89) | < 0.001 | 23% | 7.0% |
| CV death | 219 | 252 | 0.85 (0.71-1.02) | 0.072 | 15% | 3.2% |
| CHF hospitalisation | 207 | 286 | 0.68 (0.57-0.81) | < 0.001 | 32% | 7.7% |
NOTE: In CHARM-Alternative 14 patients needed to be treated for the duration of the study (median 34 months) to prevent one patient from dying of a cardiovascular event or being hospitalised for treatment of heart failure.
Table 5 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) | Relative Risk Reduction | Absolute Risk Reduction |
| CV death or CHF hospitalisation | 483 | 538 | 0.85 (0.75-0.96) | 0.011 | 15% | 4.4% |
| CV death | 302 | 347 | 0.84 (0.72-0.98) | 0.029 | 16% | 3.6% |
| CHF hospitalisation | 309 | 356 | 0.83 (0.71-0.96) | 0.013 | 17% | 3.8% |
NOTE: In CHARM-Added 23 patients needed to be treated for the duration of the study (median 41 months) to prevent one patient from dying of a cardiovascular event or being hospitalised for treatment of heart failure
The secondary composite endpoint of all-cause mortality or first CHF hospitalisation was also significantly reduced with candesartan cilexetil in CHARM-Alternative (HR 0.80, 95% CI 0.70- 0.92, p=0.001) and CHARM-Added (HR 0.87, 95% CI 0.78-0.98, p=0.021). This corresponds to a relative risk reduction of 20% and 13% respectively.
Treatment with candesartan cilexetil resulted in improved NYHA functional class in CHARM Alternative and CHARM-Added (p=0.008 and p=0.020 respectively).
DETAILED PHARMACOLOGY
Animal Pharmacology
In isolated rabbit aorta helical strips, candesartan at 3 x 10-11 to 10-9 M decreased the maximal contractile response induced by angiotensin II. Candesartan at a concentration of 1 nM completely inhibits the response to angiotensin II in a concentration range of 10-10 - 10-7M, an angiotensin II concentration which elicits a full concentration-response curve in the absence of candesartan. The dissociation rate of [3H] candesartan binding from bovine adrenal cortical membranes, in vitro, was 5 times slower (t½ = 66 min) than that of [125I] angiotensin II binding (t½ = 12 min).
TOXICOLOGY
Acute Toxicity
Table 6 Acute toxicity
| Route | Species | Sex | LD50 Values |
| intraperitoneal | mouse | female male | 891 807 |
| intraperitoneal | rat | female male | 1210 940 |
| intravenous | mouse | female male | 1,170 1,120 |
| intravenous | rat | female male | 1,550 1,350 |
| oral study with active metabolite (candesartan) and related substances | mouse | female male | >2,000 mg/kg for all substances tested |
| oral | mouse | female male | >2,000 mg/kg |
| oral | rat | female male | >2,000 mg/kg |
| oral | dog | male | >2,000 mg/kg |
| oral (4 week study) | monkey | female male | >60 mg/kg |
Chronic Toxicity
The toxic potential of candesartan cilexetil was evaluated in a series of repeated dose oral toxicity studies of up to 26 weeks in rats and up to one year in dog. The "no tox effect" dosage levels were concluded to be 10 mg/kg/day in the rat and 20 mg/kg/day in the dog.
