Candestan

Candestan uses

• Recent major changes
• Warning: fetal toxicity
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Patient information
• Candestan reviews

Recent Major Changes

Warnings and Precautions, Fetal Toxicity (5.1) 04/2012

WARNING: FETAL TOXICITY

• When pregnancy is detected, discontinue Candestan as soon as possible. (5.1)
• Drugs that directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1)

WARNING: FETAL TOXICITY

See Full Prescribing Information for complete boxed warning.

• When pregnancy is detected, discontinue Candestan as soon as possible. (5.1)
• Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1)

1 INDICATIONS AND USAGE

Candestan is an angiotensin II receptor blocker indicated for:

• Treatment of hypertension in adults and children 1 to < 17 years of age (1.1).
• Treatment of heart failure (NYHA class II-IV); Candestan reduces cardiovascular death and heart failure hospitalization (1.2).

1.1 Hypertension

Candestan is indicated for the treatment of hypertension in adults and children 1 to < 17 years of age. It may be used alone or in combination with other antihypertensive agents.

1.2 Heart Failure

Candestan is indicated for the treatment of heart failure (NYHA class II-IV) in adults with left ventricular systolic dysfunction (ejection fraction ≤ 40%) to reduce cardiovascular death and to reduce heart failure hospitalizations . Candestan also has an added effect on these outcomes when used with an ACE inhibitor.

2 DOSAGE AND ADMINISTRATION

2.1 Adult Hypertension

Dosage must be individualized. Blood pressure response is dose related over the range of 2 to 32 mg. The usual recommended starting dose of Candestan is 16 mg once daily when it is used as monotherapy in patients who are not volume depleted. Candestan can be administered once or twice daily with total daily doses ranging from 8 mg to 32 mg. Larger doses do not appear to have a greater effect, and there is relatively little experience with such doses. Most of the antihypertensive effect is present within 2 weeks, and maximal blood pressure reduction is generally obtained within 4 to 6 weeks of treatment with Candestan.

No initial dosage adjustment is necessary for elderly patients, for patients with mildly impaired renal function, or for patients with mildly impaired hepatic function . In patients with moderate hepatic impairment, consideration should be given to initiation of Candestan at a lower dose . For patients with possible depletion of intravascular volume (eg, patients treated with diuretics, particularly those with impaired renal function), Candestan should be initiated under close medical supervision and consideration should be given to administration of a lower dose .

Candestan may be administered with or without food.

If blood pressure is not controlled by Candestan alone, a diuretic may be added. Candestan may be administered with other antihypertensive agents.

2.2 Pediatric Hypertension 1 to < 17 Years of age

Candestan may be administered once daily or divided into two equal doses. Adjust the dosage according to blood pressure response. For patients with possible depletion of intravascular volume, initiate Candestan under close medical supervision and consider administration of a lower dose .

Children 1 to < 6 years of age:

The dose range is 0.05 to 0.4 mg/kg per day. The recommended starting dose is 0.20 mg/kg (oral suspension).

Children 6 to < 17 years of age:

For those less than 50 kg, the dose range is 2 to 16 mg per day. The recommended starting dose is 4 to 8 mg.

For those greater than 50 kg, the dose range is 4 to 32 mg per day. The recommended starting dose is 8 to 16 mg.

Doses above 0.4 mg/kg (1 to < 6 year olds) or 32 mg (6 to < 17 year olds) have not been studied in pediatric patients .

An antihypertensive effect is usually present within 2 weeks, with full effect generally obtained within 4 weeks of treatment with Candestan.

Children < 1 year of age must not receive Candestan for hypertension.

All pediatric patients with a glomerular filtration rate less than 30 ml/min/1.73m² should not receive Candestan since Candestan has not been studied in this population.

For children who cannot swallow tablets, an oral suspension may be substituted as described below:

Preparation of Oral Suspension:

Candestan oral suspension can be prepared in concentrations within the range of 0.1 to 2.0 mg/mL. Typically, a concentration of 1 mg/mL will be suitable for the prescribed dose. Any strength of Candestan tablets can be used in the preparation of the suspension.

Follow the steps below for preparation of the suspension. The number of tablets and volume of vehicle specified below will yield 160 mL of a 1 mg/mL suspension.

• Prepare the vehicle by adding equal volumes of Ora-Plus®, Ora-Sweet SF®, and Ora-Blend SF® are registered trademarks of Paddock Laboratories, Inc.Ora-Plus® (80 mL) and ¹Ora-Sweet SF® (80 mL) or, alternatively, use¹, Supplied as a 50/50% pre-mix of Ora-Plus® and Ora-Sweet SF®Ora-Blend SF® (160 mL).
• Add a small amount of vehicle to the required number of Candestan tablets (five 32 mg tablets) and grind into a smooth paste using a mortar and pestle.
• Add the paste to a preparation vessel of suitable size.
• Rinse the mortar and pestle clean using the vehicle and add this to the vessel. Repeat, if necessary.
• Prepare the final volume by adding the remaining vehicle.
• Mix thoroughly.
• Dispense into suitably sized amber PET bottles.
• Label with an expiry date of 100 days and include the following instructions:

Store at room temperature (below 30°C/86°F). Use within 30 days after first opening. Do not use after the expiry date stated on the bottle.

Do not freeze.

Shake well before each use.

2.3 Adult Heart Failure

The recommended initial dose for treating heart failure is 4 mg once daily. The target dose is 32 mg once daily, which is achieved by doubling the dose at approximately 2-week intervals, as tolerated by the patient.

3 DOSAGE FORMS and STRENGTHS

4 mg are white to off-white, circular/biconvex-shaped, non-film-coated scored tablets, coded ACF on one side and 004 on the other.

