BENAZEPRIL HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE- benazepril hydrochloride and hydrochlorothiazide tablet
Padagis US LLC
10 mg/12.5 mg
20 mg/12.5 mg
20 mg/25 mg
When pregnancy is detected, discontinue Benazepril HCl and Hydrochlorothiazide 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).
Benazepril hydrochloride USP is a white to off-white crystalline powder, soluble (>100 mg/mL) in water, in ethanol, and in methanol. Benazepril hydrochloride’s chemical name is 3-[[1-(ethoxycarbonyl)-3- phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H -1-(3S)-benzazepine- 1-acetic acid monohydrochloride; its structural formula is
Its empirical formula is C24 H28 N2 O5 ·HCl, and its molecular weight is 460.96.
Benazeprilat, the active metabolite of benazepril, is a nonsulfhydryl angiotensin converting enzyme inhibitor. Benazepril is converted to benazeprilat 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:
Its empirical formula is C7 H8 ClN3 O4 S2 , and its molecular weight is 297.73. Hydrochlorothiazide is a thiazide diuretic.
Benazepril HCl and Hydrochlorothiazide is a combination of benazepril and hydrochlorothiazide USP. The tablets are formulated for oral administration with a combination of 10 or 20 mg of benazepril and 12.5 or 25 mg of hydrochlorothiazide USP. The inactive ingredients of the tablets are cellulose compounds, crospovidone, hydrogenated castor oil, iron oxides (10/12.5 mg, 20/12.5 mg, and 20/25 mg tablets), lactose, polyethylene glycol, talc, and titanium dioxide.
Mechanism of Action
Benazepril and benazeprilat 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 benazepril alone for up to 52 weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients treated with benazepril and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum potassium (see PRECAUTIONS).
Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine.
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 Benazepril HCl and Hydrochlorothiazide remains to be elucidated.
While the mechanism through which benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, benazepril 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
Following oral administration of Benazepril HCl and Hydrochlorothiazide, peak plasma concentrations of benazepril are reached within 0.5 to 1.0 hour. As determined by urinary recovery, the extent of absorption is at least 37%. In fasting subjects, the rate and extent of absorption of benazepril and hydrochlorothiazide from Benazepril HCl and Hydrochlorothiazide are not different, respectively, from the rate and extent of absorption of benazepril and hydrochlorothiazide from immediate release monotherapy formulations.
The estimated absolute bioavailability of hydrochlorothiazide after oral administration is about 70%. Peak plasma hydrochlorothiazide concentrations (Cmax ) are reached within 2 to 5 hours after oral administration. Hydrochlorothiazide binds to albumin (40% to 70%) and distributes into erythrocytes.
The absorption of benazepril from Benazepril HCl and Hydrochlorothiazide tablets is not influenced by the presence of food in the gastrointestinal tract. There is no clinically significant effect of food on the bioavailability of hydrochlorothiazide.
Cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat. Peak plasma concentrations of benazeprilat are reached 1 to 2 hours after drug intake in the fasting state and 2 to 4 hours after drug intake in the nonfasting state. The serum protein binding of benazepril is about 96.7% and that of benazeprilat about 95.3%, as measured by equilibrium dialysis; on the basis of in vitro studies, the degree of protein binding should be unaffected by age, hepatic dysfunction, or – over the concentration range of 0.24 to 23.6 μmol/L – concentration.
In studies of rats given 14 C-benazepril, benazepril and its metabolites crossed the blood-brain barrier only to an extremely low extent. Multiple doses of benazepril did not result in accumulation in any tissue except the lung, where, as with other ACE inhibitors in similar studies, there was a slight increase in concentration due to slow elimination in that organ.
Benazepril is almost completely metabolized to benazeprilat, which has much greater ACE inhibitory activity than benazepril, and to the glucuronide conjugates of benazepril and benazeprilat. Only trace amounts of an administered dose of benazepril can be recovered unchanged in the urine; about 20% of the dose is excreted as benazeprilat, 4% as benazepril glucuronide, and 8% as benazeprilat glucuronide.
In patients with hepatic dysfunction due to cirrhosis, levels of benazeprilat are essentially unaltered.
Similarly, the pharmacokinetics of benazepril and benazeprilat do not appear to be influenced by age.
The kinetics of benazepril are dose-proportional within the dosage range of 5 mg to 20 mg. Small deviations from dose proportionality were observed when the broader range of 2 mg to 80 mg was studied, possibly due to the saturable binding of the compound to ACE.
The effective half-life of accumulation of benazeprilat following multiple dosing of benazepril is 10 to 11 hours. Thus, steady-state concentrations of benazeprilat should be reached after 2 or 3 doses of benazepril given once daily.
During chronic administration (28 days) of once-daily doses of benazepril between 5 mg and 20 mg, the kinetics did not change, and there was no significant accumulation. Accumulation ratios based on AUC and urinary recovery of benazeprilat were 1.19 and 1.27, respectively.
When dialysis was started 2 hours after ingestion of 10 mg of benazepril, approximately 6% of benazeprilat was removed in 4 hours of dialysis. The parent compound, benazepril, was not detected in the dialysate.
Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11% to 12% of benazeprilat excretion in healthy subjects. In patients with renal failure, biliary clearance may compensate to an extent for deficient renal clearance.
The disposition of benazepril and benazeprilat in patients with mild-to-moderate renal insufficiency (creatinine clearance > 30 mL/min) is similar to that in patients with normal renal function. In patients with creatinine clearance ≤ 30 mL/min, peak benazeprilat levels and the initial (alpha phase) half-life increase, and time to steady-state may be delayed (see DOSAGE AND ADMINISTRATION).
Following oral administration, plasma hydrochlorothiazide concentrations decline bi-exponentially, with a mean distribution half-life of about 2 hours and an elimination half-life of about 10 hours. About 70% of an orally administered dose of hydrochlorothiazide is eliminated in the urine as unchanged drug. In a study in individuals with impaired renal function, the mean elimination half-life of hydrochlorothiazide was increased to 2 fold in individuals with mild/moderate renal impairment (30 < CLcr < 90 mL/min) and 3 fold in individuals with severe renal impairment (≤ 30 mL/min), when compared to individuals with normal renal function (CLcr > 90 mL/min).
Single and multiple doses of 10 mg or more of benazepril cause inhibition of plasma ACE activity by at least 80% to 90% for at least 24 hours after dosing. For up to 4 hours after a 10 mg dose, pressor responses to exogenous angiotensin I were inhibited by 60% to 90%.
In normal human volunteers, single doses of benazepril caused an increase in renal blood flow but had no effect on glomerular filtration rate.
After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.
Benazepril HCl and Hydrochlorothiazide potentiates the antihypertensive action of other antihypertensive drugs (e.g., curare derivatives, guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers ACE inhibitors and ARBs and DRIs).
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