UNIRETIC- moexipril hydrochloride and hydrochlorothiazide tablet, film coated
UCB, Inc.
Rx Only
WARNING: FETAL TOXICITY
See full prescribing information for complete boxed warning.
When pregnancy is detected, discontinue uniretic� 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
uniretic� (moexipril hydrochloride/hydrochlorothiazide) is a combination of an angiotensin-converting enzyme (ACE) inhibitor, moexipril hydrochloride, and a diuretic, hydrochlorothiazide. Moexipril hydrochloride is a fine white to off-white powder. It is soluble (about 10% weight-to-volume) in distilled water at room temperature. It has the empirical formula C27 H34 N2 O7 �HCl and a molecular weight of 535.04. It is chemically described as [3S-[2[R*(R*)],3R*]]-2-[2-[[1-(Ethoxycarbonyl)-3-phenyl-propyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquino-linecarboxylic acid, monohydrochloride. Moexipril hydrochloride is a non-sulfhydryl containing precursor of the active ACE inhibitor moexiprilat
Hydrochlorothiazide is a white, or practically white, crystalline powder. It is slightly soluble in water, freely soluble in sodium hydroxide solution, in n-butylamine and in dimethylformamide. Hydrochlorothiazide has the empirical formula C7 H8 ClN3 O4 S2 and a molecular weight of 297.75. It is chemically described as 2H -1,2,4-Benzothiadiazine-7-sulfonamide,6-chloro-3,4-dihydro-,1,1-dioxide. Hydrochlorothiazide is a thiazide diuretic.
uniretic� is available for oral administration in three tablet strengths. The inactive ingredients in all strengths are lactose, magnesium oxide, crospovidone, magnesium stearate and gelatin. The film coating in all strengths contains hydroxypropyl cellulose, hypromellose, polyethylene glycol 6000, magnesium stearate and titanium dioxide. In addition, the film coating for uniretic� 7.5 mg / 12.5 mg and uniretic� 15 mg / 25 mg contains ferric oxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
Moexipril Hydrochloride
Moexipril hydrochloride is a prodrug for moexiprilat, which inhibits ACE in humans and animals. The mechanism through which moexiprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes the conversion of the inactive decapeptide angiotensin I to the vasoconstrictor substance angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor that also stimulates aldosterone secretion by the adrenal cortex and provides negative feedback on renin secretion. ACE is identical to kininase II, an enzyme that degrades bradykinin, an endothelium-dependent vasodilator. Moexiprilat is about 1000 times as potent as moexipril in inhibiting ACE and kininase II. Inhibition of ACE results in decreased angiotensin II formation, leading to decreased vasoconstriction, increased plasma renin activity, and decreased aldosterone secretion. The latter results in diuresis and natriuresis and a small increase in serum potassium concentration (mean increases of about 0.25 mEq/L were seen when moexipril was used alone).
Hydrochlorothiazide
Hydrochlorothiazide is a thiazide diuretic and antihypertensive. Thiazides affect the distal 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.
Uniretic Indications and Usage
uniretic� is indicated for treatment of patients with hypertension. This fixed combination is not indicated for the initial therapy of hypertension (see DOSAGE AND ADMINISTRATION).
In using uniretic� , consideration should be given to the fact that another ACE inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. Available data are insufficient to show that uniretic� does not have a similar risk (see WARNINGS, Neutropenia/Agranulocytosis). In addition, ACE inhibitors, for which adequate data are available, cause a higher rate of angioedema in black than in nonblack patients
DOSAGE AND ADMINISTRATION
Moexipril and hydrochlorothiazide are effective treatments for hypertension. The recommended dosage range of moexipril is 7.5 to 30 mg daily, administered in a single or two divided doses one hour before meals, while hydrochlorothiazide is effective in a dosage of 12.5 to 50 mg daily.
The side effects (see WARNINGS) of moexipril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of moexipril and hydrochlorothiazide will be associated with both sets of dose-independent side effects, but regimens in which moexipril is combined with low doses of hydrochlorothiazide produce minimal effects on serum potassium. In uniretic� controlled clinical trials, the average change in serum potassium was near zero in subjects who received 3.75 mg / 6.25 mg or 7.5 mg / 12.5 mg, but subjects who received 15 mg / 12.5 mg or 15 mg / 25 mg experienced a mild decrease in serum potassium, similar to that experienced by subjects who received the same dose of hydrochlorothiazide monotherapy. To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.