8 mg are light pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACG on one side and 008 on the other.

16 mg are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACH on one side and 016 on the other.

32 mg are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACL on one side and 032 on the other.

Tablets 4 mg, 8 mg, 16 mg, 32 mg (3).

4 CONTRAINDICATIONS

Candestan is contraindicated in patients who are hypersensitive to any component of this product.

Known hypersensitivity to product components (4).

5 WARNINGS AND PRECAUTIONS

• Avoid fetal and neonatal exposure (5.1).
• Children < 1 year of age must not receive Candestan for hypertension (5.2).
• Observe for signs and symptoms of hypotension (5.3).
• Use with caution in patients with impaired hepatic (5.4) or renal (5.5) function.
• Hyperkalemia may occur in heart failure patients treated with Candestan (5.6).

5.1 Fetal Toxicity

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure and death. When pregnancy is detected, discontinue Candestan as soon as possible [see USE IN SPECIFIC POPULATIONS (8.1) ].

Oral doses ≥10 mg of Candestan cilexetil/kg/day administered to pregnant rats during late gestation and continued through lactation were associated with reduced survival and an increased incidence of hydronephrosis in the offspring. The 10-mg/kg/day dose in rats is approximately 2.8 times the maximum recommended daily human dose (MRHD) of 32 mg on a mg/m² basis (comparison assumes human body weight of 50 kg). Candestan cilexetil given to pregnant rabbits at an oral dose of 3 mg/kg/day (approximately 1.7 times the MRHD on a mg/m² basis) caused maternal toxicity (decreased body weight and death) but, in surviving dams, had no adverse effects on fetal survival, fetal weight, or external, visceral, or skeletal development. No maternal toxicity or adverse effects on fetal development were observed when oral doses up to 1000 mg of Candestan cilexetil/kg/day (approximately 138 times the MRHD on a mg/m² basis) were administered to pregnant mice.

5.2 Morbidity in Infants

Children < 1 year of age must not receive Candestan for hypertension. Drugs that act directly on the renin-angiotensin system can have effects on the development of immature kidneys.

5.3 Hypotension

In adult or children patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (eg, those being treated with diuretics), symptomatic hypotension may occur. These conditions should be corrected prior to administration of Candestan, or the treatment should start under close medical supervision.

If hypotension occurs, the patients should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment which usually can be continued without difficulty once the blood pressure has stabilized.

Caution should be observed when initiating therapy in patients with heart failure. Patients with heart failure given Candestan commonly have some reduction in blood pressure. In patients with symptomatic hypotension this may require temporarily reducing the dose of Candestan, or diuretic, or both, and volume repletion. In the CHARM program, hypotension was reported in 18.8% of patients on Candestan versus 9.8% of patients on placebo. The incidence of hypotension leading to drug discontinuation in ATACAND-treated patients was 4.1% compared with 2.0% in placebo-treated patients.

Monitoring of blood pressure is recommended during dose escalation and periodically thereafter.

Major Surgery/Anesthesia

Hypotension may occur during major surgery and anesthesia in patients treated with angiotensin II receptor antagonists, including Candestan, due to blockade of the renin-angiotensin system. Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors.

5.4 Impaired Hepatic Function

Based on pharmacokinetic data which demonstrate significant increases in Candestan AUC and C_max in patients with moderate hepatic impairment, a lower initiating dose should be considered for patients with moderate hepatic impairment .

5.5 Renal Function Deterioration

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in some individuals treated with Candestan. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (eg, patients with severe heart failure), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results may be anticipated in patients treated with Candestan.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of Candestan in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.

In heart failure patients treated with Candestan, increases in serum creatinine may occur. Dosage reduction or discontinuation of the diuretic or Candestan, and volume repletion may be required. In the CHARM program, the incidence of abnormal renal function (e.g., creatinine increase) was 12.5% in patients treated with Candestan versus 6.3% in patients treated with placebo. The incidence of abnormal renal function (eg, creatinine increase) leading to drug discontinuation in ATACAND-treated patients was 6.3% compared with 2.9% in placebo-treated patients. Evaluation of patients with heart failure should always include assessment of renal function and volume status. Monitoring of serum creatinine is recommended during dose escalation and periodically thereafter.

Pediatrics - Candestan has not been studied in children with estimated glomerular filtration rate < 30 mL/min/1.73m².

5.6 Hyperkalemia

In heart failure patients treated with Candestan, hyperkalemia may occur, especially when taken concomitantly with ACE inhibitors and potassium-sparing diuretics such as spironolactone. In the CHARM program, the incidence of hyperkalemia was 6.3% in patients treated with Candestan versus 2.1% in patients treated with placebo. The incidence of hyperkalemia leading to drug discontinuation in ATACAND-treated patients was 2.4% compared with 0.6% in placebo-treated patients. During treatment with Candestan in patients with heart failure, monitoring of serum potassium is recommended during dose escalation and periodically thereafter.

6 ADVERSE REACTIONS

• Most common adverse reactions which caused adult patients to discontinue therapy for:
• Hypertension were headache and dizziness (0.3%) (6.1).
• Heart Failure were hypotension (4.1%) (5.3), abnormal renal function (6.3%) (5.5), and hyperkalemia (2.4%) (5.6).
• Most common adverse reactions (incidence ≥ 2% and greater than placebo) are back pain, dizziness, upper respiratory tract infection, pharyngitis and rhinitis (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1–800–236–9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adult Hypertension

Candestan has been evaluated for safety in more than 3600 patients/subjects, including more than 3200 patients treated for hypertension. About 600 of these patients were studied for at least 6 months and about 200 for at least 1 year. In general, treatment with Candestan was well tolerated. The overall incidence of adverse events reported with Candestan was similar to placebo.

