FOSINOPRIL SODIUM AND HYDROCHLOROTHIAZIDE

FOSINOPRIL SODIUM AND HYDROCHLOROTHIAZIDE- fosinopril sodium and hydrochlorothiazide tablet
Andrx Pharmaceuticals, Inc.

Rx Only

USE IN PREGNANCY

When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, fosinopril sodium and hydrochlorothiazide tablets should be discontinued as soon as possible. See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

DESCRIPTION

Fosinopril sodium is a white to off-white crystalline powder, soluble (>100 mg/mL) in water, in ethanol, and in methanol, and slightly soluble in hexane. Fosinopril sodium’s chemical name is L-proline, 4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)- propoxy]-(4 phenylbutyl)- phosphinyl]acetyl]-, sodium salt, trans -; its structural formula is:

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Its empirical formula is C30 H45 NNaO7 P, and its molecular weight is 585.65.

Fosinoprilat, the active metabolite of fosinopril, is a non-sulfhydryl angiotensin-converting enzyme inhibitor. Fosinopril is converted to fosinoprilat by hepatic cleavage of the ester group.

Hydrochlorothiazide, USP is a white, or practically white, practically odorless, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in n-butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether, in chloroform, and in dilute mineral acids. Hydrochlorothiazide’s chemical name is 6-chloro-3,4-dihydro-2H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide; its structural formula is:

Image from Drug Label Content

Its empirical formula is C7 H8 ClN3 O4 S2 , and its molecular weight is 297.73.

Hydrochlorothiazide is a thiazide diuretic.

Fosinopril sodium and hydrochlorothiazide tablets are a combination of fosinopril sodium and hydrochlorothiazide, USP. It is available for oral use in two tablet strengths: Fosinopril sodium and hydrochlorothiazide tablets 10/12.5, containing 10 mg of fosinopril sodium and 12.5 mg of hydrochlorothiazide, USP; and fosinopril sodium and hydrochlorothiazide tablets 20/12.5, containing 20 mg of fosinopril sodium and 12.5 mg of hydrochlorothiazide, USP. The inactive ingredients of the tablets include Colloidal silicon dioxide, FD&C Red #40 HT aluminum lake, lactose monohydrate, microcrystalline cellulose, and sodium stearyl fumarate.

CLINICAL PHARMACOLOGY

Mechanism of Action

Fosinopril and fosinoprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and in animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. Hypertensive patients treated with fosinopril alone for an average of 8 weeks had elevations of serum potassium of approximately 0.1 mEq/L. Similar patients treated with hydrochlorothiazide alone had a mean reduction in serum potassium of 0.15 mEq/L, while patients who received combined treatment with 10/12.5 mg or 20/12.5 mg of fosinopril and hydrochlorothiazide had reductions of 0.07 and 0.03 mEq/L, respectively. (See PRECAUTIONS.)

Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.

ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of fosinopril sodium and hydrochlorothiazide tablets remains to be elucidated.

While the mechanism through which fosinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, fosinopril has an antihypertensive effect even in patients with low-renin hypertension.

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, so coadministration of an ACE inhibitor tends to reverse the potassium loss associated with these diuretics.

The mechanism of the antihypertensive effect of thiazides is unknown.

Pharmacokinetics and Metabolism

The absolute absorption of fosinopril averages 36% of an oral dose. The primary site of absorption is the proximal small intestine. While the rate of absorption may be slowed by the presence of food in the gastrointestinal tract, the extent of absorption of fosinopril is essentially unaffected.

Following oral administration of hydrochlorothiazide, peak plasma concentrations are achieved in 1–2.5 hours, and the extent of absorption is 50–80%. The reported studies of food effects on hydrochlorothiazide absorption have been inconclusive. The absorption of hydrochlorothiazide is increased by agents that reduce gastrointestinal motility. It is reported to be decreased by 50% in patients with congestive heart failure.

