Benazepril Hydrochloride And Hydrochlorothiazide Prescribing Information
Benazepril HCl and Hydrochlorothiazide is indicated for the treatment of hypertension.
Dose once daily. The dosage may then be increased after 2 to 3 weeks as needed to help achieve blood pressure goals. The maximum recommended dose is 20/25 mg.
Dose once daily. The dosage may then be increased after 2 to 3 weeks as needed to help achieve blood pressure goals. The maximum recommended dose is 20/25 mg.
Benazepril HCl and Hydrochlorothiazide is contraindicated in patients who are anuric.
Benazepril HCl and Hydrochlorothiazide is 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.
Benazepril HCl and Hydrochlorothiazide is also contraindicated in patients with a history of angioedema with or without previous ACE inhibitor treatment.
Benazepril HCl and Hydrochlorothiazide is contraindicated in combination with a neprilysin (e.g., sacubitril). Do not administer Benazepril HCl and Hydrochlorothiazide within 36 hours of switching to or from sacubitril/valsartan a neprilysin inhibitor
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including benazepril) may be subject to a variety of adverse reactions, some of them serious.
Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to nonblacks.
Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema
Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.
Benazepril HCl and 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 HCl and Hydrochlorothiazide.
Benazepril HCl and Hydrochlorothiazide should be used cautiously in patients receiving concomitant therapy with other antihypertensives. The thiazide component of Benazepril HCl and 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 HCl and 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 in a supine position, and, if necessary, treated with intravenous infusion of physiological saline. Benazepril HCl and Hydrochlorothiazide treatment usually can be continued following restoration of blood pressure and volume.
Monitor renal function periodically in patients treated with Benazepril HCl and Hydrochlorothiazide.
Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on Benazepril HCl and Hydrochlorothiazide. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Benazepril HCl and Hydrochlorothiazide.
In a small study of hypertensive patients with
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 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.
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Benazepril HCl and Hydrochlorothiazide as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Benazepril HCl and Hydrochlorothiazide, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of
No teratogenic effects of Benazepril HCl and hydrochlorothiazide were seen in studies of pregnant rats, mice, and rabbits. On a mg/m2basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and more than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50-kg woman). On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum recommended human dose. 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.
Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion. It accumulates in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not prevent or alter the course of EPH (Edema, Proteinuria, Hypertension) gestosis (pre-eclampsia), these drugs must not be used to treat hypertension in pregnant women. The use of hydrochlorothiazide for other indications (e.g., heart disease) in pregnancy should be avoided.
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.
Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
In clinical trials of Benazepril HCl and Hydrochlorothiazide, 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.
Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesema can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically.
Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.
Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.
Thiazides decrease urinary calcium excretion and may cause mild elevation of serum calcium. Avoid using Benazepril HCl and Hydrochlorothiazide in patients with hypercalcemia.
All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
The hydrochlorothiazide component of Benazepril HCl and Hydrochlorothiazide may decrease serum PBI levels without signs of thyroid disturbance.
Therapy with Benazepril HCl and Hydrochlorothiazide should be interrupted for a few days before carrying out tests of parathyroid function.
Patients taking concomitant neprilysin may be at increased risk for angioedema.
Do not coadminister aliskiren with Benazepril HCl and Hydrochlorothiazide in patients with diabetes. Avoid use of aliskiren with Benazepril HCl and Hydrochlorothiazide in patients with renal impairment (GFR < 60 mL/min).
The antihypertensive effect of benazepril and hydrochlorothiazide may be attenuated by NSAIDs.
Benazepril has been used concomitantly with beta-adrenergic-blocking agents, calcium-blocking agents, cimetidine, diuretics, digoxin, hydralazine, and naproxen without evidence of clinically important adverse interactions. Other ACE inhibitors have had less than additive effects with beta adrenergic blockers, presumably because drugs of both classes lower blood pressure by inhibiting parts of the renin-angiotensin system.
Interaction studies with warfarin and acenocoumarol have failed to identify any clinically important effects of benazepril on the serum concentrations or clinical effects of these anticoagulants.
Ion exchange resins: Stagger the dosage of hydrochlorothiazide and ion exchange resins such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.
No evidence of carcinogenicity was found when
Under the auspices of the National Toxicology Program, rats and mice received
Hydrochlorothiazide was not genotoxic in
There are no human fertility data for hydrochlorothiazide. In animal studies, benazepril and hydrochlorothiazide alone or in combination had no effect on fertility and conception
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 HCl and Hydrochlorothiazide, taking into account the importance of the drug to the mother.