The rate of withdrawals due to adverse events in all trials in patients (7510 total) was 3.3% (ie, 108 of 3260) of patients treated with Candestan as monotherapy and 3.5% (ie, 39 of 1106) of patients treated with placebo. In placebo-controlled trials, discontinuation of therapy due to clinical adverse events occurred in 2.4% (ie, 57 of 2350) of patients treated with Candestan and 3.4% (ie, 35 of 1027) of patients treated with placebo.

The most common reasons for discontinuation of therapy with Candestan were headache (0.6%) and dizziness (0.3%).

The adverse events that occurred in placebo-controlled clinical trials in at least 1% of patients treated with Candestan and at a higher incidence in Candestan cilexetil (n = 2350) than placebo (n = 1027) patients included back pain (3% vs. 2%), dizziness (4% vs. 3%), upper respiratory tract infection (6% vs. 4%), pharyngitis (2% vs. 1%), and rhinitis (2% vs. 1%).

The following adverse events occurred in placebo-controlled clinical trials at a more than 1% rate but at about the same or greater incidence in patients receiving placebo compared to Candestan: fatigue, peripheral edema, chest pain, headache, bronchitis, coughing, sinusitis, nausea, abdominal pain, diarrhea, vomiting, arthralgia, albuminuria.

Other potentially important adverse events that have been reported, whether or not attributed to treatment, with an incidence of 0.5% or greater from the 3260 patients worldwide treated in clinical trials with Candestan are listed below. It cannot be determined whether these events were causally related to Candestan. Body as a Whole: asthenia, fever; Central and Peripheral Nervous System: paresthesia, vertigo; Gastrointestinal System Disorder: dyspepsia, gastroenteritis; Heart Rate and Rhythm Disorders: tachycardia, palpitation; Metabolic and Nutritional Disorders: creatine phosphokinase increased, hyperglycemia, hypertriglyceridemia, hyperuricemia; Musculoskeletal System Disorders: myalgia; Platelet/Bleeding-Clotting Disorders: epistaxis; Psychiatric Disorders: anxiety, depression, somnolence; Respiratory System Disorders: dyspnea; Skin and Appendages Disorders: rash, sweating increased; Urinary System Disorders: hematuria.

Other reported events seen less frequently included angina pectoris, myocardial infarction, and angioedema.

Adverse events occurred at about the same rates in men and women, older and younger patients, and black and non-black patients.

Pediatric Hypertension

Among children in clinical studies, 1 in 93 children age 1 to < 6 and 3 in 240 age 6 to < 17 experienced worsening renal disease. The association between Candestan and exacerbation of the underlying condition could not be excluded.

Heart Failure

The adverse event profile of Candestan in adult heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM program, comparing Candestan in total daily doses up to 32 mg once daily (n=3803) with placebo (n=3796), 21.0% of patients discontinued Candestan for adverse events vs. 16.1% of placebo patients.

6.2 Postmarketing Experience

The following adverse reactions were identified during post-approval use of Candestan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following have been very rarely reported in post-marketing experience:

Digestive: Abnormal hepatic function and hepatitis.

Hematologic: Neutropenia, leukopenia, and agranulocytosis.

Metabolic and Nutritional Disorders: hyperkalemia, hyponatremia.

Renal: renal impairment, renal failure.

Skin and Appendages Disorders: Pruritus and urticaria.

Rare reports of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

6.3 Laboratory Test Findings

Hypertension

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with the administration of Candestan.

Creatinine, Blood Urea Nitrogen

Minor increases in blood urea nitrogen (BUN) and serum creatinine were observed infrequently.

Hyperuricemia

Hyperuricemia was rarely found (19 or 0.6% of 3260 patients treated with Candestan and 5 or 0.5% of 1106 patients treated with placebo).

Hemoglobin and Hematocrit

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

Potassium

A small increase (mean increase of 0.1 mEq/L) was observed in patients treated with Candestan alone but was rarely of clinical importance. One patient from a congestive heart failure trial was withdrawn for hyperkalemia (serum potassium = 7.5 mEq/L). This patient was also receiving spironolactone.

Liver Function Tests

Elevations of liver enzymes and/or serum bilirubin were observed infrequently. Five patients assigned to Candestan in clinical trials were withdrawn because of abnormal liver chemistries. All had elevated transaminases. Two had mildly elevated total bilirubin, but one of these patients was diagnosed with Hepatitis A.

Heart Failure

In the CHARM program, small increases in serum creatinine (mean increase 0.2 mg/dL in candesartan-treated patients and 0.1 mg/dL in placebo-treated patients) and serum potassium (mean increase 0.15 mEq/L in ATACAND-treated patients and 0.02 mEq/L in placebo-treated patients), and small decreases in hemoglobin (mean decrease 0.5 gm/dL in ATACAND-treated patients and 0.3 gm/dL in placebo-treated patients) and hematocrit (mean decrease 1.6% in ATACAND-treated patients and 0.9% in placebo-treated patients) were observed.

7 DRUG INTERACTIONS

No significant drug interactions have been reported in studies of Candestan cilexetil given with other drugs such as glyburide, nifedipine, digoxin, warfarin, hydrochlorothiazide, and oral contraceptives in healthy volunteers, or given with enalapril to patients with heart failure (NYHA class II and III). Because Candestan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effects on P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors). In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including Candestan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Candestan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including Candestan may be attenuated by NSAIDs including selective COX-2 inhibitors.

