candesartan cilexetil 8 MG Oral Tablet

Generic Name: CANDESARTAN CILEXETIL
Brand Name: ATACAND
  • Substance Name(s):
  • CANDESARTAN CILEXETIL

DRUG INTERACTIONS

7 No significant drug interactions have been reported in studies of candesartan 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 candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effects on P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors).

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including candesartan, may result in deterioration of renal function, including possible acute renal failure.

These effects are usually reversible.

Monitor renal function periodically in patients receiving candesartan and NSAID therapy.

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

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 ATACAND, 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).

OVERDOSAGE

10 No lethality was observed in acute toxicity studies in mice, rats, and dogs given single oral doses of up to 2000 mg/kg of candesartan cilexetil.

In mice given single oral doses of the primary metabolite, candesartan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg.

The most likely manifestation of overdosage with ATACAND would be hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation.

If symptomatic hypotension should occur, supportive treatment should be instituted.

Candesartan cannot be removed by hemodialysis.

Treatment: To obtain up-to-date information about the treatment of overdose, consult your Regional Poison Control Center.

Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR).

In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and altered pharmacokinetics in your patient.

DESCRIPTION

11 ATACAND (candesartan cilexetil), a prodrug, is hydrolyzed to candesartan during absorption from the gastrointestinal tract.

Candesartan is a selective AT1 subtype angiotensin II receptor antagonist.

Candesartan 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: Candesartan 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.

Candesartan cilexetil is a racemic mixture containing one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group.

Following oral administration, candesartan cilexetil undergoes hydrolysis at the ester link to form the active drug, candesartan, which is achiral.

ATACAND is available for oral use as tablets containing either 4 mg, 8 mg, 16 mg, or 32 mg of candesartan 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.

structural formula

CLINICAL STUDIES

14

HOW SUPPLIED

16 /STORAGE AND HANDLING No.

3782 — Tablets ATACAND, 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: Bottles of 30 NDC 54868-5591-0 No.

3780 — Tablets ATACAND, 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: Bottles of 30 NDC 54868-5489-0 No.

3781 — Tablets ATACAND, 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: Bottles of 30 NDC 54868-4413-0 No.

3791 — Tablets ATACAND, 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: Bottles of 30 NDC 54868-4612-0 Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Keep container tightly closed.

GERIATRIC USE

8.5 Geriatric Use Hypertension Of the total number of subjects in clinical studies of ATACAND, 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 candesartan 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 ATACAND 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 ATACAND 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.

DOSAGE FORMS AND STRENGTHS

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).

MECHANISM OF ACTION

12.1 Mechanism of Action Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II).

Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium.

Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland.

Its action is, therefore, independent of the pathways for angiotensin II synthesis.

There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis.

Candesartan has much greater affinity (>10,000-fold) for the AT1 receptor than for the AT2 receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension.

ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE.

Because candesartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin.

Whether this difference has clinical relevance is not yet known.

Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

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

INDICATIONS AND USAGE

1 ATACAND is an angiotensin II receptor blocker (ARB) 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); ATACAND reduces cardiovascular death and heart failure hospitalization (1.2).

1.1 Hypertension ATACAND 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 ATACAND 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 [see CLINICAL STUDIES (14.2)].

ATACAND also has an added effect on these outcomes when used with an ACE inhibitor.

PEDIATRIC USE

8.4 Pediatric Use The antihypertensive effects of ATACAND were evaluated in hypertensive children 1 to < 17 years of age in randomized, double-blind clinical studies [see CLINICAL STUDIES (14.1)].

The pharmacokinetics of ATACAND have been evaluated in pediatric patients 1 to < 17 years of age [see Pharmacokinetics (12.3)].

Children < 1 year of age must not receive ATACAND for hypertension [see WARNINGS AND PRECAUTIONS (5.2)].

PREGNANCY

8.1 Pregnancy Pregnancy Categories C (first trimester) and D (second and third trimesters) [see WARNINGS AND PRECAUTIONS (5.1)].

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether candesartan is excreted in human milk, but candesartan has been shown to be present in rat milk.

Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue ATACAND, taking into account the importance of the drug to the mother.

BOXED WARNING

Warning Use in Pregnancy When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus.

When pregnancy is detected, ATACAND should be discontinued as soon as possible [see WARNINGS AND PRECAUTIONS, Fetal/Neonatal Morbidity and Mortality (5.1)].

WARNING: USE IN PREGNANCY: See Full Prescribing Information for complete boxed warning.

When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus.

When pregnancy is detected, ATACAND should be discontinued as soon as possible.

See WARNINGS AND PRECAUTIONS, Fetal/Neonatal Morbidity and Mortality (5.1).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS · Avoid fetal (in utero) and neonatal exposure (5.1).

· Children < 1 year of age must not receive ATACAND 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 ATACAND (5.6).

5.1 Fetal/Neonatal Morbidity and Mortality Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women.

Several dozen cases have been reported in the world literature in patients who were taking angiotensin-converting enzyme inhibitors.

Post-marketing experience has identified reports of fetal and neonatal toxicity in babies born to women treated with ATACAND during pregnancy.

When pregnancy is detected, ATACAND should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.

Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.

Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed.

Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of ATACAND as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found.

In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, ATACAND should be discontinued unless it is considered life saving for the mother.

Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy.

Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia.

If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion.

Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

Oral doses ≥10 mg of candesartan cilexetil/kg/day administered to pregnant rats during late gestation and continued through lactation were associated with reduced survival and an increased incidence of hydronephrosis in the offspring.

The 10-mg/kg/day dose in rats is approximately 2.8 times the maximum recommended daily human dose (MRHD) of 32 mg on a mg/m2 basis (comparison assumes human body weight of 50 kg).

Candesartan 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 candesartan cilexetil/kg/day (approximately 138 times the MRHD on a mg/m2 basis) were administered to pregnant mice.

5.2 Morbidity in Infants Children < 1 year of age must not receive ATACAND for hypertension.

The consequences of administering drugs that act directly on the renin-angiotensin system (RAS) 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 ATACAND, or the treatment should start under close medical supervision [see DOSAGE AND ADMINISTRATION (2.1)].

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 ATACAND commonly have some reduction in blood pressure.

In patients with symptomatic hypotension this may require temporarily reducing the dose of ATACAND, or diuretic, or both, and volume repletion.

In the CHARM program, hypotension was reported in 18.8% of patients on ATACAND 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 ATACAND, due to blockade of the renin-angiotensin system.

Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors.

5.4 Impaired Hepatic Function Based on pharmacokinetic data which demonstrate significant increases in candesartan AUC and Cmax in patients with moderate hepatic impairment, a lower initiating dose should be considered for patients with moderate hepatic impairment [see CLINICAL PHARMACOLOGY (12.3)].

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 ATACAND.

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 ATACAND [see CLINICAL PHARMACOLOGY (12.3)].

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 ATACAND in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.

In heart failure patients treated with ATACAND, increases in serum creatinine may occur.

Dosage reduction or discontinuation of the diuretic or ATACAND, 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 ATACAND 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 – ATACAND 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 ATACAND, 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 ATACAND 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 ATACAND in patients with heart failure, monitoring of serum potassium is recommended during dose escalation and periodically thereafter.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Pregnancy – Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to drugs that act on the renin-angiotensin system, and they should also be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.

These patients should be asked to report pregnancies to their physicians as soon as possible.

Post-menarche adolescents should be questioned on a regular basis as to changes in menstrual pattern and the possibility of pregnancy.

Manufactured under the license from Takeda Pharmaceutical Company, Ltd.

by: AstraZeneca AB, S-151 85 Södertälje, Sweden for: AstraZeneca LP, Wilmington, DE 19850 ATACAND is a trademark of the AstraZeneca group of companies.

Rev.

04/11 ©AstraZeneca 2009 Relabeling and Repackaging by: Physicians Total Care, Inc.

Tulsa, Oklahoma 74146

DOSAGE AND ADMINISTRATION

2 Starting Dose Dose Range Target Maintenance Dose Adult Hypertension (2.1) 16 mg tablet once daily 8 – 32 mg tablet total daily dose – Pediatric Hypertension (1 to < 6 years) (2.2) 0.20 mg/kg oral suspension once daily 0.05 – 0.4 mg/kg oral suspension once daily or consider divided dose – Pediatric Hypertension (6 to < 17 years) (2.2) 50 kg 8 – 16 mg tablet once daily 50 kg 4 – 32 mg tablet once daily or consider divided dose – Adult Heart Failure (2.3) 4 mg tablet once daily 32 mg tablet once daily 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 ATACAND is 16 mg once daily when it is used as monotherapy in patients who are not volume depleted.

ATACAND 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 ATACAND.

No initial dosage adjustment is necessary for elderly patients, for patients with mildly impaired renal function, or for patients with mildly impaired hepatic function [see CLINICAL PHARMACOLOGY (12.3)].

In patients with moderate hepatic impairment, consideration should be given to initiation of ATACAND at a lower dose [see CLINICAL PHARMACOLOGY (12.3)].

For patients with possible depletion of intravascular volume (eg, patients treated with diuretics, particularly those with impaired renal function), ATACAND should be initiated under close medical supervision and consideration should be given to administration of a lower dose [see WARNINGS AND PRECAUTIONS (5.3)].

ATACAND may be administered with or without food.

If blood pressure is not controlled by ATACAND alone, a diuretic may be added.

ATACAND may be administered with other antihypertensive agents.

2.2 Pediatric Hypertension 1 to < 17 Years of age ATACAND 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 (e.g., patients treated with diuretics, particularly those with impaired renal function), initiate ATACAND under close medical supervision and consider administration of a lower dose [see WARNINGS AND PRECAUTIONS (5.3)].

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 [see CLINICAL STUDIES (14.1)].

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

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

All pediatric patients with a glomerular filtration rate less than 30 ml/min/1.73m2 should not receive ATACAND since ATACAND has not been studied in this population [see WARNINGS AND PRECAUTIONS (5.2)].

For children who cannot swallow tablets, an oral suspension may be substituted [see Preparation of Oral Suspension].

Preparation of Oral Suspension: ATACAND 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 ATACAND 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® (80 mL) and *Ora-Sweet SF® (80 mL) or, alternatively, use *,†Ora-Blend SF® (160 mL).

· Add a small amount of vehicle to the required number of ATACAND 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.

*Ora-Plus®, Ora-Sweet SF®, and Ora-Blend SF® are registered trademarks of Paddock Laboratories, Inc.

†Supplied as a 50/50% pre-mix of Ora-Plus® and Ora-Sweet SF®.

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.