Benazepril Hydrochloride and Hydrochlorothiazide Tablets

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 hydrochloride and hydrochlorothiazide tablets 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 co-administration 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 benazepril hydrochloride and hydrochlorothiazide tablets, peak plasma concentrations of benazepril are reached within 0.5 to 1 hours. As determined by urinary recovery, the extent of absorption is at least 37%. The absorption of hydrochlorothiazide is somewhat slower (1 to 2.5 hours) and somewhat more complete (50% to 80%). In fasting subjects, the rate and extent of absorption of benazepril and hydrochlorothiazide from benazepril hydrochloride and hydrochlorothiazide tablets are not different, respectively, from the rate and extent of absorption of benazepril and hydrochlorothiazide from immediate-release monotherapy formulations.

The absorption of benazepril from benazepril hydrochloride tablets is not influenced by the presence of food in the gastrointestinal tract, but possible effects of food upon absorption of either component from benazepril hydrochloride and hydrochlorothiazide tablets have not been studied. The reported studies of food effects on hydrochlorothiazide absorption have been inconclusive. The absorption of hydrochlorothiazide is increased by agents that reduce gastrointestinal motility, but it is reported to be reduced by 50% in patients with congestive heart failure.

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 µmol/L to 23.6 µmol/L - concentration. Hydrochlorothiazide is not metabolized. Its apparent volume of distribution is 3.6 L/kg to 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 to 1.8 times those measured in plasma.

In studies of rats given ¹⁴C-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.

Some placental passage occurred when benazepril was administered to pregnant rats. In humans, hydrochlorothiazide crosses the placenta freely and levels in umbilical-cord blood are similar to those in the maternal circulation.

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 hydrochloride is 10 to 11 hours. Thus, steady-state concentrations of benazeprilat should be reached after 2 or 3 doses of benazepril hydrochloride 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 two 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).

Thiazide diuretics are eliminated by the kidney, with a terminal half-life of 5 to 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.

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%.

Administration of benazepril to patients with mild-to-moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent, with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt and/or volume depleted (see WARNINGS, Hypotension ).

In single-dose studies, benazepril lowered blood pressure within 1 hour, with peak reductions achieved 2 to 4 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In multiple-dose studies, once-daily doses of 20 mg to 80 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 6-12/4-7 mmHg. The reductions at trough are about 50% of those seen at peak.

Four dose-response studies of benazepril monotherapy using once-daily dosing were conducted in 470 mild-to-moderate hypertensive patients not using diuretics. The minimal effective once-daily dose of benazepril was 10 mg; further falls in blood pressure, especially at morning trough, were seen with higher doses in the studied dosing range (10 mg to 80 mg). In studies comparing the same daily dose of benazepril given as a single morning dose or as a twice-daily dose, blood pressure reductions at the time of morning trough blood levels were greater with the divided regimen.

During chronic therapy with benazepril, the maximum reduction in blood pressure with any given dose is generally achieved after 1 to 2 weeks. The antihypertensive effects of benazepril have continued during therapy for at least 2 years. Abrupt withdrawal of benazepril has not been associated with a rapid increase in blood pressure.

In patients with mild-to-moderate hypertension, total daily doses of benazepril hydrochloride tablets 20 mg to 40 mg, were similar in effectiveness to total daily doses of captopril 50 mg to 100 mg, hydrochlorothiazide 25 mg to 50 mg, nifedipine SR 40 mg to 80 mg and propranoloI 80 mg to 160 mg.

The antihypertensive effects of benazepril were not appreciably different in patients receiving high- or low-sodium diets.

In hemodynamic studies in dogs, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance, with an increase in cardiac output and renal blood flow and little or no change in heart rate. In normal human volunteers, single doses of benazepril caused an increase in renal blood flow but had no effect on glomerular filtration rate.

In clinical trials of benazepril/hydrochlorothiazide using benazepril doses of 5 mg to 20 mg and hydrochlorothiazide doses of 6.25 mg to 25 mg, the antihypertensive effects were sustained for at least 24 hours and they increased with increasing dose of either component. Although benazepril monotherapy is somewhat less effective in blacks than in nonblacks, the efficacy of combination therapy appears to be independent of race.

By blocking the renin-angiotensin-aldosterone axis, administration of benazepril tends to reduce the potassium loss associated with the diuretic. In clinical trials of benazepril hydrochloride and hydrochlorothiazide tablets, the average change in serum potassium was near zero in subjects who received 5 mg/6.25 mg or 20 mg/12.5 mg, but the average subject who received 10 mg/12.5 mg or 20 mg/25 mg experienced a mild reduction in serum potassium, similar to that experienced by the average subject receiving the same dose of hydrochlorothiazide monotherapy.

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including benazepril hydrochloride and hydrochlorothiazide tablets) may be subject to a variety of adverse reactions, some of them serious.

Benazepril hydrochloride and hydrochlorothiazide tablets can cause symptomatic hypotension. Like other ACE inhibitors, benazepril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume and/or salt depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting. Volume and/or salt depletion should be corrected before initiating therapy with benazepril hydrochloride and hydrochlorothiazide tablets.

Benazepril hydrochloride and hydrochlorothiazide tablets should be used cautiously in patients receiving concomitant therapy with other antihypertensives. The thiazide component of benazepril hydrochloride and hydrochlorothiazide tablets may potentiate the action of other antihypertensive drugs, especially ganglionic or peripheral adrenergic-blocking drugs. The antihypertensive effects of the thiazide component may also be enhanced in the postsympathectomy patient.

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria, azotemia and (rarely) with acute renal failure and death. In such patients, benazepril hydrochloride and hydrochlorothiazide tablet therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of benazepril or diuretic is increased.

If hypotension occurs, the patient should be placed in a supine position and, if necessary, treated with intravenous infusion of physiological saline. Benazepril hydrochloride and hydrochlorothiazide treatment usually can be continued following restoration of blood pressure and volume.

Benazepril hydrochloride and hydrochlorothiazide tablets should be used with caution in patients with severe renal disease. Thiazides may precipitate azotemia in such patients and the effects of repeated dosing may be cumulative.

When the renin-angiotensin-aldosterone system is inhibited by benazepril, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure, whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors (including benazepril) may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death.

In a small study of hypertensive patients with unilateral or bilateral renal artery stenosis, treatment with benazepril was associated with increases in blood urea nitrogen and serum creatinine; these increases were reversible upon discontinuation of benazepril therapy, concomitant diuretic therapy or both. When such patients are treated with benazepril hydrochloride and hydrochlorothiazide tablets, renal function should be monitored during the first few weeks of therapy.

Some benazepril-treated hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when benazepril has been given concomitantly with a diuretic. Dosage reduction of benazepril hydrochloride and hydrochlorothiazide tablets may be required. Evaluation of the hypertensive patient should always include assessment of renal function (see DOSAGE AND ADMINISTRATION).

Another angiotensin-converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients (incidence probably less than once per 10,000 exposures) but more frequently (incidence possibly as great as once per 1,000 exposures) in patients with renal impairment, especially those who also have collagen-vascular diseases such as systemic lupus erythematosus or scleroderma. Available data from clinical trials of benazepril are insufficient to show that benazepril does not cause agranulocytosis at similar rates. Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.

ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, benazepril hydrochloride and hydrochlorothiazide tablets should be discontinued as soon as possible and monitoring of the fetal development should be performed on a regular basis.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation and hypoplastic lung development. Prematurity, intrauterine growth retardation and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure.

In addition, use of ACE inhibitors during the first trimester of pregnancy has been associated with a potentially increased risk of birth defects. In women planning to become pregnant, ACE inhibitors (including benazepril hydrochloride and hydrochlorothiazide tablets) should not be used. Women of childbearing age should be made aware of the potential risk and ACE inhibitors (including benazepril hydrochloride and hydrochlorothiazide tablets) should only be given after careful counseling and consideration of individual risks and benefits.

Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses and serial ultrasound examinations should be performed to assess the intraamniotic environment.

If oligohydramnios is observed, benazepril should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST) or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or peritoneal dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers, but experience is limited.

Intrauterine exposure to thiazide diuretics is associated with fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions that have occurred in adults.