Of the total number of patients who received Benazepril HCl and Hydrochlorothiazide in U.S. clinical studies of Benazepril HCl and Hydrochlorothiazide, 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.
A limited amount of data suggests that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a 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 with another ACE inhibitor, but experience is limited.
Safety and effectiveness in pediatric patients have not been established.
Safety and effectiveness of Benazepril HCl and Hydrochlorothiazide in patients with severe renal impairment (CrCL ≤ 30 mL/min) have not been established. No dose adjustment is required in patients with mild (CrCL 60 to 90 mL/min) or moderate (CrCL 30 to 60 mL/min) renal impairment.
No adjustment of the initial dose is required for patients with mild to moderate hepatic impairment
Minor alterations of fluid and electrolyte imbalance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.
Do not coadminister aliskiren with angiotensin receptor blockers, ACE inhibitors, including Benazepril HCl and Hydrochlorothiazide in patients with diabetes.
Benazepril HCl and Hydrochlorothiazide has been evaluated for safety in over 2500 patients with hypertension; over 500 of these patients were treated for at least 6 months, and over 200 were treated for more than 1 year.
The reported side effects were generally mild and transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy due to side effects was required in approximately 7% of U.S. patients treated with Benazepril HCl and Hydrochlorothiazide and in 4% of patients treated with placebo.
The most common reasons for discontinuation of therapy with Benazepril HCl and Hydrochlorothiazide in U.S. studies were cough (1.0%;
In clinical trials of Benazepril HCl and Hydrochlorothiazide, 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.
Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesema can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically.
Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.
Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.
Thiazides decrease urinary calcium excretion and may cause mild elevation of serum calcium. Avoid using Benazepril HCl and Hydrochlorothiazide in patients with hypercalcemia.
All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
The hydrochlorothiazide component of Benazepril HCl and Hydrochlorothiazide may decrease serum PBI levels without signs of thyroid disturbance.
Therapy with Benazepril HCl and Hydrochlorothiazide should be interrupted for a few days before carrying out tests of parathyroid function.
Patients taking concomitant neprilysin may be at increased risk for angioedema.
Do not coadminister aliskiren with Benazepril HCl and Hydrochlorothiazide in patients with diabetes. Avoid use of aliskiren with Benazepril HCl and Hydrochlorothiazide in patients with renal impairment (GFR < 60 mL/min).
The antihypertensive effect of benazepril and hydrochlorothiazide may be attenuated by NSAIDs.
Benazepril has been used concomitantly with beta-adrenergic-blocking agents, calcium-blocking agents, cimetidine, diuretics, digoxin, hydralazine, and naproxen without evidence of clinically important adverse interactions. Other ACE inhibitors have had less than additive effects with beta adrenergic blockers, presumably because drugs of both classes lower blood pressure by inhibiting parts of the renin-angiotensin system.
Interaction studies with warfarin and acenocoumarol have failed to identify any clinically important effects of benazepril on the serum concentrations or clinical effects of these anticoagulants.
Ion exchange resins: Stagger the dosage of hydrochlorothiazide and ion exchange resins such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.
No evidence of carcinogenicity was found when
Under the auspices of the National Toxicology Program, rats and mice received
Hydrochlorothiazide was not genotoxic in
There are no human fertility data for hydrochlorothiazide. In animal studies, benazepril and hydrochlorothiazide alone or in combination had no effect on fertility and conception
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 HCl and Hydrochlorothiazide, taking into account the importance of the drug to the mother.
Of the total number of patients who received Benazepril HCl and Hydrochlorothiazide in U.S. clinical studies of Benazepril HCl and Hydrochlorothiazide, 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.
A limited amount of data suggests that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a 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 with another ACE inhibitor, but experience is limited.
Safety and effectiveness in pediatric patients have not been established.
Safety and effectiveness of Benazepril HCl and Hydrochlorothiazide in patients with severe renal impairment (CrCL ≤ 30 mL/min) have not been established. No dose adjustment is required in patients with mild (CrCL 60 to 90 mL/min) or moderate (CrCL 30 to 60 mL/min) renal impairment.
No adjustment of the initial dose is required for patients with mild to moderate hepatic impairment
Minor alterations of fluid and electrolyte imbalance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.
The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with Benazepril HCl and Hydrochlorothiazide are shown in the table below.
