Candesartan (Actavis Pharma) Product Monograph

SUMMARY PRODUCT INFORMATION

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).

• Concomitant use of angiotensin receptor antagonists (ARBs), including

  CANDESARTAN, with aliskiren-containing drugs in patients with diabetes mellitus (type 1 or type 2) or moderate to severe renal impairment (GFR < 60 ml/min/1.73m²) is contraindicated (see WARNINGS and PRECAUTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) and Renal, and DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACEIs or aliskiren-containing drugs).

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.

Dual blockade of the Renin-Angiotensin System (RAS)

There is evidence that co-administration of angiotensin receptor antagonists (ARBs), such as candesartan cilexetil, or of angiotensin converting enzyme inhibitors (ACEIs) with aliskiren increases the risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe renal impairment (GFR < 60 ml/min/1.73m²). Therefore, the use of CANDESARTAN in combination with aliskiren-containing drugs is contraindicated in these patients (see CONTRAINDICATIONS).

Further, co-administration of ARBs, including CANDESARTAN, with other agents blocking the RAS, such as ACEIs or aliskiren-containing drugs, is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, renal failure, and hyperkalemia.

Endocrine and Metabolism

Hyperkalemia

In heart failure patients treated with CANDESARTAN, hyperkalemia may occur. During treatment with CANDESARTAN 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.

The use of ARBs, including CANDESARTAN, or ACEIs with aliskiren-containing drugs is contraindicated in patients with moderate to severe renal impairment (GFR < 60 ml/min/1.73m²) (see CONTRAINDICATIONS and DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACEIs, or aliskiren-containing drugs).

Use of CANDESARTAN 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, and/or volume repletion may be required. Monitoring of serum creatinine is recommended during dose escalation and periodically thereafter.

Renal Transplantation

There is limited experience regarding the administration of candesartan cilexetil in patients with renal transplant.

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

Fatigue

Abdominal pain

Peripheral edema

3.2 1.5 1.5 1.0

0.9 1.6 1.3 0.7 Digestive

Nausea

Diarrhea

Vomiting

1.9 1.5 1.0

1.3 1.9 1.2 Nervous/Psychiatric

Headache

Dizziness

10.4 2.5

10.3 2.3 Respiratory

Upper respiratory infection

Coughing

Influenza-like symptoms

Pharyngitis

Bronchitis

Rhinitis

5.1 1.6 1.5 1.1 1.0 1.0

3.8 1.1 0.8 0.4 2.2 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 Placebo n=2289 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 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 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

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Drug-Food Interactions

CANDESARTAN may be taken with or without food (see DOSAGE AND ADMINISTRATION).

DOSAGE AND ADMINISTRATION

Dosing Considerations

The dosage of CANDESARTAN (candesartan cilexetil) 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 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

For management of a suspected drug overdose, contact your regional Poison Control Centre.

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.

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 reninangiotensin-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 (C_max) 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) (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.

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 (Cl_creat 31-60 mL/min/1.73m²), C_max and AUC of candesartan increased by 40-60% and 50-90%, 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 15-30 mL/min/1.73m²) were 40-60% 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 AND ADMINISTRATION, Renal Impairment).

STORAGE AND STABILITY

Store at 15-30°C.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms

CANDESARTAN tablets are formulated for oral administration and are available as 4 mg, 8 mg, 16 mg and 32 mg tablets with the following descriptions:

CANDESARTAN 4 mg tablets are white to off-white, round, biconvex scored tablets marked with “CD” on one side and “ ” on the other side. 4

CANDESARTAN 8 mg tablets are light pink, round, biconvex scored tablets marked with “CD” on one side and “ ” on the other side. 8

CANDESARTAN 16 mg tablets are pink, round, biconvex scored tablets marked with “CD” on one side and “ ” on the other side. 16

CANDESARTAN 32 mg tablets are pink, round, biconvex scored tablets marked with “CD” on one side and “ ” on the other side. 32

Composition

Each CANDESARTAN tablet contains candesartan cilexetil 4 mg, 8 mg, 16 mg or 32 mg as the active ingredient.

Each tablet also contains the following non-medicinal ingredients: carmellose calcium, corn starch, hydroxypropyl cellulose, iron oxide (except 4 mg tablets), lactose, magnesium stearate, and stearic acid.

Packaging

CANDESARTAN 4 mg, 8 mg, 16 mg and 32 tablets are available in HDPE bottles of 100 and 500 tablets, and in unit dose 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: C₃₃H₃₄N₆O₆

Molecular Mass: 610.67 g/mol

Structural Formula:

Physicochemical Properties: Description:

Candesartan cilexetil is a white to off-white powder. The solubility in benzyl alcohol is 205 g/L, and the solubility in water is < 5x10^-5 g/L.

Melting Point:

163° C with decomposition.