No teratogenic effects were seen when benazepril and hydrochlorothiazide were administered to pregnant rats at a dose ratio of 4:5. On a mg/kg basis, the doses used were up to 167 times the maximum recommended human dose. Similarly, no teratogenic effects were seen when benazepril and hydrochlorothiazide were administered to pregnant mice at total doses up to 160 mg/kg/day, with benazepril:hydrochlorothiazide ratios of 15:1. When hydrochlorothiazide was orally administered without benazepril to pregnant mice and rats during their respective periods of major organogenesis, at doses up to 3,000 mg/kg/day and 1,000 mg/kg/day respectively, there was no evidence of harm to the fetus. Similarly, no teratogenic effects of benazepril were seen in studies of pregnant rats, mice and rabbits; on a mg/kg basis, the doses used in these studies were 300 times (in rats), 90 times (in mice) and more than 3 times (in rabbits) the maximum recommended human dose.

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Benazepril hydrochloride and hydrochlorothiazide tablets should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma (see WARNINGS, Hepatic Failure, above). In patients with hepatic dysfunction due to cirrhosis, levels of benazeprilat are essentially unaltered. No formal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function.

Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

The hydrochlorothiazide component of benazepril hydrochloride and hydrochlorothiazide tablets may decrease serum PBI levels without signs of thyroid disturbance.

Therapy with benazepril hydrochloride and hydrochlorothiazide tablets should be interrupted for a few days before carrying out tests of parathyroid function.

No evidence of carcinogenicity was found when benazepril was given to rats and mice for 104 weeks at doses up to 150 mg/kg/day. On a body-weight basis, this dose is over 100 times the maximum recommended human dose; on a body-surface-area basis, this dose is 18 times (rats) and 9 times (mice) the maximum recommended human dose. No mutagenic activity was detected in the Ames test in bacteria (with or without metabolic activation), in an in vitro test for forward mutations in cultured mammalian cells or in a nucleus anomaly test. At doses of 50 mg/kg/day to 500 mg/kg/day (38 to 375 times the maximum recommended human dose on a body-weight basis; 6 to 61 times the maximum recommended dose on a body-surface-area basis), benazepril had no adverse effect on the reproductive performance of male and female rats.

Under the auspices of the National Toxicology Program, rats and mice received hydrochlorothiazide in their feed for two years, at doses up to 600 mg/kg/day in mice and up to 100 mg/kg/day in rats. These studies uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in rats or female mice, but there was equivocal evidence of hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 of Salmonella typhimurium (the Ames test); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43 µg/mL to 1,300 µg/mL. Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using an unspecified concentration of hydrochlorothiazide.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diets, to doses up to 100 mg/kg/day and 4 mg/kg/day, respectively, prior to mating and throughout gestation.

Pregnancy Category D: See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

Minimal amounts of unchanged benazepril and benazeprilat are excreted into the breast milk of lactating women treated with benazepril, so that a newborn child ingesting nothing but breast milk would receive less than 0.1% of the maternal doses of benazepril and benazeprilat. Thiazides, on the other hand, are definitely excreted into breast milk. Because of the potential for serious adverse reactions in nursing infants from hydrochlorothiazide and the unknown effects of benazepril in infants, a decision should be made whether to discontinue nursing or to discontinue benazepril hydrochloride and hydrochlorothiazide tablets, taking into account the importance of the drug to the mother.

Of the total number of patients who received benazepril hydrochloride and hydrochlorothiazide tablets in U.S. clinical studies of benazepril hydrochloride and hydrochlorothiazide tablets, 19% were 65 or older while about 1.5% were 75 or older. Overall differences in effectiveness or safety were not observed between these patients and younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Benazepril and benazeprilat are substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.

Safety and effectiveness in pediatric patients have not been established.

A patient whose blood pressure is not adequately controlled with benazepril monotherapy may be switched to benazepril hydrochloride and hydrochlorothiazide tablets 10 mg/12.5 mg or 20 mg/12.5 mg. Further increases of either or both components could depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2 to 3 weeks have elapsed. Patients whose blood pressures are adequately controlled with 25 mg of daily hydrochlorothiazide, but who experience significant potassium loss with this regimen, may achieve similar blood-pressure control without electrolyte disturbance if they are switched to benazepril hydrochloride and hydrochlorothiazide tablets 5 mg/6.25 mg.

The combination may be substituted for the titrated individual components.

Regimens of therapy with benazepril hydrochloride and hydrochlorothiazide tablets need not take account of renal function as long as the patient's creatinine clearance is >30 mL/min/1.73 m² (serum creatinine roughly ≤3 mg/dL or 265 µmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so benazepril hydrochloride and hydrochlorothiazide tablets are not recommended (see WARNINGS).