UNIRETIC- moexipril hydrochloride and hydrochlorothiazide tablet, film coated
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
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 and its structural formula is:
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 and its structural formula is:
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.
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).
Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of moexipril remains to be elucidated. Although the principal mechanism of moexipril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect on blood pressure even in apparent low-renin hypertension. As is the case with other ACE inhibitors, however, the antihypertensive effect of moexipril is smaller in black patients, a predominantly low-renin population, than in nonblack hypertensive patients. Although moexipril monotherapy is less effective in blacks than in nonblacks, the efficacy of combination therapy appears to be independent of race.
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.
Following oral administration of uniretic® , the moexipril peak plasma concentration was reached within 0.8 hour and the peak plasma concentration of moexiprilat occurred 1.6 hours after administration. After reaching the peak plasma level (Cmax ), moexiprilat plasma concentrations decreased biphasically. After administration of uniretic® , renal excretion of unchanged hydrochlorothiazide is about 60% in 24 hours. The pharmacokinetics of moexipril and hydrochlorothiazide after administration of uniretic® are not different, respectively, from the pharmacokinetics of moexipril and hydrochlorothiazide from immediate-release monotherapy formulations.
Moexipril’s antihypertensive activity is almost entirely due to its deesterified metabolite, moexiprilat. Bioavailability of oral moexipril is about 13% compared to intravenous (I.V.) moexipril (both measuring the metabolite moexiprilat), and is markedly affected by food, which reduces Cmax and AUC (see Absorption). Moexipril should therefore be taken in a fasting state. The time of peak plasma concentration (Tmax ) of moexiprilat is about 1 ½ hours and elimination half-life (t½ ) is estimated at 2 to 9 hours in various studies, the variability reflecting a complex elimination pattern that is not simply exponential. Like all ACE inhibitors, moexiprilat has a prolonged terminal elimination phase, presumably reflecting slow release of drug bound to the ACE. Accumulation of moexiprilat with repeated dosing is minimal, about 30%, compatible with a functional elimination t½ of about 12 hours. Over the dose range of 7.5 to 30 mg, pharmacokinetics are approximately dose proportional.
Moexipril is incompletely absorbed, with bioavailability as moexiprilat of about 13%. Bioavailability varies with formulation and food intake which reduces Cmax and AUC of moexiprilat by about 70% and 40% respectively after the ingestion of a low-fat breakfast or by 80% and 50% respectively after the ingestion of a high-fat breakfast.
The clearance (CL) for moexipril is 441 mL/min and for moexiprilat 232 mL/min with a t½ of 1.3 and 9.8 hours, respectively. Moexiprilat is about 50% protein bound. The volume of distribution of moexiprilat is about 2.8 L/kg.
Moexipril is relatively rapidly converted to its active metabolite moexiprilat, but persists longer than some other ACE inhibitor prodrugs, such that its t½ is over one hour and it has a significant AUC. Both moexipril and moexiprilat are converted to diketopiperazine derivatives and unidentified metabolites. After I.V. administration of moexipril, about 40% of the dose appears in urine as moexiprilat, about 26% as moexipril, with small amounts of the metabolites; about 20% of the I.V. dose appears in feces, principally as moexiprilat. After oral administration, only about 7% of the dose appears in urine as moexiprilat, about 1% as moexipril, with about 5% as other metabolites. Fifty-two percent of the dose is recovered in feces as moexiprilat and 1% as moexipril.
Decreased Renal Function
The effective elimination t½ and AUC of both moexipril and moexiprilat are increased with decreasing renal function. There is insufficient information available to characterize this relationship fully, but at creatinine clearances in the range of 10 to 40 mL/min, the t½ of moexiprilat is increased by a factor of 3 to 4.
Decreased Hepatic Function
In patients with mild to moderate cirrhosis given single 15 mg doses of moexipril, the Cmax of moexipril was increased by about 50% and the AUC increased by about 120%, while the Cmax for moexiprilat was decreased by about 50% and the AUC increased by almost 300%.
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