Partition Coefficient:

pH of

aqueous layer

Partition Coefficient (K at 20°C) Ethyl Ether 1-Octanol 1.1

6.9

8.9

> 1000

> 1000

141

> 1000 > 1000 > 1000

K = Concentration of Candesartan Cilexetil in the organic layer Concentration of Candesartan Cilexetil in the aqueous layer

CLINICAL TRIALS

Comparative Bioavailability Studies

A blinded, single-dose, randomized, two-period, two-sequence, two-treatment, crossover comparative bioavailability study of CANDESARTAN (candesartan cilexetil) 4 mg tablets and Atacand^® (candesartan cilexetil) 4 mg tablets by AstraZeneca Canada Inc., was conducted under fasting conditions with 28 healthy male and female volunteers. A summary of the bioavailability data is presented from 26 patients who completed the study.

* Test product: Candesartan Cilexetil 4 mg Tablets (Actavis Pharma Company, Canada)

^† Canadian Reference Product: Atacand^® (Candesartan Cilexetil 4 mg Tablets) (AstraZeneca Canada Inc.) was purchased in Canada ^§ Expressed as the median (range) only

^† Expressed as the arithmetic mean (CV%) only

^‡ Calculation based on least square estimate

A blinded, single-dose, randomized, two-period, two-sequence, two-treatment, crossover comparative bioavailability study of CANDESARTAN (candesartan cilexetil) 32 mg tablets and Atacand^® (candesartan cilexetil) 32 mg tablets by AstraZeneca Canada Inc., was conducted under fasting conditions with 40 healthy male and female volunteers. A summary of the bioavailability data from 36 patients who completed the study is presented.

Candesartan Cilexetil

(1 x 32 mg)

From measured data uncorrected for potency

Geometric LS Mean Arithmetic Mean (CV %)

* Test product: Candesartan Cilexetil 32 mg Tablets (Actavis Pharma Company, Canada)

^† Canadian Reference Product: Atacand^® (Candesartan Cilexetil 32 mg Tablets) (AstraZeneca Canada Inc.) was purchased in Canada

^§ Expressed as the median (range) only

^† Expressed as the arithmetic mean (CV%) only

^‡ Calculation based on least square estimate

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

1. 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. CHARMAlternative (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

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

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 (t_½ = 66 min) than that of [¹²⁵I] angiotensin II binding (t_½ = 12 min).

TOXICOLOGY

Acute Toxicity

Table 6: Acute toxicity

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

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. Fetuses 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.

REFERENCES

Bell TP, DeQuattro V, Lasseter KC, Ruff D, Hardison JD, Cushing D, Kezer AE, Michelson EL. Effective dose range of candesartan cilexetil for systemic hypertension. Am J of Cardiology 1999; 83: 272-275.

Delacrétaz E, Nussberger J, Biollaz J, Waeber B, Brunner HR. Characterization of the angiotensin II receptor antagonist TCV-116 in healthy volunteers. Hypertension 1995; 25: 14-21.

Gradman AH, Lewin A, Bowling BT, Tonkon M, Deedwania PC, Kezer AE, Hardison JD, Cushing DJ, Michelson EL. Comparative effects of candesartan cilexetil and losartan in patients with systemic hypertension. Heart Disease 1999; 1: 52-57.

Granger CB, McMurray JJV, Yusuf S, Held P, Michelson EL, Olofsson B, Östergren J, Pfeffer MA, Swedberg K, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM- Alternative trial. The Lancet 2003; 362 (9386): 772-776.

Malerczyk C, Fuchs B, Belz GG, Roll S, Butzer R, Breithaupt-Grogler, Herrmann V, Magin SG, Högemann A, Voith B, Mutschler E. Angiotensin II antagonism and plasma radioreceptor-kinetics of candesartan in man. Br J Clin Pharmacol 1998; 45: 567-573.

McMurray JJV, Östergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S, Pfeffer MA, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin converting-enzyme inhibitors: the CHARM-Added trial. The Lancet 2003; 362 (9386): 767-771.

Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, Cooper ME. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. Br Medical Journal 2000; 321: 1440-1444.

Weinberg MS, Weinberg AJ, Cord R, Zappe DH. The effects of high-dose angiotensin II receptor blockade beyond maximal recommended doses in reducing urinary protein excretion. JRAAS 2001; 2 (Supp 1): S196-S198.

Weir MR, Weber MA, Neutel JM, Vendetti J, Michelson EL, Wang RY. Efficacy of candesartan cilexetil as add-on therapy in hypertensive patients uncontrolled on background therapy: a clinical experience trial. Am J of Hypertension 2001; 14: 567-572.

Product Monograph for Atacand^® (candesartan cilexetil), 4 mg, 8 mg, 16 mg and 32 mg tablets. AstraZeneca Canada Inc., Mississauga, Ontario, Canada. Submission Control # 165654. Date of Revision: September 10, 2013.