Candesartan Cilexetil and Hydrochlorothiazide: Package Insert and Label Information

CANDESARTAN CILEXETIL AND HYDROCHLOROTHIAZIDE- candesartan cilexetil and hydrochlorothiazide tablet
REMEDYREPACK INC.

WARNING: FETAL TOXICITY

  • When pregnancy is detected, discontinue candesartan cilexetil and hydrochlorothiazide tablets as soon as possible.
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See Warnings: Fetal Toxicity

DESCRIPTION

Candesartan Cilexetil and Hydrochlorothiazide Tablets USP combine an angiotensin II receptor (type AT 1 ) antagonist and a diuretic, hydrochlorothiazide.

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

Its empirical formula is C 33 H 34 N 6 O 6 and its structural formula is:

Chemical Structure for Candesartan cilexetil
(click image for full-size original)

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.

Hydrochlorothiazide is 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C 7 H 8 ClN 3 O 4 S 2 and its structural formula is:

Chemical Structure for Hydrochlorothiazide

Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.72, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.

Candesartan cilexetil and hydrochlorothiazide tablets are available for oral administration in three tablet strengths of candesartan cilexetil and hydrochlorothiazide.

Candesartan cilexetil and hydrochlorothiazide tablets contain 16 mg or 32 mg of candesartan cilexetil and 12.5 mg or 25 mg of hydrochlorothiazide providing for the following available combinations: 16 mg/12.5 mg, 32 mg/12.5 mg or 32 mg/25 mg. The inactive ingredients of the tablets are carboxymethylcellulose calcium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, corn starch, polyethylene glycol 8000, and ferric oxide (yellow). Ferric oxide (reddish brown) is also added to the 16 mg/12.5 mg and 32 mg/25 mg tablets as colorant.

CLINICAL PHARMACOLOGY

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 AT 1 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 AT 2 receptor found in many tissues, but AT 2 is not known to be associated with cardiovascular homeostasis. Candesartan has much greater affinity (>10,000-fold) for the AT 1 receptor than for the AT 2 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.

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so co‑administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.

The mechanism of the antihypertensive effect of thiazides is unknown.

Pharmacokinetics

General

Candesartan Cilexetil

Candesartan cilexetil is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan, a selective AT 1 subtype angiotensin II receptor antagonist. Candesartan 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 candesartan is approximately 9 hours. After single and repeated administration, the pharmacokinetics of candesartan are linear for oral doses up to 32 mg of candesartan cilexetil. Candesartan and its inactive metabolite do not accumulate in serum upon repeated once-daily dosing.

Following administration of candesartan cilexetil, the absolute bioavailability of candesartan 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 candesartan after candesartan cilexetil administration.

Hydrochlorothiazide

When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours.

Metabolism and Excretion

Candesartan Cilexetil

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

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours.

Distribution

Candesartan Cilexetil

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

Hydrochlorothiazide

Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Special Populations

Pediatric

The pharmacokinetics of candesartan cilexetil have not been investigated in patients <18 years of age.

Geriatric

The pharmacokinetics of candesartan have been studied in the elderly (≥ 65 years). The plasma concentration of candesartan 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 candesartan were linear in the elderly, and candesartan and its inactive metabolite did not accumulate in the serum of these subjects upon repeated, once-daily administration. No initial dosage adjustment is necessary (see DOSAGE AND ADMINISTRATION).

Gender

There is no difference in the pharmacokinetics of candesartan between male and female subjects.

Renal Insufficiency

In hypertensive patients with renal insufficiency, serum concentrations of candesartan were elevated. After repeated dosing, the AUC and C max were approximately doubled in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73m 2) compared to patients with normal kidney function. The pharmacokinetics of candesartan in hypertensive patients undergoing hemodialysis are similar to those in hypertensive patients with severe renal impairment. Candesartan cannot be removed by hemodialysis.

Thiazide diuretics are eliminated by the kidney, with a terminal half-life of 5-15 hours. In a study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours (see DOSAGE AND ADMINISTRATION).

Safety and effectiveness of candesartan cilexetil and hydrochlorothiazide tablets in patients with severe renal impairment (CrCL ≤30 mL/min) have not been established. No dose adjustment is required in patients with mild (CrCL 60-90 mL/min) or moderate (CrCL 30-60 mL/min) renal impairment.

Hepatic Insufficiency

The pharmacokinetics of candesartan were compared in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment to matched healthy volunteers following a single dose of 16 mg candesartan cilexetil. The AUC for candesartan in patients with mild and moderate hepatic impairment was increased 30% and 145% respectively. The C max for candesartan was increased 56% and 73% respectively. The pharmacokinetics of candesartan in severe hepatic impairment have not been studied. No dose adjustment is recommended for patients with mild hepatic impairment. In patients with moderate hepatic impairment, candesartan cilexetil and hydrochlorothiazide tablets are not recommended for initiation because the appropriate starting dose, 8 mg, cannot be given (see DOSAGE AND ADMINISTRATION).

Monitor patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Pharmacodynamics

Candesartan Cilexetil

Candesartan inhibits the pressor effects of angiotensin II infusion in a dose-dependent manner. After 1 week of once-daily dosing with 8 mg of candesartan 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 candesartan cilexetil to healthy subjects and hypertensive patients. ACE activity was not altered in healthy subjects after repeated candesartan cilexetil administration. The once-daily administration of up to 16 mg of candesartan 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 candesartan cilexetil was administered to hypertensive patients. In spite of the effect of candesartan cilexetil on aldosterone secretion, very little effect on serum potassium was observed.

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 .

Hydrochlorothiazide

After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.

Clinical Trials

Candesartan Cilexetil and Hydrochlorothiazide

Of 12 controlled clinical trials involving 4588 patients, 5 were double-blind, placebo controlled and evaluated the antihypertensive effects of single entities vs the combination. These 5 trials, of 8 to 12 weeks duration, randomized 3037 hypertensive patients. Doses ranged from 2 to 32 mg candesartan cilexetil and from 6.25 to 25 mg hydrochlorothiazide administered once daily in various combinations.

The combination of candesartan cilexetil and hydrochlorothiazide resulted in placebo-adjusted decreases in sitting systolic and diastolic blood pressures of 14-18/8-11 mm Hg at doses of 16 mg/12.5 mg and 32 mg/12.5 mg. The combination of candesartan cilexetil and hydrochlorothiazide 32 mg/25 mg resulted in placebo-adjusted decreases in sitting systolic and diastolic blood pressures of 16-19/9-11 mm Hg. The placebo corrected trough to peak ratio was evaluated in a study of candesartan cilexetil and hydrochlorothiazide 32 mg/12.5 mg and was 88%.

Most of the antihypertensive effect of the combination of candesartan cilexetil and hydrochlorothiazide was seen in 1 to 2 weeks with the full effect observed within 4 weeks. In long-term studies of up to 1 year, the blood pressure lowering effect of the combination was maintained. The antihypertensive effect was similar regardless of age or gender, and overall response to the combination was similar in black and non-black patients. No appreciable changes in heart rate were observed with combination therapy in controlled trials.

INDICATIONS AND USAGE

Candesartan cilexetil and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal 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 the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with candesartan cilexetil and hydrochlorothiazide tablets.

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, 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, and 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.

This fixed dose combination is not indicated for initial therapy (see DOSAGE AND ADMINISTRATION).

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