Table 7 Toxicity upon repeated oral administration
| Species/ Strain | Number of Animals per Group | Duration and Route of Administration | Daily Dose (mg/kg) | Results |
| rat/F344 | 4 M+4 F | 4 weeks dietary | 0 600 2,000 6,000 | Food consumption decr. in F at 2,000 mg and in M+F at 6,000mg dose level. Urea N2 incr. in M at ≥600 mg dosing, and in F at 6,000 mg dosing. Erythrocyte count, hematocrit value, hemoglobin concentration decr. in ≥ 2,000 mg groups. Extramedullary hemapoiesis in all male spleens, hypocellularity in bone marrow of 2 F and gastric ulcer/erosion in 2 F of 6,000 mg group. Hypertrophy of juxtaglomerular cells in kidneys and atrophy of zona glomerulosa in adrenal gland in all treated groups -- expected pharmacological responses. “No toxic effect”: 2,000 mg/kg/day. |
| rat/F344 | 10 M+10 F | 13 weeks dietary | 0 300 1,000 3,000 | No deaths. Body weight gain suppression in M at ≥ 1,000 mg level. Slight decr. in erythrocyte count, hematocrit value, hemoglobin concentration in F of 300 mg group, M+F at ≥ 1,000 mg dose. Incr. inorganic phosphorus in all M groups, decr. Triglycerides (≥ 1,000 mg male group) and incr. cholesterol (3000 mg male group). |
| rat/F344/Jcl | 10 M+10 F | 26 weeks oral | 0 1 10 100 1,000 | No treatment-related deaths, nor abnormal appearance, clinical signs, opthalmoscopy and urinalysis. Decr. in body weight gain and food consumption (M, 1000 mg dose, week 25). H2O intake + urine output incr. (M, 100, 1,000 mg dose). RBC parameter values decr. (M: 10-1,000 dose; F: 100-1,000 dose). Heart wt. decr. in all except M at 1 mg dose. Ratio of kidney wt:body wt. incr. in M ≥ 10 mg dose, and in F ≥ 100 mg dose level. In M at 1000 mg level, incr. in adrenal wt., decr. in thymus wt. Hypertrophy of juxtaglomerular cell and intimal proliferation of interlobular arteries on kidneys of M+F at 10-1,000 mg. Minor incr. in erosion of stomach in M+F at 1,000 mg. “No toxic effect”: 10 mg/kg/day. |
| rat/F344/Jcl | 10 M+10 F | 2 week study of candesartan cilexetil and rel. substances, oral | 300 (283.2 mg can.cil. + 16.8 mg rel. sub.) | No effects by related substances on the changes caused by candesartan cilexetil alone. No toxic effects caused by related substances. |
| dog/Beagle | 3 M+3 F | 29-31 days oral gavage | 0 20 100 300 | No animals died during dosing. Decr. erythrocyte parameters in 1 F in each of 100 mg and 300 mg groups. Dark red focus in stomach mucosa in 1 F at 300 mg dose level. Regeneration of tubular epithelium and dilatation of kidney tubules in 1 F at 100 mg level, 2 F at 300 mg level. Mononuclear cell infiltration in kidney in 2 F in both 100 mg and 300 mg groups. Erosion of stomach mucosa in 1 F at 300 mg. No testicular abnormalities. “No toxic effect”: 20 mg/kg/day. |
| dog/Beagle | 4 M+4 F | 26 weeks oral | 0 4 20 100 | Suppression of body wt. and decr. erythrocyte parameters in F at 100 mg. Hypertrophy of juxtaglomerular cells at all dosage levels. Plasma levels of candesartan cilexetil dose-dependent. |
| dog/Beagle | 4 M+4 F | 52 weeks oral | 0 4 20 100 300 | No clinical signs, effects on body wt., food consumption, physiological measurements, urine output, H2O intake, hemotology, coagulation, or organ wts. Hypertrophy of juxtaglomerular cells at all dosage levels. Regeneration of renal tubule incr. in 100-300 mg dose groups. Plasma levels of candesartan cilexetil and metabolite M II dose-dependent. “No toxic effect” at 20 mg/kg/day in dog. |
Reproduction Studies
In studies concerning male and female rat fertility, no adverse effects were found on the reproductive organs. Mating performance, fertility and necropsy findings were unaffected by candesartan cilexetil treatment of males at 0-300 mg/kg/day from nine weeks before mating to the day before necropsy, and similar findings were observed in females treated from two weeks before mating to day 7 of gestation. Foetuses showed no treatment-related abnormalities in mortality, weight, sex ratio, placentae or upon external, visceral or skeletal examinations.
Animal studies with candesartan cilexetil have demonstrated late fetal and neonatal injury in the kidney. The mechanism is believed to be pharmacologically mediated through effects on the renin-angiotensin-aldosterone system.
Mutagenicity
In vitro studies (bacterial mutagenicity, gene mutation in mammalian (mouse) cells, and cytogenic tests (hamster lung cells) showed candesartan cilexetil has no mutagenic activity in these systems. Study at the highest doses of the candesartan metabolites (2.5 and 5 mM in the 24-hour treatment series, and 1.25 and 2.5 mM in the 48-hour treatment series) suggest cytotoxicity-mediated clastogenicity as a mechanism for the breakage-type chromosome aberration effects observed. In vivo studies (micronucleus test in mice, and unscheduled DNA synthesis assay in rat) indicate that candesartan cilexetil and its metabolites have no mutagenic nor clastogenic potential.
Carcinogenicity
The carcinogenic potential of candesartan cilexetil was studied in rats after administration in the diet for 24 months. Dose levels were 100, 300 and 1000 mg/kg/day (50 male and 50 female rats per group). No alteration in tumour profile was observed. A two-year oral gavage study of candesartan cilexetil in mice was performed at daily dosages of 3, 10, 30 and 100 mg/kg/day. There was no alteration in the tumour profile.
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Product Monograph, ATACAND (candesartan celexitil) AstraZeneca Canada Inc.; Control Number: 149610, Date of Revision: December 8, 2011.