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EDARBYCLOR (azilsartan medoxomil and chlorthalidone) tablets
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HIGHLIGHTS OF PRESCRIBING INFORMATION |
These highlights do not include all the information needed to use EDARBYCLOR safely and effectively. See full prescribing information for EDARBYCLOR.
EDARBYCLOR (azilsartan medoxomil and chlorthalidone) tablets, for oral use
Initial U.S. Approval: 2011
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WARNING: FETAL TOXICITY
See full prescribing information for complete boxed warning.
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When pregnancy is detected, discontinue EDARBYCLOR as soon as possible (5.1)
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Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (5.1)
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INDICATIONS AND USAGE
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Edarbyclor is an angiotensin II receptor blocker (ARB) and a thiazide-like diuretic combination product indicated for the treatment of hypertension, to lower blood pressure:
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In patients not adequately controlled with monotherapy (1)
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As initial therapy in patients likely to need multiple drugs to help achieve blood pressure goals (1)
Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (1)
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DOSAGE AND ADMINISTRATION
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Starting dose is 40/12.5 mg once daily (2.1)
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Edarbyclor may be used to provide additional blood pressure lowering for patients not adequately controlled on azilsartan medoxomil 80 mg or chlorthalidone 25 mg (2.1)
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Dose may be increased to 40/25 mg after 2 to 4 weeks as needed to achieve blood pressure goals (2.1)
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Maximal dose is 40/25 mg (2.1)
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May be administered with other antihypertensive agents (2.1)
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Edarbyclor may be administered with or without food (2.1)
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Replace volume in volume-depleted patients prior to use (2.2)
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DOSAGE FORMS AND STRENGTHS
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Tablets (azilsartan/chlorthalidone): 40/12.5 mg and 40/25 mg (3)
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CONTRAINDICATIONS
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WARNINGS AND PRECAUTIONS
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In patients with an activated renin-angiotensin-aldosterone system (RAAS), such as volume- and/or salt-depleted patients, Edarbyclor can cause excessive hypotension. Correct volume or salt depletion prior to administration of Edarbyclor (5.2)
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In patients with renal artery stenosis, Edarbyclor may cause renal failure (5.3)
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Monitor renal function in patients with renal impairment. Consider discontinuing Edarbyclor with progressive renal impairment (5.3)
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ADVERSE REACTIONS
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Most common adverse reactions (incidence ≥2%) are dizziness and fatigue (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-877-825-3327 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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DRUG INTERACTIONS
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Renal clearance of lithium is reduced by diuretics, such as chlorthalidone increasing the risk of lithium toxicity (7)
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NSAIDS increase risk of renal dysfunction and interfere with antihypertensive effect (7)
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See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling |
Revised: 12/2011 |
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FULL PRESCRIBING INFORMATION: CONTENTS* |
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FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Edarbyclor contains an angiotensin II receptor blocker (ARB) and a thiazide-like diuretic and is indicated for the treatment of hypertension, to lower blood pressure.
Edarbyclor may be used in patients whose blood pressure is not adequately controlled on monotherapy.
Edarbyclor may be used as initial therapy if a patient is likely to need multiple drugs to achieve blood pressure goals.
Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including thiazide-like diuretics such as chlorthalidone and ARBs such as azilsartan medoxomil. There are no controlled trials demonstrating risk reduction with Edarbyclor.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management of high blood pressure, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, eva luation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients; however, the blood pressure effect of Edarbyclor in blacks is similar to that in non-blacks. Many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.
The choice of Edarbyclor as initial therapy for hypertension should be based on an assessment of potential benefits and risks including whether the patient is likely to tolerate the starting dose of Edarbyclor.
Patients with moderate-to-severe hypertension are at a relatively high risk of cardiovascular events (e.g., stroke, heart attack, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. Consider the patient's baseline blood pressure, target goal and the incremental likelihood of achieving the goal with a combination product, such as Edarbyclor, versus a monotherapy product when deciding upon initial therapy. Individual blood pressure goals may vary based on the patient's risk.
Data from an 8-week, active-controlled, factorial trial provide estimates of the probability of reaching a target blood pressure with Edarbyclor compared with azilsartan medoxomil or chlorthalidone monotherapy [see Clinical Studies (14)].
Figures 1.a-1.d provide estimates of the likelihood of achieving target clinic systolic and diastolic blood pressure control with Edarbyclor 40/25 mg tablets after 8 weeks, based on baseline systolic or diastolic blood pressure. The curve for each treatment group was estimated by logistic regression modeling and is more variable at the tails.