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors, and with some angiotensin II receptor antagonists. An increase in serum lithium concentration has been reported during concomitant administration of lithium with Candestan, so careful monitoring of serum lithium levels is recommended during concomitant use.

• Lithium: Reversible increases in serum lithium concentrations and toxicity (7).
• NSAIDS use may lead to increased risk of renal impairment and loss of antihypertensive effect (7).

8 USE IN SPECIFIC POPULATIONS

• Nursing Mothers: Either nursing or drug should be discontinued.
• Pediatrics: Children < 1 year of age must not receive Candestan for hypertension (5.2). Inhibitors of the renin-angiotensin system can cause renal abnormalities in neonatal animals (12.3).
• Geriatrics: No overall difference in efficacy or safety vs. younger adult patients, but greater sensitivity of some older individuals cannot be ruled out (8.5).

8.1 Pregnancy

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Candestan as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Candestan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Candestan for hypotension, oliguria, and hyperkalemia. [see USE IN SPECIFIC POPULATIONS (8. 4) ]

8.2 Labor and Delivery

The effect of Candestan on labor and delivery in humans is unknown .

8.3 Nursing Mothers

It is not known whether Candestan is excreted in human milk, but Candestan has been shown to be present in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue Candestan, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Neonates with a history of in utero exposure to Candestan:

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

The antihypertensive effects of Candestan were evaluated in hypertensive children 1 to < 17 years of age in randomized, double-blind clinical studies. The pharmacokinetics of Candestan have been evaluated in pediatric patients 1 to < 17 years of age .

Children < 1 year of age must not receive Candestan for hypertension .

8.5 Geriatric Use

Hypertension

Of the total number of subjects in clinical studies of Candestan, 21% (683/3260) were 65 and over, while 3% (87/3260) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger adult subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In a placebo-controlled trial of about 200 elderly hypertensive patients (ages 65 to 87 years), administration of Candestan cilexetil was well tolerated and lowered blood pressure by about 12/6 mm Hg more than placebo.

Heart Failure

Of the 7599 patients with heart failure in the CHARM program, 4343 (57%) were age 65 years or older and 1736 (23%) were 75 years or older. In patients ≥ 75 years of age, the incidence of drug discontinuations due to adverse events was higher for those treated with Candestan or placebo compared with patients <75 years of age. In these patients, the most common adverse events leading to drug discontinuation at an incidence of at least 3%, and more frequent with Candestan than placebo, were abnormal renal function (7.9% vs. 4.0%), hypotension (5.2% vs. 3.2%) and hyperkalemia (4.2% vs. 0.9%). In addition to monitoring of serum creatinine, potassium, and blood pressure during dose escalation and periodically thereafter, greater sensitivity of some older individuals with heart failure must be considered.

10 OVERDOSAGE

No lethality was observed in acute toxicity studies in mice, rats, and dogs given single oral doses of up to 2000 mg/kg of Candestan cilexetil. In mice given single oral doses of the primary metabolite, Candestan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg.

The most likely manifestation of overdosage with Candestan would be hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.

Candestan cannot be removed by hemodialysis.

Treatment: To obtain up-to-date information about the treatment of overdose, consult your Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and altered pharmacokinetics in your patient.

11 DESCRIPTION

Candestan (candesartan cilexetil), a prodrug, is hydrolyzed to Candestan during absorption from the gastrointestinal tract. Candestan is a selective AT₁ subtype angiotensin II receptor antagonist.

Candestan cilexetil, a nonpeptide, is chemically described as (±)-1-Hydroxyethyl 2-ethoxy-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester).

Its empirical formula is C₃₃H₃₄N₆O₆, and its structural formula is:

Candestan cilexetil is a white to off-white powder with a molecular weight of 610.67. It is practically insoluble in water and sparingly soluble in methanol. Candestan cilexetil is a racemic mixture containing one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group. Following oral administration, Candestan cilexetil undergoes hydrolysis at the ester link to form the active drug, Candestan, which is achiral.

Candestan is available for oral use as tablets containing either 4 mg, 8 mg, 16 mg, or 32 mg of Candestan cilexetil and the following inactive ingredients: hydroxypropyl cellulose, polyethylene glycol, lactose, corn starch, carboxymethylcellulose calcium, and magnesium stearate. Ferric oxide (reddish brown) is added to the 8-mg, 16-mg, and 32-mg tablets as a colorant.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme. Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Candestan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT₁ receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathways for angiotensin II synthesis.

There is also an AT₂ receptor found in many tissues, but AT₂ is not known to be associated with cardiovascular homeostasis. Candestan has much greater affinity (>10,000-fold) for the AT₁ receptor than for the AT₂ receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because Candestan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Candestan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of Candestan on blood pressure.

12.2 Pharmacodynamics

Candestan inhibits the pressor effects of angiotensin II infusion in a dose-dependent manner. After 1 week of once daily dosing with 8 mg of Candestan cilexetil, the pressor effect was inhibited by approximately 90% at peak with approximately 50% inhibition persisting for 24 hours.

Plasma concentrations of angiotensin I and angiotensin II, and plasma renin activity (PRA), increased in a dose-dependent manner after single and repeated administration of Candestan cilexetil to healthy subjects, hypertensive, and heart failure patients. ACE activity was not altered in healthy subjects after repeated Candestan cilexetil administration. The once-daily administration of up to 16 mg of Candestan cilexetil to healthy subjects did not influence plasma aldosterone concentrations, but a decrease in the plasma concentration of aldosterone was observed when 32 mg of Candestan cilexetil was administered to hypertensive patients. In spite of the effect of Candestan cilexetil on aldosterone secretion, very little effect on serum potassium was observed.

