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Azilsartan Medoxomil and Chlorthalidone Tablets

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

BLACK BOX WARNING


WARNING: FETAL TOXICITY

• When pregnancy is detected, discontinue azilsartan/chlorthalidone as soon as possible [see Warnings and Precautions].

• Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions].


 

1. DESCRIPTION

Azilsartan/chlorthalidone is a combination of azilsartan medoxomil (ARB; as its potassium salt) and chlorthalidone (thiazide-like diuretic).

Azilsartan medoxomil, a prodrug, is hydrolyzed to azilsartan in the gastrointestinal tract during absorption. Azilsartan is a selective AT1 subtype angiotensin II receptor antagonist.

The drug substance used in the drug product formulation is the potassium salt of azilsartan medoxomil, also known by the US accepted name of azilsartan kamedoxomil and is chemically described as (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate monopotassium salt.

Molecular formula: C30H23KN4O8 - Molecular weight: 606.62

Azilsartan kamedoxomil is a white to nearly white powder. It is practically insoluble in water and freely soluble in methanol.

Chlorthalidone is chemically described as 2-chloro-5(1-hydroxy-3-oxo-1- isoindolinyl) benzenesulfonamide. The structural formula for chlorthalidone is:

Molecular formula: C14H11ClN2O4S - Molecular weight: 338.76

Chlorthalidone is a white to yellowish white powder. Chlorthalidone is practically insoluble in water, in ether, and in chloroform; soluble in methanol; slightly soluble in ethanol.

Azilsartan/chlorthalidone is available for oral use as tablets. The tablets have a characteristic odor. Each azilsartan/chlorthalidone tablet contains 42.68 mg of azilsartan kamedoxomil, which is equivalent to containing azilsartan medoxomil 40 mg plus 12.5 or 25 mg of chlorthalidone.

Inactive ingredients: mannitol, microcrystalline cellulose, fumaric acid, sodium hydroxide, hydroxypropyl cellulose, crospovidone, magnesium stearate, hypromellose 2910, talc, titanium dioxide, ferric oxide red, polyethylene glycol 8000, and printing ink gray F1.

2. INDICATIONS AND USAGE

Azilsartan/chlorthalidone contains an angiotensin II receptor blocker (ARB) and a thiazide-like diuretic and is indicated for the treatment of hypertension, to lower blood pressure.

Azilsartan/chlorthalidone may be used in patients whose blood pressure is not adequately controlled on monotherapy.

Azilsartan/chlorthalidone 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 azilsartan/chlorthalidone.

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, Evaluation, 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 azilsartan/chlorthalidone 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 azilsartan/chlorthalidone 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 azilsartan/chlorthalidone.

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 azilsartan/chlorthalidone, versus a monotherapy product when deciding upon initial therapy. Individual blood pressure goals may vary based on the patient’s risk.

3. DOSAGE AND ADMINISTRATION

3.1 Dosing Information

The recommended starting dose of azilsartan/chlorthalidone 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. Azilsartan/chlorthalidone doses above 40/25 mg are probably not useful.

Azilsartan/chlorthalidone 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 azilsartan/chlorthalidone 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 azilsartan/chlorthalidone 40/12.5 mg.

Azilsartan/chlorthalidone 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 azilsartan/chlorthalidone.

Azilsartan/chlorthalidone may be taken with or without food.

Azilsartan/chlorthalidone may be administered with other antihypertensive agents as needed.

3.2 Prior to Dosing

Correct any volume depletion prior to administration of azilsartan/chlorthalidone, particularly in patients with impaired renal function or those treated with high doses of diuretics [see Warnings and Precautions].

Patients who experience dose-limiting adverse reactions on chlorthalidone may be switched to azilsartan/chlorthalidone, initially with a lower dose of chlorthalidone [see Warnings and Precautions].

3.3 Handling Instructions

As azilsartan/chlorthalidone is moisture sensitive, dispense and store azilsartan/chlorthalidone in its original container to protect azilsartan/chlorthalidone from light and moisture.

4. CONTRAINDICATIONS

Azilsartan/chlorthalidone is contraindicated in patients with anuria [see Warnings and Precautions].

Do not co-administer aliskiren with azilsartan/chlorthalidone in patients with diabetes.

5. MECHANISM OF ACTION

The active ingredients of azilsartan/chlorthalidone target two separate mechanisms involved in blood pressure regulation. Azilsartan blocks the vasoconstriction and sodium retaining effects of angiotensin II on cardiac, vascular smooth muscle, adrenal and renal cells. Chlorthalidone produces diuresis with increased excretion of sodium and chloride at the cortical diluting segment of the ascending limb of Henle’s loop of the nephron.

Azilsartan medoxomil

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzymes (ACE, kinase II). Angiotensin II is the principle 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. Azilsartan blocks the vasoconstrictor and aldosteronesecreting 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 pathway for angiotensin II synthesis.