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Figure 1.a Probability of Achieving Systolic Blood Pressure <140 mmHg at Week 8 |
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Figure 1.b Probability of Achieving Systolic Blood Pressure <130 mmHg at Week 8 |
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Figure 1.c Probability of Achieving Diastolic Blood Pressure <90 mmHg at Week 8 |
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Figure 1.d Probability of Achieving Diastolic Blood Pressure <80 mmHg at Week 8 |
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For example, a patient with a baseline blood pressure of 170/105 mm Hg has approximately a 48% likelihood of achieving a goal of <140 mm Hg (systolic) and 48% likelihood of achieving <90 mm Hg (diastolic) on azilsartan medoxomil 80 mg. The likelihood of achieving these same goals on chlorthalidone 25 mg is approximately 51% (systolic) and 40% (diastolic). These likelihoods rise to 85% (systolic) and 85% (diastolic) with Edarbyclor 40/25 mg.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Information
The recommended starting dose of Edarbyclor is 40/12.5 mg taken orally once daily. Most of the antihypertensive effect is apparent within 1 to 2 weeks. The dosage may be increased to 40/25 mg after 2 to 4 weeks as needed to achieve blood pressure goals. Edarbyclor doses above 40/25 mg are probably not useful.
Edarbyclor may be used to provide additional blood pressure lowering for patients not adequately controlled on ARB or diuretic monotherapy treatment. Patients not controlled with azilsartan medoxomil 80 mg may have an additional systolic/diastolic clinic blood pressure reduction of 13/6 mm Hg when switched to Edarbyclor 40/12.5 mg. Patients not controlled with chlorthalidone 25 mg may have an additional clinic blood pressure reduction of 10/7 mm Hg when switched to Edarbyclor 40/12.5 mg.
Edarbyclor may be used as initial therapy if a patient is likely to need multiple drugs to achieve blood pressure goals.
Patients titrated to the individual components (azilsartan medoxomil and chlorthalidone) may instead receive the corresponding dose of Edarbyclor.
Edarbyclor may be taken with or without food [see Clinical Pharmacology (12.3)].
Edarbyclor may be administered with other antihypertensive agents as needed.
2.2 Prior to Dosing
Correct any volume depletion prior to administration of Edarbyclor, particularly in patients with impaired renal function or those treated with high doses of diuretics [see Warnings and Precautions (5.2)].
Patients who experience dose-limiting adverse reactions on chlorthalidone may be switched to Edarbyclor, initially with a lower dose of chlorthalidone [see Warnings and Precautions (5.4)].
2.3 Handling Instructions
As Edarbyclor is moisture sensitive, dispense and store Edarbyclor in its original container to protect Edarbyclor from light and moisture.
3 DOSAGE FORMS AND STRENGTHS
Edarbyclor is supplied in the following dosage strengths:
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40/12.5 mg: pale red, round, biconvex, film-coated tablets, approximately 9.7 mm in diameter, with "A/C" and "40/12.5" imprinted on one side. Each tablet contains 40 mg of azilsartan medoxomil and 12.5 mg of chlorthalidone.
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40/25 mg: light red, round, biconvex, film-coated tablets, approximately 9.7 mm in diameter, with "A/C" and "40/25" imprinted on one side. Each tablet contains 40 mg of azilsartan medoxomil and 25 mg of chlorthalidone.
5 WARNINGS AND PRECAUTIONS
5.1 Fetal Toxicity
Azilsartan medoxomil
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 Edarbyclor as soon as possible [see Use in Specific Populations (8.1)].
Chlorthalidone
Thiazides cross the placental barrier and appear in cord blood. Adverse reactions include fetal or neonatal jaundice and thrombocytopenia.
5.2 Hypotension in Volume- or Salt-Depleted Patients
In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Edarbyclor. Such patients are probably not good candidates to start therapy with more than one drug; therefore, correct volume prior to administration of Edarbyclor. If hypotension does occur, the patient 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.
5.3 Impaired Renal Function
Edarbyclor
Monitor for worsening renal function in patients with renal impairment. Consider withholding or discontinuing Edarbyclor if progressive renal impairment becomes evident.
Azilsartan medoxomil
As a consequence of inhibiting the renin-angiotensin system, changes in renal function may be anticipated in susceptible individuals treated with Edarbyclor. In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g., patients with severe congestive heart failure, renal artery stenosis, or volume depletion), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. Similar results may be anticipated in patients treated with Edarbyclor [see Use in Specific Populations (8.6) and 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 have been reported. There has been no long-term use of azilsartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar results are expected.
Chlorthalidone
In patients with renal disease, chlorthalidone may precipitate azotemia. If progressive renal impairment becomes evident, as indicated by increased blood urea nitrogen, consider withholding or discontinuing diuretic therapy.
5.4 Hypokalemia
Chlorthalidone
Hypokalemia is a dose-dependent adverse reaction that may develop with chlorthalidone. Co-administration of digitalis may exacerbate the adverse effects of hypokalemia.
Edarbyclor attenuates chlorthalidone-associated hypokalemia. In patients with normal potassium levels at baseline, 1.7% of Edarbyclor-treated patients, 0.9% of azilsartan medoxomil-treated patients, and 13.4% of chlorthalidone-treated patients shifted to low potassium values (less than 3.4 mmol/L).
5.5 Hyperuricemia
Chlorthalidone
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving chlorthalidone or other thiazide diuretics.