Hypertension

Adults

In multiple-dose studies with hypertensive patients, there were no clinically significant changes in metabolic function, including serum levels of total cholesterol, triglycerides, glucose, or uric acid. In a 12-week study of 161 patients with non-insulin-dependent (type 2) diabetes mellitus and hypertension, there was no change in the level of HbA_1c.

Heart Failure

In heart failure patients, Candestan ≥ 8 mg resulted in decreases in systemic vascular resistance and pulmonary capillary wedge pressure.

12.3 Pharmacokinetics

Distribution

The volume of distribution of Candestan is 0.13 L/kg. Candestan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. The protein binding is constant at Candestan plasma concentrations well above the range achieved with recommended doses. In rats, it has been demonstrated that Candestan crosses the blood-brain barrier poorly, if at all. It has also been demonstrated in rats that Candestan passes across the placental barrier and is distributed in the fetus.

Metabolism and Excretion

Total plasma clearance of Candestan is 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg. When Candestan is administered orally, about 26% of the dose is excreted unchanged in urine. Following an oral dose of ¹⁴C-labeled Candestan cilexetil, approximately 33% of radioactivity is recovered in urine and approximately 67% in feces. Following an intravenous dose of ¹⁴C-labeled Candestan, approximately 59% of radioactivity is recovered in urine and approximately 36% in feces. Biliary excretion contributes to the elimination of Candestan.

Adults

Candestan cilexetil is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to Candestan, a selective AT₁ subtype angiotensin II receptor antagonist. Candestan is mainly excreted unchanged in urine and feces (via bile). It undergoes minor hepatic metabolism by O-deethylation to an inactive metabolite. The elimination half-life of Candestan is approximately 9 hours. After single and repeated administration, the pharmacokinetics of Candestan are linear for oral doses up to 32 mg of Candestan cilexetil. Candestan and its inactive metabolite do not accumulate in serum upon repeated once-daily dosing.

Following administration of Candestan cilexetil, the absolute bioavailability of Candestan was estimated to be 15%. After tablet ingestion, the peak serum concentration (C_max) is reached after 3 to 4 hours. Food with a high fat content does not affect the bioavailability of Candestan after Candestan cilexetil administration.

Pediatrics

In children 1 to 17 years of age, plasma levels are greater than 10–fold higher at peak (approximately 4 hours) than 24 hours after a single dose.

Children 1 to < 6 years of age, given 0.2 mg/kg had exposure similar to adults given 8 mg.

Children > 6 years of age had exposure similar to adults given the same dose.

The pharmacokinetics (C_max and AUC) were not modified by age, sex or body weight.

Candestan cilexetil pharmacokinetics have not been investigated in pediatric patients less than 1 year of age.

From the dose-ranging studies of Candestan cilexetil, there was a dose related increase in plasma Candestan concentrations.

The renin-angiotensin system (RAS) plays a critical role in kidney development. RAS blockade has been shown to lead to abnormal kidney development in very young mice. Children < 1 year of age must not receive Candestan. Administering drugs that act directly on the renin-angiotensin system (RAS) can alter normal renal development.

Geriatric and Sex

The pharmacokinetics of Candestan have been studied in the elderly (≥ 65 years) and in both sexes. The plasma concentration of Candestan was higher in the elderly (C_max was approximately 50% higher, and AUC was approximately 80% higher) compared to younger subjects administered the same dose. The pharmacokinetics of Candestan were linear in the elderly, and Candestan and its inactive metabolite did not accumulate in the serum of these subjects upon repeated, once-daily administration. No initial dosage adjustment is necessary . There is no difference in the pharmacokinetics of Candestan between male and female subjects.

Renal Insufficiency

In hypertensive patients with renal insufficiency, serum concentrations of Candestan were elevated. After repeated dosing, the AUC and C_max were approximately doubled in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73m²) compared to patients with normal kidney function. The pharmacokinetics of Candestan in hypertensive patients undergoing hemodialysis are similar to those in hypertensive patients with severe renal impairment. Candestan cannot be removed by hemodialysis. No initial dosage adjustment is necessary in patients with renal insufficiency.

In heart failure patients with renal impairment, AUC_0-72h was 36% and 65% higher in mild and moderate renal impairment, respectively. C_max was 15% and 55% higher in mild and moderate renal impairment, respectively.

Pediatrics:

Candestan pharmacokinetics have not been determined in children with renal insufficiency.

Hepatic Insufficiency

The pharmacokinetics of Candestan were compared in patients with mild and moderate hepatic impairment to matched healthy volunteers following a single oral dose of 16 mg Candestan cilexetil. The increase in AUC for Candestan was 30% in patients with mild hepatic impairment (Child-Pugh A) and 145% in patients with moderate hepatic impairment (Child-Pugh B). The increase in C_max for Candestan was 56% in patients with mild hepatic impairment and 73% in patients with moderate hepatic impairment. The pharmacokinetics after Candestan cilexetil administration have not been investigated in patients with severe hepatic impairment. No initial dosage adjustment is necessary in patients with mild hepatic impairment. In hypertensive patients with moderate hepatic impairment, consideration should be given to initiation of Candestan at a lower dose.

Heart Failure

The pharmacokinetics of Candestan were linear in patients with heart failure (NYHA class II and III) after Candestan cilexetil doses of 4, 8, and 16 mg. After repeated dosing, the AUC was approximately doubled in these patients compared with healthy, younger patients. The pharmacokinetics in heart failure patients is similar to that in healthy elderly volunteers [see DOSAGE AND ADMINISTRATION (2.3) ].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no evidence of carcinogenicity when Candestan cilexetil was orally administered to mice and rats for up to 104 weeks at doses up to 100 and 1000 mg/kg/day, respectively. Rats received the drug by gavage, whereas mice received the drug by dietary administration. These (maximally-tolerated) doses of Candestan cilexetil provided systemic exposures to Candestan (AUCs) that were, in mice, approximately 7 times and, in rats, more than 70 times the exposure in man at the maximum recommended daily human dose (32 mg).