An AT2 receptor is also found in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Azilsartan has more than a 10,000-fold greater affinity 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 catalyzed by ACE. Because azilsartan does not inhibit ACE (kinase II), it should not affect bradykinin levels. Whether this difference has clinical relevance is not yet known. Azilsartan does not bind to or block other 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 azilsartan on blood pressure.

Chlorthalidone

Chlorthalidone produces diuresis with increased excretion of sodium and chloride. The site of action appears to be the cortical diluting segment of the ascending limb of Henle's loop of the nephron. The diuretic effects of chlorthalildone lead to decreased extracellular fluid volume, plasma volume, cardiac output, total exchangeable sodium, glomerular filtration rate, and renal plasma flow. Although the mechanism of action of chlorthalidone and related drugs is not wholly clear, sodium and water depletion appear to provide a basis for its antihypertensive effect.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in 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 neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue azilsartan/chlorthalidone 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 azilsartan/chlorthalidone, 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 azilsartan/chlorthalidone for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations].

6.2 Nursing Mothers

It is not known if azilsartan is excreted in human milk, but azilsartan is excreted at low concentrations in the milk of lactating rats and thiazide-like diuretics like chlorthalidone are excreted in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

6.3 Pediatric Use

Safety and effectiveness of azilsartan/chlorthalidone in pediatric patients under 18 years of age have not been established.

Neonates with a history of in utero exposure to azilsartan/chlorthalidone:

If oliguria or hypotension occurs, support blood pressure and renal function. Exchange transfusions or dialysis may be required.

6.4 Geriatric Use

Azilsartan/Chlorthalidone

No dose adjustment with azilsartan/chlorthalidone is necessary in elderly patients. Of the total patients in clinical studies with azilsartan/chlorthalidone, 24% were elderly (65 years of age or older); 5.7% were 75 years and older. No overall differences in safety or effectiveness were observed between elderly patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

6.5 Renal Impairment

Azilsartan/Chlorthalidone

Safety and effectiveness of azilsartan/chlorthalidone in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) have not been established. No dose adjustment is required in patients with mild (eGFR 60-90 mL/min/1.73 m2) or moderate (eGFR 30-60 mL/min/1.73 m2) renal impairment.

Chlorthalidone

Chlorthalidone may precipitate azotemia.

6.6 Hepatic Impairment

Azilsartan medoxomil

No dose adjustment is necessary for subjects with mild or moderate hepatic impairment. Azilsartan medoxomil has not been studied in patients with severe hepatic impairment.

Chlorthalidone

Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.

7. WARNINGS AND PRECAUTIONS

7.1 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 azilsartan/chlorthalidone as soon as possible [see Use in Specific Populations].

Chlorthalidone

Thiazides cross the placental barrier and appear in cord blood. Adverse reactions include fetal or neonatal jaundice and thrombocytopenia.

7.2 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 azilsartan/chlorthalidone. Such patients are probably not good candidates to start therapy with more than one drug; therefore, correct volume prior to administration of azilsartan/chlorthalidone. 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.

7.3 Impaired Renal Function

Azilsartan/Chlorthalidone

Monitor for worsening renal function in patients with renal impairment. Consider withholding or discontinuing azilsartan/chlorthalidone 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 azilsartan/chlorthalidone. 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 azilsartan/chlorthalidone [see Use in Specific Populations].

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.

7.4 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.

Azilsartan/chlorthalidone attenuates chlorthalidone-associated hypokalemia. In patients with normal potassium levels at baseline, 1.7% of azilsartan/chlorthalidone-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).

7.5 Hyperuricemia

Chlorthalidone

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving chlorthalidone or other thiazide diuretics.

8. ADVERSE REACTIONS

The following potential adverse reactions with azilsartan/chlorthalidone, azilsartan medoxomil, or chlorthalidone and similar agents are included in more detail in the Warnings and Precautions section of the label:

• Fetal toxicity

• Hypotension in Volume- or Salt-Depleted Patients

• Impaired Renal Function

• Hypokalemia

• Hyperuricemia

8.1 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.

Azilsartan/chlorthalidone has been evaluated 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 azilsartan/chlorthalidone-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 azilsartan/chlorthalidone-treated Patients and > Azilsartan medoxomil or Chlorthalidone

Hypotension and syncope were reported in 1.7% and 0.3%, respectively, of patients treated with azilsartan/chlorthalidone.

Study discontinuation because of adverse reactions occurred in 8.3% of patients treated with the recommended doses of azilsartan/chlorthalidone 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 azilsartan/chlorthalidone 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 azilsartan/chlorthalidone was similar to that observed during the double-blind, active controlled trials.

In 3 double-blind, active controlled, titration studies, in which azilsartan/chlorthalidone 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 evaluated 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.

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 Azilsartan/Chlorthalidone

In the factorial design trial, clinically relevant changes in standard laboratory parameters were uncommon with administration of the recommended doses of azilsartan/chlorthalidone.

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 azilsartan/chlorthalidone 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 azilsartan/chlorthalidone (5.3 mg/dL) compared with azilsartan medoxomil (1.5 mg/dL) and with chlorthalidone (2.5 mg/dL).

