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Basic Drug Info
Drug Name:Benazepril Hydrochloride and Hydrochlorothiazide
Manufacturer:GENHARM, L.P.
Other Info:

Benazepril is an effective treatment of hypertension in once-daily doses of 10 to 80 mg, while hydrochlorothiazide is effective in doses of 12.5 to 50 mg per day.

In clinical trials of benazepril/hydrochlorothiazide combination therapy using benazepril doses of 5 to 20 mg and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects increased with increasing dose of either component.The side effects (see WARNINGS) of benazepril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dosedependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter.

Therapy with any combination of benazepril and hydrochlorothiazide will be associated with both sets of dose-independent side effects, but regimens in which benazepril is combined with low doses of hydrochlorothiazide produce minimal effects on serum potassium.

In clinical trials of Benazepril Hydrochloride and Hydrochlorothiazide Tablets, the average change in serum potassium was near zero in subjects who received 5/6.25 mg or 20/12.5 mg, but the average subject who received 10/12.5 mg or 20/25 mg experienced a mild reduction in serum potassium, similar to that experienced by the average subject receiving 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.Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled with benazepril monotherapy may be switched to Benazepril Hydrochloride and Hydrochlorothiazide Tablets 10/12.5 or Benazepril Hydrochloride and Hydrochlorothiazide Tablets 20/12.5.

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 5/6.25.Replacement Therapy: The combination may be substituted for the titrated individual components.Use in Renal Impairment: 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/1.73m2 (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).



Clinical Trials:


Indications and Usage

Benazepril Hydrochloride and Hydrochlorothiazide Tablets are indicated for the treatment of hypertension.This fixed combination drug is not indicated for the initial therapy of hypertension (see DOSAGE AND ADMINISTRATION).In using Benazepril Hydrochloride and Hydrochlorothiazide Tablets, consideration should be given to the fact that another angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease.

Available data are insufficient to show that benazepril does not have a similar risk (see WARNINGS, Neutropenia/Agranulocytosis).Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to nonblacks.
Hypertensive disease -- Persistently high systemic arterial BLOOD PRESSURE. Based on multiple readings (BLOOD PRESSURE DETERMINATION), hypertension is currently defined as when SYSTOLIC PRESSURE is consistently greater than 140 mm Hg or when DIASTOLIC PRESSURE is consistently 90 mm Hg or more.

Agranulocytosis -- A decrease in the number of GRANULOCYTES; (BASOPHILS; EOSINOPHILS; and NEUTROPHILS).

COLLAGEN VASCULAR DISEASE --

Angioedema -- Swelling involving the deep DERMIS, subcutaneous, or submucosal tissues, representing localized EDEMA. Angioedema often occurs in the face, lips, tongue, and larynx.

Contraindications

Benazepril Hydrochloride and Hydrochlorothiazide Tablets are contraindicated in patients who are anuric.

Benazepril Hydrochloride and Hydrochlorothiazide Tablets are also contraindicated in patients who are hypersensitive to benazepril, to any other ACE inhibitor, to hydrochlorothiazide, or to other sulfonamide derived drugs.

Hypersensitivity reactions are more likely to occur in patients with a history of allergy or bronchial asthma.
Anuria -- Absence of urine formation. It is usually associated with complete bilateral ureteral (URETER) obstruction, complete lower urinary tract obstruction, or unilateral ureteral obstruction when a solitary kidney is present.

Hypersensitivity -- Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen.

Immediate hypersensitivity -- Hypersensitivity reactions which occur within minutes of exposure to challenging antigen due to the release of histamine which follows the antigen-antibody reaction and causes smooth muscle contraction and increased vascular permeability.

Asthma -- A form of bronchial disorder with three distinct components: airway hyper-responsiveness (RESPIRATORY HYPERSENSITIVITY), airway INFLAMMATION, and intermittent AIRWAY OBSTRUCTION. It is characterized by spasmodic contraction of airway smooth muscle, WHEEZING, and dyspnea (DYSPNEA, PAROXYSMAL).

Warnings

Anaphylactoid and Possibly Related ReactionsPresumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including benazepril/hydrochlorothiazide) may be subject to a variety of adverse reactions, some of them serious.Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors.

In U.S.

clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received benazepril.

Angioedema associated with laryngeal edema can be fatal.

If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with benazepril/hydrochlorothiazide should be discontinued and appropriate therapy instituted immediately.

When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection 1:1000 (0.3 to 0.5 mL) should be promptly administered (see PRECAUTIONS and ADVERSE REACTIONS).Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors.

These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.

The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor.

Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions.

In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor.

Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.HypotensionBenazepril/hydrochlorothiazide 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/hydrochlorothiazide.Benazepril/hydrochlorothiazide should be used cautiously in patients receiving concomitant therapy with other antihypertensives.

The thiazide component of benazepril/hydrochlorothiazide 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/hydrochlorothiazide 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 on a supine position, and, if necessary, treated with intravenous infusion of physiological saline.

Benazepril/hydrochlorothiazide treatment usually can be continued following restoration of blood pressure and volume.Impaired Renal FunctionBenazepril/hydrochlorothiazide 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 acuterenal 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/hydrochlorothiazide, renal function should be monitored during the first few weeks of therapy.

Some benazepril-treated hypertensive patients with no apparent preexisting 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).Neutropenia/AgranulocytosisAnother 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 1000 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.Fetal/Neonatal Morbidity and MortalityACE 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.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.These adverse effects do not appear to have resulted from intrauterine ACE inhibitor exposure that has been limited to the first trimester.

Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be informed.

Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of benazepril as soon as possible.Rarely (probably less often that 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 3000 and 1000 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.Hepatic FailureRarely, 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.Impaired Hepatic FunctionBenazepril/hydrochlorothiazide 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 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.

Systemic Lupus ErythematousThiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

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