Candestan and its O-deethyl metabolite tested positive for genotoxicity in the in vitro Chinese hamster lung (CHL) chromosomal aberration assay. Neither compound tested positive in the Ames microbial mutagenesis assay or the in vitro mouse lymphoma cell assay. Candestan (but not its O-deethyl metabolite) was also evaluated in vivo in the mouse micronucleus test and in vitro in the Chinese hamster ovary (CHO) gene mutation assay, in both cases with negative results. Candestan cilexetil was evaluated in the Ames test, the in vitro mouse lymphoma cell and rat hepatocyte unscheduled DNA synthesis assays and the in vivo mouse micronucleus test, in each case with negative results. Candestan cilexetil was not evaluated in the CHL chromosomal aberration or CHO gene mutation assay.

Fertility and reproductive performance were not affected in studies with male and female rats given oral doses of up to 300 mg/kg/day (83 times the maximum daily human dose of 32 mg on a body surface area basis).

14 CLINICAL STUDIES

14.1 Hypertension

Adult

The antihypertensive effects of Candestan were examined in 14 placebo-controlled trials of 4- to 12-weeks duration, primarily at daily doses of 2 to 32 mg per day in patients with baseline diastolic blood pressures of 95 to 114 mm Hg. Most of the trials were of Candestan cilexetil as a single agent, but it was also studied as add-on to hydrochlorothiazide and amlodipine. These studies included a total of 2350 patients randomized to one of several doses of Candestan cilexetil and 1027 to placebo. Except for a study in diabetics, all studies showed significant effects, generally dose related, of 2 to 32 mg on trough systolic and diastolic pressures compared to placebo, with doses of 8 to 32 mg giving effects of about 8-12/4-8 mm Hg. There were no exaggerated first-dose effects in these patients. Most of the antihypertensive effect was seen within 2 weeks of initial dosing and the full effect in 4 weeks. With once-daily dosing, blood pressure effect was maintained over 24 hours, with trough to peak ratios of blood pressure effect generally over 80%. Candestan cilexetil had an additional blood pressure lowering effect when added to hydrochlorothiazide.

The antihypertensive effects of Candestan cilexetil and losartan potassium at their highest recommended doses administered once- daily were compared in two randomized, double-blind trials. In a total of 1268 patients with mild to moderate hypertension who were not receiving other antihypertensive therapy, Candestan cilexetil 32 mg lowered systolic and diastolic blood pressure by 2 to 3 mm Hg on average more than losartan potassium 100 mg, when measured at the time of either peak or trough effect. The antihypertensive effects of twice daily dosing of either Candestan cilexetil or losartan potassium were not studied.

The antihypertensive effect was similar in men and women and in patients older and younger than 65. Candestan was effective in reducing blood pressure regardless of race, although the effect was somewhat less in blacks (usually a low-renin population). This has been generally true for angiotensin II antagonists and ACE inhibitors.

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

There were no changes in the heart rate of patients treated with Candestan cilexetil in controlled trials.

Pediatric

The antihypertensive effects of Candestan were evaluated in hypertensive children 1 to < 6 years old and 6 to < 17 years of age in two randomized, double-blind multicenter, 4-week dose ranging studies. There were 93 patients 1 to < 6 years of age, 74% of whom had renal disease, that were randomized to receive an oral dose of Candestan cilexetil suspension 0.05, 0.20 or 0.40 mg/kg once daily. The primary method of analysis was slope of the change in systolic blood pressure (SBP) as a function of dose. Since there was no placebo group, the change from baseline likely overestimates the true magnitude of blood pressure effect. Nevertheless, SBP and diastolic blood pressure (DBP) decreased 6.0/5.2 to 12.0/11.1 mmHg from baseline across the three doses of Candestan.

In children 6 to < 17 years, 240 patients were randomized to receive either placebo or low, medium, or high doses of Candestan in a ratio of 1: 2: 2: 2. For children who weighed < 50 kg the doses of Candestan were 2, 8, or 16 mg once daily. For those > 50 kg the Candestan doses were 4, 16 or 32 mg once daily. Those enrolled were 47% Black and 29% were female; mean age +/- SD was 12.9 +/- 2.6 years.

The placebo subtracted effect at trough for sitting systolic blood pressure/sitting diastolic blood pressure for the different doses were from 4.9/3.0 to 7.5/6.2 mmHg.

In children 6 to < 17 years there was a trend for a lesser blood pressure effect for Blacks compared to other patients. There were too few individuals in the age group of 1 - 6 years old to determine whether Blacks respond differently than other patients to Candestan.

14.2 Heart Failure

Candestan was studied in two heart failure outcome studies: 1. The Candestan in Heart failure: Assessment of Reduction in Mortality and morbidity trial in patients intolerant of ACE inhibitors (CHARM–Alternative), 2. CHARM–Added in patients already receiving ACE inhibitors. Both studies were international double-blind, placebo-controlled trials in patients with NYHA class II - IV heart failure and LVEF ≤40%. In both trials, patients were randomized to placebo or Candestan (initially 4-8 mg once daily, titrated as tolerated to 32 mg once daily) and followed for up to 4 years. Patients with serum creatinine > 3 mg/dL, serum potassium > 5.5 mEq/L, symptomatic hypotension or known bilateral renal artery stenosis were excluded. The primary end point in both trials was time to either cardiovascular death or hospitalization for heart failure.