9. OVERDOSAGE

Limited data are available related to overdosage in humans.

Azilsartan medoxomil

During controlled clinical trials in healthy subjects, once daily doses up to 320 mg of azilsartan medoxomil were administered for 7 days and were well tolerated. In the event of an overdose, supportive therapy should be instituted as dictated by the patient's clinical status. Azilsartan is not dialyzable.

Chlorthalidone

Symptoms of acute overdosage include nausea, weakness, dizziness, and disturbances of electrolyte balance. The oral LD50 of the drug in the mouse and the rat is more than 25,000 mg/kg body weight. The minimum lethal dose (MLD) in humans has not been established. There is no specific antidote, but gastric lavage is recommended, followed by supportive treatment. Where necessary, this may include intravenous dextrose-saline with potassium, administered with caution.

10. DRUG INTERACTIONS

Azilsartan/Chlorthalidone

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 azilsartan/chlorthalidone, 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 azilsartan/chlorthalidone and NSAID therapy.

The antihypertensive effect of azilsartan/chlorthalidone 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 azilsartan/chlorthalidone.

11. PHARMACOKINETICS

Azilsartan/Chlorthalidone

Following oral administration of azilsartan/chlorthalidone, peak plasma concentrations of azilsartan and chlorthalidone are reached at 3 and 1 hours, respectively. The rate (Cmax and Tmax) and extent (AUC) of absorption of azilsartan are similar when it is administered alone or with chlorthalidone. The extent (AUC) of absorption of chlorthalidone is similar when it is administered alone or with azilsartan medoxomil; however, the Cmax of chlorthalidone from azilsartan/chlorthalidone was 47% higher. The elimination half-lives of azilsartan and chlorthalidone are approximately 12 hours and 45 hours, respectively.

There is no clinically significant effect of food on the bioavailability of azilsartan/chlorthalidone.

Absorption

Azilsartan medoxomil is rapidly hydrolyzed to azilsartan, the active metabolite, in the gastrointestinal tract during absorption. Azilsartan medoxomil is not detected in plasma after oral administration. Dose proportionality in exposure was established for azilsartan in the azilsartan medoxomil dose range of 20 mg to 320 mg after single or multiple dosing.

The estimated absolute bioavailability of azilsartan following administration of azilsartan medoxomil is approximately 60%. After oral administration of azilsartan medoxomil, peak plasma concentrations (Cmax) of azilsartan are reached within 1.5 to 3 hours. Food does not affect the bioavailability of azilsartan.

Distribution

Azilsartan medoxomil: The volume of distribution of azilsartan is approximately 16L. Azilsartan is highly bound to human plasma proteins (>99%), mainly serum albumin. Protein binding is constant at azilsartan plasma concentrations well above the range achieved with recommended doses.

In rats, minimal azilsartan-associated radioactivity crossed the blood-brain barrier. Azilsartan passed across the placental barrier in pregnant rats and was distributed to the fetus.

Chlorthalidone: In whole blood, chlorthalidone is predominantly bound to erythrocyte carbonic anhydrase. In the plasma, approximately 75% of chlorthalidone is bound to plasma proteins, 58% of the drug being bound to albumin.

Metabolism and Elimination

Azilsartan medoxomil: Azilsartan is metabolized to two primary metabolites. The major metabolite in plasma is formed by O-dealkylation, referred to as metabolite M-II, and the minor metabolite is formed by decarboxylation, referred to as metabolite M-I. Systemic exposures to the major and minor metabolites in humans were approximately 50% and less than 1% of azilsartan, respectively. M-I and M-II do not contribute to the pharmacologic activity of azilsartan medoxomil. The major enzyme responsible for azilsartan metabolism is CYP2C9.

Following an oral dose of 14C-labeled azilsartan medoxomil, approximately 55% of radioactivity was recovered in feces and approximately 42% in urine, with 15% of the dose excreted in urine as azilsartan. The elimination half-life of azilsartan is approximately 11 hours and renal clearance is approximately 2.3 mL/min. Steady-state levels of azilsartan are achieved within 5 days and no accumulation in plasma occurs with repeated once-daily dosing.

Chlorthalidone: The major portion of the drug is excreted unchanged by the kidneys. Nonrenal routes of elimination have yet to be clarified. Data are not available regarding percentage of dose as unchanged drug and metabolites, concentration of the drug in body fluids, degree of uptake by a particular organ or in the fetus, or passage across the blood-brain barrier.

Special Populations

Azilsartan medoxomil: The effect of demographic and functional factors on the pharmacokinetics of azilsartan was studied in single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of the effect on azilsartan are presented in Figure 1 as change relative to reference (test/reference).

Figure 1. Impact of intrinsic factors on the pharmacokinetics of azilsartan

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: EDARBYCLOR, by Takeda Pharms.

b) Generic drugs: None.

2) How Supplied:

Edarbyclor is supplied as fixed dose combination tablets that are round, biconvex, film-coated, and 9.7 mm in diameter.

3) 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. Protect from moisture and light. Do not repackage; dispense and store in original container.

Rx only

Rev 07/12