Cleavage of the ester group (primarily in the liver) converts fosinopril to its active metabolite, fosinoprilat. The time to peak plasma concentrations of fosinoprilat is about 3 hours, independent of the administered dose of fosinopril. In patients with hepatic dysfunction due to cirrhosis, conversion of fosinopril to fosinoprilat may be slowed, but the extent of this conversion is unchanged.

Fosinoprilat is highly protein bound (95%), but has negligible binding to cellular components of blood. The peak serum concentration and the area under the concentration-time curve of fosinoprilat is directly proportional to the administered dose of fosinopril.

After an oral dose of radiolabeled fosinopril, 75% of radioactivity in plasma was present as active fosinoprilat, 20–30% as a glucuronide conjugate of fosinoprilat, and 1–5% as a p -hydroxy metabolite of fosinoprilat. Since fosinoprilat is not biotransformed after intravenous administration, fosinopril, not fosinoprilat, appears to be the precursor for the glucuronide and p -hydroxy metabolites. In rats, the p -hydroxy metabolite of fosinoprilat is as potent an inhibitor of ACE as fosinoprilat; the glucuronide conjugate is devoid of ACE inhibitory activity.

Studies in animals indicate that fosinopril and fosinoprilat do not cross the blood-brain barrier, but fosinoprilat does cross the placenta of pregnant animals. In humans, hydrochlorothiazide crosses the placenta freely, and levels in umbilical-cord blood are similar to those in the maternal circulation.

Hydrochlorothiazide is not metabolized. Its apparent volume of distribution is 3.6–7.8 L/kg, and its measured plasma protein binding is 67.9%. The drug also accumulates in red blood cells, so that whole blood levels are 1.6–1.8 times those measured in plasma.

After intravenous administration, fosinoprilat is eliminated approximately equally by the liver and kidney. After oral administration of radiolabeled fosinopril, approximately half of the absorbed dose is excreted in the urine and the remainder is excreted in the feces. In two studies involving healthy subjects, the mean body clearance of intravenous fosinoprilat was between 26 and 39 mL/min.

In hypertensive patients with normal renal and hepatic function, the effective half-life of accumulation of fosinoprilat following multiple dosing of fosinopril sodium is 11.5 hours. Thus, steady-state concentrations of fosinoprilat should be reached after 2 or 3 doses of fosinopril sodium and hydrochlorothiazide tablets given once daily.

In patients with renal insufficiency (creatinine clearance <80 mL/min/1.73m2), the total body clearance of fosinoprilat is approximately one half of that in patients with normal renal function, while absorption, bioavailability, and protein binding are not appreciably altered. The clearance of fosinoprilat does not differ appreciably with the degree of renal insufficiency, because the diminished renal elimination is offset by increased hepatobiliary elimination. A modest increase in plasma AUC levels (less than two times that in normals) was observed in patients with various degrees of renal insufficiency, including end-stage renal failure (creatinine clearance <10 mL/min/1.73m2). (See DOSAGE AND ADMINISTRATION.)

Fosinopril is not well dialyzed. Clearance of fosinoprilat by hemodialysis and peritoneal dialysis averages 2% and 7%, respectively, of urea clearances.

In patients with hepatic insufficiency (alcoholic or biliary cirrhosis), the apparent total body clearance of fosinoprilat is approximately one half of that in patients with normal hepatic function.

In elderly (male) subjects (65–74 years old) with clinically normal renal and hepatic function, there appear to be no significant differences in pharmacokinetic parameters for fosinoprilat compared to those of younger subjects (20–35 years old).

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 creatine clearance of 19 mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours.

When fosinopril and hydrochlorothiazide are administered concomitantly, the pharmacokinetics of hydrochlorothiazide are essentially unaffected. Serum levels of fosinoprilat are increased after several weeks of coadministration of hydrochlorothiazide and fosinopril, but the increase is not sufficient to warrant any change in dosing.

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