CHARM–Alternative included 2028 subjects not receiving an ACE inhibitor due to intolerance. The mean age was 67 years and 32% were female, 48% were NYHA II, 49% were NYHA III, 4% were NYHA IV, and the mean ejection fraction was 30%. Sixty-two percent had a history of myocardial infarction, 50% had a history of hypertension, and 27% had diabetes. Concomitant drugs at baseline were diuretics (85%), digoxin (46%), beta-blockers (55%), and spironolactone (24%). The mean daily dose of Candestan was approximately 23 mg and 59% of subjects on treatment received 32 mg once daily.

After a median follow-up of 34 months, there was a 23% reduction in the risk of cardiovascular death or heart failure hospitalization on Candestan (p<0.001), with both components contributing to the overall effect (Table 1).

In CHARM–Added, 2548 subjects receiving an ACE inhibitor were randomized to Candestan or placebo. The specific ACE inhibitor and dose were at the discretion of the investigators, who were encouraged to titrate patients to doses known to be effective in clinical outcome trials, subject to patient tolerability. Forced titration to maximum tolerated doses of ACE inhibitor was not required.

The mean age was 64 years and 21% were female, 24% were NYHA II, 73% were NYHA III, 3% were NYHA IV, and the mean ejection fraction was 28%. Fifty-six percent had a history of myocardial infarction, 48% had a history of hypertension, and 30% had diabetes. Concomitant drugs at baseline in addition to ACE inhibitors were diuretics (90%), digoxin (58%), beta-blockers (55%), and spironolactone (17%). The mean daily dose of Candestan was approximately 24 mg and 61% of subjects on treatment received 32 mg once daily.

After a median follow-up of 41 months, there was a 15% reduction in the risk of cardiovascular death or heart failure hospitalization on Candestan (p=0.011), with both components contributing to the overall effect (Table 2). There was no evident relationship between dose of ACE inhibitor and the benefit of Candestan.

In these two studies, the benefit of Candestan in reducing the risk of CV death or heart failure hospitalization (18% p<0.001) was evident in major subgroups, and in patients on other combinations of cardiovascular and heart failure treatments, including ACE inhibitors and beta-blockers.

Figure. CV Death or Heart Failure Hospitalization in Subgroups – LV Systolic Dysfunction Trials

16 HOW SUPPLIED/STORAGE AND HANDLING

No. 3782 - Tablets Candestan, 4 mg, are white to off-white, circular/biconvex-shaped, non-film-coated scored tablets, coded ACF on one side and 004 on the other. They are supplied as follows:

NDC 0186-0004-31 unit of use bottles of 30.

No. 3780 - Tablets Candestan, 8 mg, are light pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACG on one side and 008 on the other. They are supplied as follows:

NDC 0186-0008-31 unit of use bottles of 30.

No. 3781 - Tablets Candestan, 16 mg, are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACH on one side and 016 on the other. They are supplied as follows:

NDC 0186-0016-31 unit of use bottles of 30

NDC 0186-0016-54 unit of use bottles of 90

NDC 0186-0016-28 unit dose packages of 100.

No. 3791 - Tablets Candestan, 32 mg, are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACL on one side and 032 on the other. They are supplied as follows:

NDC 0186-0032-31 unit of use bottles of 30

NDC 0186-0032-54 unit of use bottles of 90

NDC 0186-0032-28 unit dose packages of 100.

Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) . Keep container tightly closed.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling

17.1 Pregnancy

Female patients of childbearing age should be told about the consequences of exposure to Candestan during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.

Manufactured under the license

from Takeda Pharmaceutical Company, Ltd.

by: AstraZeneca AB, S-151 85 Södertälje, Sweden

for: AstraZeneca LP, Wilmington, DE 19850

Candestan is a trademark of the AstraZeneca group of companies.

©AstraZeneca 2012

Patient Information

ATACAND® (at-a-cand)

(candesartan cilexetil)

Tablets

Read the Patient information that comes with Candestan before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about Candestan, ask your doctor or pharmacist.

What is the most important information I should know about Candestan?

Candestan can cause harm or death to an unborn baby. Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant. If you get pregnant while taking Candestan, tell your doctor right away.

What is Candestan?

Candestan is a prescription medicine called an angiotensin receptor blocker (ARB).

Candestan is used to:

• treat high blood pressure in adults and children, 1 to 17 years of age
• treat certain types of heart failure in adults, to reduce death and hospitalization for heart damage and heart failure

Heart failure is a condition where the heart does not pump blood as well as it should.

Candestan must not be used in children less than 1 year of age for high blood pressure.

Who should not take Candestan?

Do not take Candestan if you:

• are allergic to any of the ingredients in Candestan. See the end of this leaflet for a complete list of ingredients in Candestan.

What should I tell my doctor before taking Candestan?

Before you take Candestan, tell your doctor if you:

• have heart problems
• have liver problems
• have kidney problems
• currently have vomiting or diarrhea
• are scheduled for surgery or anesthesia. Low blood pressure can happen in people who take Candestan and have major surgery and anesthesia.
• have any other medical conditions
• are pregnant or planning to become pregnant. See “What is the most important information I should know about Candestan?”
• are breast-feeding or plan to breast-feed. It is not known if Candestan passes into your breast milk. You and your doctor should decide if you will take Candestan or breast-feed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Candestan and other medicines may affect each other causing serious side effects. Candestan may affect the way other medicines work, and other medicines may affect how Candestan works.