6 ADVERSE REACTIONS
The following potential adverse reactions with Edarbyclor, azilsartan medoxomil, or chlorthalidone and similar agents are included in more detail in the Warnings and Precautions section of the label:
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Edarbyclor has been eva luated for safety in more than 3900 patients with hypertension; more than 700 patients were treated for at least 6 months and more than 280 for at least 1 year. Adverse reactions have generally been mild and transient in nature.
Common adverse reactions that occurred in the 8-week factorial design trial in at least 2% of Edarbyclor-treated patients and greater than azilsartan medoxomil or chlorthalidone are presented in Table 1.
Table 1. Adverse Reactions Occurring at an Incidence of ≥2% of Edarbyclor-treated Patients and > Azilsartan medoxomil or Chlorthalidone
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Preferred Term |
Azilsartan medoxomil
20, 40, 80 mg
(N=470) |
Chlorthalidone
12.5, 25 mg
(N=316) |
Edarbyclor
40 / 12.5, 40 / 25 mg
(N=302) |
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Dizziness |
1.7% |
1.9% |
8.9% |
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Fatigue |
0.6% |
1.3% |
2.0% |
Hypotension and syncope were reported in 1.7% and 0.3%, respectively, of patients treated with Edarbyclor.
Study discontinuation because of adverse reactions occurred in 8.3% of patients treated with the recommended doses of Edarbyclor compared with 3.2% of patients treated with azilsartan medoxomil and 3.2% of patients treated with chlorthalidone. The most common reasons for discontinuation of therapy with Edarbyclor were serum creatinine increased (3.6%) and dizziness (2.3%).
The adverse reaction profile obtained from 52 weeks of open-label combination therapy with azilsartan medoxomil plus chlorthalidone or Edarbyclor was similar to that observed during the double-blind, active controlled trials.
In 3 double-blind, active controlled, titration studies, in which Edarbyclor was titrated to higher doses in a step-wise manner, adverse reactions and discontinuations for adverse events were less frequent than in the fixed-dose factorial trial.
Azilsartan medoxomil
A total of 4814 patients were eva luated for safety when treated with azilsartan medoxomil at doses of 20, 40 or 80 mg in clinical trials. This includes 1704 patients treated for at least 6 months, of these, 588 were treated for at least 1 year. Generally, adverse reactions were mild, not dose related and similar regardless of age, gender and race.
Adverse reactions with a plausible relationship to treatment that have been reported with an incidence of ≥0.3% and greater than placebo in more than 3300 patients treated with azilsartan medoxomil in controlled trials are listed below:
Gastrointestinal Disorders: diarrhea, nausea
General Disorders and Administration Site Conditions: asthenia, fatigue
Musculoskeletal and Connective Tissue Disorders: muscle spasm
Nervous System Disorders: dizziness, dizziness postural
Respiratory, Thoracic and Mediastinal Disorders: cough
Chlorthalidone
The following adverse reactions have been observed in clinical trials of chlorthalidone: rash, headache, dizziness, GI upset, and elevations of uric acid and cholesterol.
Clinical Laboratory Findings with Edarbyclor
In the factorial design trial, clinically relevant changes in standard laboratory parameters were uncommon with administration of the recommended doses of Edarbyclor.
Renal parameters:
Increased blood creatinine is a known pharmacologic effect of renin-angiotensin aldosterone system (RAAS) blockers, such as ARBs and ACE inhibitors, and is related to the magnitude of blood pressure reduction. The incidence of consecutive increases of creatinine ≥50% from baseline and >ULN was 2.0% in patients treated with the recommended doses of Edarbyclor compared with 0.4% and 0.3% with azilsartan medoxomil and chlorthalidone, respectively. Elevations of creatinine were typically transient, or non-progressive and reversible, and associated with large blood pressure reductions.
Mean increases in blood urea nitrogen (BUN) were observed with Edarbyclor (5.3 mg/dL) compared with azilsartan medoxomil (1.5 mg/dL) and with chlorthalidone (2.5 mg/dL).
7 DRUG INTERACTIONS
Edarbyclor
The pharmacokinetics of azilsartan medoxomil and chlorthalidone are not altered when the drugs are co-administered.
No drug interaction studies have been conducted with other drugs and Edarbyclor, although studies have been conducted with azilsartan medoxomil and chlorthalidone.
Azilsartan medoxomil
No clinically significant drug interactions have been observed in studies of azilsartan medoxomil or azilsartan given with amlodipine, antacids, chlorthalidone, digoxin, fluconazole, glyburide, ketoconazole, metformin, pioglitazone, and warfarin. Therefore, azilsartan medoxomil may be used concomitantly with these medications.
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 who have compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including azilsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Edarbyclor and NSAID therapy.
The antihypertensive effect of Edarbyclor may be attenuated by NSAIDs, including selective COX-2 inhibitors.
Chlorthalidone
Lithium renal clearance is reduced by diuretics, such as chlorthalidone, increasing the risk of lithium toxicity. Consider monitoring lithium levels when using Edarbyclor.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D
Use of drugs that affect 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 ne |
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