Reactions Possibly or Probably Drug Related Patients in U.S. Placebo-Controlled Studies | ||||
Benazepril HCl and Hydrochlorothiazide N = 665 | Placebo N=235 | |||
N | % | N | % | |
“Dizziness” | 41 | 6.3 | 8 | 3.4 |
Fatigue | 34 | 5.2 | 6 | 2.6 |
Postural Dizziness | 23 | 3.5 | 1 | 0.4 |
Headache | 20 | 3.1 | 10 | 4.3 |
Cough | 14 | 2.1 | 3 | 1.3 |
Hypertonia | 10 | 1.5 | 3 | 1.3 |
Vertigo | 10 | 1.5 | 2 | 0.9 |
Nausea | 9 | 1.4 | 2 | 0.9 |
Impotence | 8 | 1.2 | 0 | 0.0 |
Somnolence | 8 | 1.2 | 1 | 0.4 |
Other side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in 0.3% to 1.0% of patients treated with Benazepril HCl and Hydrochlorothiazide were the following:
Other adverse experiences reported in 0.3% or more of Benazepril HCl and Hydrochlorothiazide patients in U.S. controlled clinical trials, and rarer events seen in post-marketing experience, were the following; asterisked entries occurred in more than 1% of patients (in some, a causal relationship to Benazepril HCl and Hydrochlorothiazide is uncertain):
The following adverse reactions have been identified during post-approval use of either benazepril or hydrochlorothiazide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure:
In clinical trials of Benazepril HCl and Hydrochlorothiazide, 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.
Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesema can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically.
Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.
Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.
Thiazides decrease urinary calcium excretion and may cause mild elevation of serum calcium. Avoid using Benazepril HCl and Hydrochlorothiazide in patients with hypercalcemia.
All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
The hydrochlorothiazide component of Benazepril HCl and Hydrochlorothiazide may decrease serum PBI levels without signs of thyroid disturbance.
Therapy with Benazepril HCl and Hydrochlorothiazide should be interrupted for a few days before carrying out tests of parathyroid function.
Patients taking concomitant neprilysin may be at increased risk for angioedema.
Do not coadminister aliskiren with Benazepril HCl and Hydrochlorothiazide in patients with diabetes. Avoid use of aliskiren with Benazepril HCl and Hydrochlorothiazide in patients with renal impairment (GFR < 60 mL/min).
The antihypertensive effect of benazepril and hydrochlorothiazide may be attenuated by NSAIDs.
Benazepril has been used concomitantly with beta-adrenergic-blocking agents, calcium-blocking agents, cimetidine, diuretics, digoxin, hydralazine, and naproxen without evidence of clinically important adverse interactions. Other ACE inhibitors have had less than additive effects with beta adrenergic blockers, presumably because drugs of both classes lower blood pressure by inhibiting parts of the renin-angiotensin system.
Interaction studies with warfarin and acenocoumarol have failed to identify any clinically important effects of benazepril on the serum concentrations or clinical effects of these anticoagulants.
Ion exchange resins: Stagger the dosage of hydrochlorothiazide and ion exchange resins such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.
No evidence of carcinogenicity was found when
Under the auspices of the National Toxicology Program, rats and mice received
Hydrochlorothiazide was not genotoxic in
There are no human fertility data for hydrochlorothiazide. In animal studies, benazepril and hydrochlorothiazide alone or in combination had no effect on fertility and conception
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 HCl and Hydrochlorothiazide, taking into account the importance of the drug to the mother.
Of the total number of patients who received Benazepril HCl and Hydrochlorothiazide in U.S. clinical studies of Benazepril HCl and Hydrochlorothiazide, 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.
A limited amount of data suggests that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a 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 with another ACE inhibitor, but experience is limited.
Safety and effectiveness in pediatric patients have not been established.
Safety and effectiveness of Benazepril HCl and Hydrochlorothiazide in patients with severe renal impairment (CrCL ≤ 30 mL/min) have not been established. No dose adjustment is required in patients with mild (CrCL 60 to 90 mL/min) or moderate (CrCL 30 to 60 mL/min) renal impairment.
No adjustment of the initial dose is required for patients with mild to moderate hepatic impairment
Minor alterations of fluid and electrolyte imbalance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.
In clinical trials of Benazepril HCl and Hydrochlorothiazide, 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.
Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesema can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically.
Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.
Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.
Thiazides decrease urinary calcium excretion and may cause mild elevation of serum calcium. Avoid using Benazepril HCl and Hydrochlorothiazide in patients with hypercalcemia.
All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
The hydrochlorothiazide component of Benazepril HCl and Hydrochlorothiazide may decrease serum PBI levels without signs of thyroid disturbance.
Therapy with Benazepril HCl and Hydrochlorothiazide should be interrupted for a few days before carrying out tests of parathyroid function.
Patients taking concomitant neprilysin may be at increased risk for angioedema.
Do not coadminister aliskiren with Benazepril HCl and Hydrochlorothiazide in patients with diabetes. Avoid use of aliskiren with Benazepril HCl and Hydrochlorothiazide in patients with renal impairment (GFR < 60 mL/min).
The antihypertensive effect of benazepril and hydrochlorothiazide may be attenuated by NSAIDs.
Benazepril has been used concomitantly with beta-adrenergic-blocking agents, calcium-blocking agents, cimetidine, diuretics, digoxin, hydralazine, and naproxen without evidence of clinically important adverse interactions. Other ACE inhibitors have had less than additive effects with beta adrenergic blockers, presumably because drugs of both classes lower blood pressure by inhibiting parts of the renin-angiotensin system.
Interaction studies with warfarin and acenocoumarol have failed to identify any clinically important effects of benazepril on the serum concentrations or clinical effects of these anticoagulants.
Ion exchange resins: Stagger the dosage of hydrochlorothiazide and ion exchange resins such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.
No evidence of carcinogenicity was found when
Under the auspices of the National Toxicology Program, rats and mice received
Hydrochlorothiazide was not genotoxic in
There are no human fertility data for hydrochlorothiazide. In animal studies, benazepril and hydrochlorothiazide alone or in combination had no effect on fertility and conception
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 HCl and Hydrochlorothiazide, taking into account the importance of the drug to the mother.
Of the total number of patients who received Benazepril HCl and Hydrochlorothiazide in U.S. clinical studies of Benazepril HCl and Hydrochlorothiazide, 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.
A limited amount of data suggests that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a 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 with another ACE inhibitor, but experience is limited.
Safety and effectiveness in pediatric patients have not been established.
Safety and effectiveness of Benazepril HCl and Hydrochlorothiazide in patients with severe renal impairment (CrCL ≤ 30 mL/min) have not been established. No dose adjustment is required in patients with mild (CrCL 60 to 90 mL/min) or moderate (CrCL 30 to 60 mL/min) renal impairment.
No adjustment of the initial dose is required for patients with mild to moderate hepatic impairment
Minor alterations of fluid and electrolyte imbalance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.
Patients taking concomitant neprilysin may be at increased risk for angioedema.
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including benazepril) may be subject to a variety of adverse reactions, some of them serious.
Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to nonblacks.
Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema
Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.
Benazepril HCl and 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 HCl and Hydrochlorothiazide.
Benazepril HCl and Hydrochlorothiazide should be used cautiously in patients receiving concomitant therapy with other antihypertensives. The thiazide component of Benazepril HCl and 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 HCl and 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 in a supine position, and, if necessary, treated with intravenous infusion of physiological saline. Benazepril HCl and Hydrochlorothiazide treatment usually can be continued following restoration of blood pressure and volume.
Monitor renal function periodically in patients treated with Benazepril HCl and Hydrochlorothiazide.
Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on Benazepril HCl and Hydrochlorothiazide. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Benazepril HCl and Hydrochlorothiazide.
In a small study of hypertensive patients with
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 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.
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Benazepril HCl and Hydrochlorothiazide as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Benazepril HCl and Hydrochlorothiazide, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of
No teratogenic effects of Benazepril HCl and hydrochlorothiazide were seen in studies of pregnant rats, mice, and rabbits. On a mg/m2basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and more than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50-kg woman). On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum recommended human dose. 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.
Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion. It accumulates in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not prevent or alter the course of EPH (Edema, Proteinuria, Hypertension) gestosis (pre-eclampsia), these drugs must not be used to treat hypertension in pregnant women. The use of hydrochlorothiazide for other indications (e.g., heart disease) in pregnancy should be avoided.
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.
Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Do not coadminister aliskiren with Benazepril HCl and Hydrochlorothiazide in patients with diabetes. Avoid use of aliskiren with Benazepril HCl and Hydrochlorothiazide in patients with renal impairment (GFR < 60 mL/min).
The antihypertensive effect of benazepril and hydrochlorothiazide may be attenuated by NSAIDs.
Benazepril has been used concomitantly with beta-adrenergic-blocking agents, calcium-blocking agents, cimetidine, diuretics, digoxin, hydralazine, and naproxen without evidence of clinically important adverse interactions. Other ACE inhibitors have had less than additive effects with beta adrenergic blockers, presumably because drugs of both classes lower blood pressure by inhibiting parts of the renin-angiotensin system.
Interaction studies with warfarin and acenocoumarol have failed to identify any clinically important effects of benazepril on the serum concentrations or clinical effects of these anticoagulants.
Ion exchange resins: Stagger the dosage of hydrochlorothiazide and ion exchange resins such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.