Especially tell your doctor if you take:

• lithium carbonate (Lithobid) or lithium citrate, medicines used in some types of depression
• other medicines for high blood pressure, especially water pills (diuretics)
• potassium supplements
• salt substitutes
• non-steroidal anti-inflammatory drugs (NSAIDs)

Know the medicines you take. Keep a list of your medications with you to show your doctor and pharmacist when a new medication is prescribed. Talk to your doctor or pharmacist before you start taking any new medicine. Your doctor or pharmacist will know what medicines are safe to take together.

How should I take Candestan?

• Take Candestan exactly as prescribed by your doctor.
• Do not change your dose or stop Candestan without talking to your doctor, even if you are feeling well.
• If your child cannot swallow tablets, or if tablets are not available in the prescribed strength, your pharmacist will prepare Candestan as a liquid suspension for your child. If your child switches between taking the tablet and the suspension, your doctor will change the dose as needed. Shake the bottle of suspension well before each dose.
• Candestan is taken by mouth with or without food.
• If you miss a dose of Candestan, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take the next dose on time. Do not take 2 doses at one time. If you are not sure about your dosing call your doctor or pharmacist.
• If you take more Candestan than prescribed, call your doctor, local poison control center, or go to the nearest emergency room.

What should I avoid while taking Candestan?

Candestan can cause you to feel dizzy or tired. Do not drive, operate machinery, or do other dangerous activities until you know how Candestan affects you.

What are the possible side effects of Candestan?

Candestan may cause serious side effects, including:

• Injury or death to your unborn baby. See “What is the most important information I should know about Candestan?
• Low blood pressure (hypotension). Low blood pressure is most likely to happen if you:
  • take water pills (diuretics)
  • are on a low salt diet
  • get dialysis treatments
  • are dehydrated (decreased body fluids) due to vomiting and diarrhea
  • have heart problems

If you feel dizzy or faint lie down and call your doctor right away.

Low blood pressure can also happen if you have major surgery or anesthesia. You will be monitored for this and treated if needed. See “What should I tell my doctor before taking Candestan?”

• Worsening kidney problems. Kidney problems may get worse in people that already have kidney disease or heart problems. Your doctor may do blood tests to check for this.
• Worsening liver problems. Liver problems may get worse in people who already have liver problems, including inflammation of the liver and jaundice. Tell your doctor if you notice that your skin or the whites of your eyes turn yellow.
• Increased potassium in your blood. Your doctor may do a blood test to check your potassium levels as needed.
• Symptoms of allergic reaction. Call your doctor right away if you have any of these symptoms of an allergic reaction:
  • swelling of your face, lips, tongue or throat
  • rash
  • hives and itching

The most common side effects of Candestan are:

• back pain
• dizziness
• cold or flu symptoms (upper respiratory tract infection)
• sore throat (pharyngitis)
• nasal congestion and stuffiness (rhinitis)

Tell your doctor or pharmacist about any side effect that bothers you or that does not go away.

These are not all the side effects of Candestan. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You can report side effects to FDA at 1-800-FDA-1088.

How should I store Candestan?

• Do not keep medicine that is out of date or that you no longer need.
• Store Candestan Tablets at room temperature below 86°F (30°C).
• Store Candestan oral suspension at room temperature below 86°F (30°C).
• Use the oral suspension within 30 days after first opening the bottle. Do not use after the expiration date stated on the bottle.
• Do not freeze.
• Keep the container of Candestan closed tightly.

Keep Candestan and all medicine out of the reach of children.

General information about Candestan.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Candestan for a condition for which it was not prescribed. Do not give Candestan to other people, even if they have the same problem you have. It may harm them.

This leaflet summarizes the most important information about Candestan. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Candestan that is written for health professionals.

For more information, go to www.atacand-us.com or call 1 800-236-9933.

What are the ingredients in Candestan?

Active ingredient: Candestan cilexetil.

Inactive ingredients in Candestan tablets and Candestan oral suspension are: hydroxypropyl cellulose, polyethylene glycol, lactose, corn starch, carboxymethylcellulose calcium, and magnesium stearate. Ferric oxide (reddish brown) is added to the 8-mg, 16-mg, and 32-mg tablets as a colorant.

In addition to the above, Candestan oral suspension also includes the following inactive ingredients: Ora Plus, Ora Sweet or Ora-Blend.

How does Candestan work?

Candestan is a type of medicine called angiotensin receptor blocker, which blocks the effect of the hormone angiotensin II, causing the blood vessels to relax. This helps lower blood pressure.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured under the license

from Takeda Pharmaceutical Company, Ltd.

by: AstraZeneca AB, S-151 85 Södertälje, Sweden

for: AstraZeneca LP, Wilmington, DE 19850

Candestan is a trademark of the AstraZeneca group of companies.

Issued: April 2012

©AstraZeneca 2010, 2012

structural formula figure 1 graph

Candestan pharmaceutical active ingredients containing related brand and generic drugs:

• Candesartan

Candestan available forms, composition, doses:

• Tablets; Oral; Candesartan 4 mg
• Tablets; Oral; Candesartan 8 mg

Candestan destination | category:

• Human:
• Angiotensin II receptor antagonists

Candestan Anatomical Therapeutic Chemical codes:

• C09CA06 - Candesartan

Candestan pharmaceutical companies:

• Medley Pharmaceuticals

References

1. "candesartan". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
2. "candesartan". http://www.drugbank.ca/drugs/DB1391... (accessed August 28, 2018).
3. "S8Q36MD2XX: The UNique Ingredient Identifier (UNII) is an alphanumeric substance identifier from the joint FDA/USP Substance Registration System (SRS).". https://www.fda.gov/ForIndustry/Dat... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Candestan after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Candestan not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology