Benazepril hydrochloride/Hydrochlorothiazide

Description

Benazepril hydrochloride USP is a white to off-white crystalline powder, soluble in water (>100 mg/mL), ethanol, and methanol. Its chemical name is 3-[1-(ethoxycarbonyl)-3-phenyl-(1S)-propylamino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid monohydrochloride, with an empirical formula of C24H28N2O5·HCl and a molecular weight of 460.96. Hydrochlorothiazide USP is a white, or practically white, practically odorless, crystalline powder. It is slightly soluble in water, freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide; sparingly soluble in methanol; and insoluble in ether, chloroform, and dilute mineral acids. Hydrochlorothiazide's chemical name is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with an empirical formula of C7H8ClN3O4S2 and a molecular weight of 297.73. The combination of benazepril HCl and hydrochlorothiazide is formulated in tablets for oral administration, containing either 10 or 20 mg of benazepril and 12.5 or 25 mg of hydrochlorothiazide USP. The inactive ingredients in the tablets include cellulose compounds, crospovidone, hydrogenated castor oil, iron oxides (in the 10/12.5 mg, 20/12.5 mg, and 20/25 mg tablets), lactose, polyethylene glycol, talc, and titanium dioxide.

Uses and Indications

Benazepril HCl and Hydrochlorothiazide is indicated for the treatment of hypertension in patients who require multiple antihypertensive agents to achieve adequate blood pressure control.

Limitations of Use: This fixed combination drug is not indicated for the initial therapy of hypertension. It is intended for use in patients who have not achieved target blood pressure with monotherapy or who require additional blood pressure-lowering effects.

Dosage and Administration

The recommended dosing regimen for the combination of Benazepril HCl and Hydrochlorothiazide is once daily. Initial therapy should begin with a dose of 10/12.5 mg, particularly for patients whose blood pressure is not adequately controlled with either benazepril or hydrochlorothiazide alone.

After an initial period of 2 to 3 weeks, the dosage may be increased as necessary to achieve desired blood pressure goals, with a maximum recommended dose of 20/25 mg.

For patients transitioning from individual components, the combination therapy may be used as a replacement for the titrated doses of benazepril and hydrochlorothiazide. It is essential for healthcare professionals to monitor blood pressure regularly and adjust the dosage accordingly to ensure optimal therapeutic outcomes.

Contraindications

Benazepril HCl and Hydrochlorothiazide is contraindicated in patients who are anuric. It is also contraindicated in individuals with hypersensitivity to benazepril, any other ACE inhibitor, hydrochlorothiazide, or other sulfonamide-derived drugs, as hypersensitivity reactions are more likely in those with a history of allergy or bronchial asthma. Additionally, the use of this combination is contraindicated in patients with a history of angioedema, regardless of previous ACE inhibitor treatment.

The administration of Benazepril HCl and Hydrochlorothiazide is contraindicated in conjunction with neprilysin inhibitors, such as sacubitril. It is essential to avoid administering this medication within 36 hours of switching to or from sacubitril/valsartan. Furthermore, coadministration of aliskiren with angiotensin receptor blockers or ACE inhibitors, including Benazepril HCl and Hydrochlorothiazide, is contraindicated in patients with diabetes.

Warnings and Precautions

Patients receiving Benazepril HCl and Hydrochlorothiazide should be aware of several critical warnings and precautions associated with their use.

Anaphylactoid and Possibly Related Reactions Patients may experience serious adverse reactions, including angioedema affecting the face, extremities, lips, tongue, glottis, and larynx. Angioedema associated with laryngeal edema can be life-threatening. In the event of laryngeal stridor or angioedema of the face, tongue, or glottis, treatment must be discontinued immediately, and appropriate medical intervention should be initiated. Notably, black patients have a higher incidence of angioedema compared to nonblack patients. Additionally, coadministration of an ACE inhibitor with an mTOR inhibitor or a neprilysin inhibitor may increase the risk of angioedema. Intestinal angioedema has also been reported, with symptoms resolving upon discontinuation of the ACE inhibitor. Anaphylactoid reactions have been documented in patients undergoing dialysis with high-flux membranes while receiving an ACE inhibitor. Furthermore, hypersensitivity reactions to hydrochlorothiazide are more prevalent in patients with a history of allergy and asthma.

Hypotension Benazepril HCl and Hydrochlorothiazide can lead to symptomatic hypotension, particularly in patients who are volume- or salt-depleted. In individuals with congestive heart failure, ACE inhibitor therapy may result in excessive hypotension, which can be associated with oliguria, azotemia, and, in rare cases, acute renal failure and death.

Impaired Renal Function Regular monitoring of renal function is essential for patients on Benazepril HCl and Hydrochlorothiazide. Consideration should be given to withholding or discontinuing therapy in patients who exhibit a clinically significant decline in renal function.

Neutropenia/Agranulocytosis Patients with collagen vascular disease, especially those with concurrent renal impairment, should have their white blood cell counts monitored.

Fetal Toxicity The use of medications that affect the renin-angiotensin system during the second and third trimesters of pregnancy can impair fetal renal function and increase the risk of fetal and neonatal morbidity and mortality. Upon detection of pregnancy, Benazepril HCl and Hydrochlorothiazide should be discontinued as soon as possible.

Hepatic Failure Patients receiving ACE inhibitors who develop jaundice or significant elevations in hepatic enzymes should discontinue the medication and seek appropriate medical follow-up.

Systemic Lupus Erythematosus Thiazide diuretics, including hydrochlorothiazide, have been associated with exacerbation or activation of systemic lupus erythematosus.

Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide may induce an idiosyncratic reaction leading to acute transient myopia and acute angle-closure glaucoma. The primary course of action is to discontinue hydrochlorothiazide as quickly as possible.

General Precautions Periodic monitoring of serum electrolytes is recommended, as hydrochlorothiazide can cause hypokalemia and hyponatremia, while drugs that inhibit the renin-angiotensin system may lead to hyperkalemia.

Laboratory Tests The hydrochlorothiazide component may reduce serum PBI levels without indicating thyroid dysfunction. It is advisable to interrupt therapy with Benazepril HCl and Hydrochlorothiazide for several days prior to conducting tests of parathyroid function.

Emergency Medical Help Immediate medical assistance is required if laryngeal stridor or angioedema of the face, tongue, or glottis occurs, necessitating the discontinuation of treatment and prompt intervention.

Management of Hypotension In cases of hypotension, the patient should be positioned supine, and intravenous infusion of physiological saline may be necessary for treatment.

Side Effects

Adverse reactions reported in clinical trials and post-marketing experiences include a range of serious and common effects.

Among the reactions possibly or probably related to the drug, dizziness was reported in 6.3% of patients (41 patients), followed by fatigue at 5.2% (34 patients). Other common adverse reactions included postural dizziness (3.5%, 23 patients), headache (3.1%, 20 patients), cough (2.1%, 14 patients), hypertonia (1.5%, 10 patients), vertigo (1.5%, 10 patients), nausea (1.4%, 9 patients), impotence (1.2%, 8 patients), and somnolence (1.2%, 8 patients).

Additional side effects occurring in 0.3% to 1.0% of patients encompassed cardiovascular issues such as palpitations and flushing, gastrointestinal disturbances including vomiting, diarrhea, dyspepsia, anorexia, and constipation, as well as neurologic and psychiatric symptoms like insomnia, nervousness, paresthesia, decreased libido, dry mouth, taste perversion, and tinnitus. Dermatologic reactions included rash and sweating, while other reported effects involved urinary frequency, arthralgia, myalgia, asthenia, and various types of pain, including chest and abdominal pain.

Serious adverse reactions noted in post-marketing experiences included Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, and thrombocytopenia. Cardiovascular events such as syncope, peripheral vascular disorder, and tachycardia were also reported. Other serious reactions involved infections, back pain, flu syndrome, fever, chills, and neck pain. Dermatologic reactions included photosensitivity and pruritus, while gastrointestinal issues such as gastroenteritis, flatulence, and tooth disorders were also observed.

Neurologic and psychiatric adverse reactions included hypesthesia, abnormal vision, abnormal dreams, and retinal disorders. Respiratory issues such as upper respiratory infections, epistaxis, bronchitis, rhinitis, sinusitis, and voice alteration were documented. Additional reactions included conjunctivitis, arthritis, urinary tract infections, alopecia, and urinary frequency.

Post-marketing experience has also revealed neurologic effects such as vertigo, lightheadedness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, and restlessness. Hematologic concerns included aplastic anemia, agranulocytosis, leukopenia, neutropenia, and thrombocytopenia. Metabolic reactions such as hyperglycemia, glycosuria, hyperuricemia, pyrexia, and changes in parathyroid gland function with hypercalcemia and hypophosphatemia were noted. Hypersensitivity reactions included anaphylactoid responses, necrotizing angiitis, respiratory distress (including pneumonitis and pulmonary edema), purpura, urticaria, rash, and photosensitivity. Skin reactions reported included erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, and toxic epidermal necrolysis.

Drug Interactions

Patients receiving concomitant neprilysin inhibitors may experience an increased risk of angioedema. Similarly, the coadministration of ACE inhibitors, including Benazepril HCl, with mTOR inhibitors such as temsirolimus, sirolimus, or everolimus also raises the risk of angioedema.

When Benazepril HCl and Hydrochlorothiazide are used together, there may be an impact on potassium levels; therefore, periodic monitoring of potassium is advised. Additionally, thiazides can reduce the renal clearance of lithium, which may lead to lithium toxicity; thus, monitoring of lithium levels is recommended during coadministration with Benazepril HCl and Hydrochlorothiazide.

The dual blockade of the renin-angiotensin system (RAS) through the combined use of angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with heightened risks of hypertension, hyperkalemia, and alterations in renal function. Therefore, such combinations should be avoided. Specifically, aliskiren should not be coadministered with Benazepril HCl and Hydrochlorothiazide in patients with diabetes or renal impairment (GFR < 60 mL/min).

Coadministration of nonsteroidal anti-inflammatory drugs (NSAIDs) with ACE inhibitors, including Benazepril, may lead to a deterioration in renal function; renal function should be monitored periodically in these patients. Furthermore, the antihypertensive effects of Benazepril and Hydrochlorothiazide may be diminished by NSAIDs.

Interaction studies have shown no clinically significant effects of Benazepril on anticoagulants such as warfarin and acenocoumarol. However, nitritoid reactions have been reported infrequently in patients receiving injectable gold alongside ACE inhibitors.

For patients taking hydrochlorothiazide, it is recommended to stagger the dosage of hydrochlorothiazide and ion exchange resins by administering hydrochlorothiazide at least 4 hours before or 4 to 6 hours after the resins. Thiazide-induced hypokalemia or hypomagnesemia may increase the risk of digoxin toxicity, and there may be an increased responsiveness to muscle relaxants, such as curare derivatives, when hydrochlorothiazide is used.

Dosage adjustments of antidiabetic medications may be necessary when hydrochlorothiazide is administered. Additionally, the use of thiazide diuretics may reduce the renal excretion of certain antineoplastic agents (e.g., cyclophosphamide, methotrexate), potentially enhancing their myelosuppressive effects. The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents due to decreased gastrointestinal motility.

Coadministration of thiazide diuretics with cyclosporin may elevate the risk of hyperuricemia and gout-type complications. Furthermore, the combination of thiazide diuretics with alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension. Hydrochlorothiazide may also diminish the response to pressor amines such as noradrenaline, although the clinical significance of this interaction is not sufficient to contraindicate their use.

Packaging & NDC

The table below lists all NDC Code configurations of Benazepril Hydrochloride and Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Pediatric patients, particularly neonates with a history of in utero exposure to Benazepril HCl and Hydrochlorothiazide, may experience complications such as oliguria or hypotension. In such cases, it is crucial to focus on supporting blood pressure and renal perfusion. Interventions such as exchange transfusions or dialysis may be necessary to address hypotension and/or to compensate for impaired renal function. Although Benazepril can cross the placenta and may theoretically be removed from the neonatal circulation through these procedures, reports of benefit from similar interventions with other ACE inhibitors are limited.

The safety and effectiveness of Benazepril HCl and Hydrochlorothiazide in pediatric patients have not been established, and caution is advised when considering its use in this population.

Geriatric Use

In clinical studies involving Benazepril HCl and Hydrochlorothiazide, 19% of the total patient population were aged 65 years or older, with approximately 1.5% being 75 years or older. The data indicate that there were no overall differences in effectiveness or safety between elderly patients and their younger counterparts.

However, it is important to note that a limited amount of data suggests a reduction in the systemic clearance of hydrochlorothiazide in both healthy and hypertensive elderly subjects when compared to young healthy volunteers. This may necessitate careful monitoring and consideration of dose adjustments in geriatric patients to ensure optimal therapeutic outcomes and minimize the risk of adverse effects.

Pregnancy

Pregnant patients should be aware that benazepril and hydrochlorothiazide have not demonstrated any evidence of carcinogenicity in animal studies, with no adverse effects observed in rats and mice administered doses up to 150 mg/kg/day of benazepril over a 104-week period. Additionally, hydrochlorothiazide has shown no genotoxic effects in various in vitro assays, including tests with Salmonella typhimurium.

Currently, there are no available human fertility data for hydrochlorothiazide. However, animal studies indicate that neither benazepril nor hydrochlorothiazide, whether administered alone or in combination, adversely affected fertility or conception outcomes.

Healthcare professionals should consider these findings when prescribing these medications to women of childbearing potential and weigh the benefits against any potential risks during pregnancy.

Lactation

Minimal amounts of unchanged benazepril and benazeprilat are excreted into the breast milk of lactating mothers treated with benazepril. A breastfed infant would receive less than 0.1% of the maternal doses of benazepril and benazeprilat through breast milk. In contrast, thiazides, including hydrochlorothiazide, are definitively excreted into breast milk.

Due to the potential for serious adverse reactions in nursing infants from hydrochlorothiazide and the unknown effects of benazepril in infants, healthcare professionals should consider the risks and benefits when advising lactating mothers. A decision should be made whether to discontinue nursing or to discontinue the use of Benazepril HCl and Hydrochlorothiazide, taking into account the importance of the medication to the mother.

Renal Impairment

Patients with renal impairment should have their renal function monitored periodically while being treated with Benazepril HCl and Hydrochlorothiazide. These medications can lead to changes in renal function, including acute renal failure, particularly in patients whose renal function may be influenced by the renin-angiotensin system, such as those with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion.

In cases where a clinically significant decrease in renal function occurs, it may be necessary to withhold or discontinue therapy. A small study involving hypertensive patients with unilateral or bilateral renal artery stenosis indicated that 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.

Additionally, it is important to note that another angiotensin-converting enzyme inhibitor, captopril, has been linked to agranulocytosis and bone marrow depression, with a higher incidence in patients with renal impairment, particularly those with collagen-vascular diseases such as systemic lupus erythematosus or scleroderma. Therefore, monitoring of white blood cell counts should be considered in patients with collagen vascular disease, especially if associated with impaired renal function.

Hepatic Impairment

Patients with hepatic impairment may experience an increased risk of adverse effects when treated with ACE inhibitors. Rarely, these medications have been associated with a syndrome characterized by cholestatic jaundice, which can progress to fulminant hepatic necrosis and, in some cases, result in death. The underlying mechanism of this syndrome remains unclear.

In patients receiving ACE inhibitors, the development of jaundice or significant elevations in hepatic enzymes necessitates the immediate discontinuation of the ACE inhibitor. Furthermore, these patients should receive appropriate medical follow-up to monitor liver function and manage any complications that may arise. Regular assessment of liver enzymes is recommended to ensure patient safety and to guide further therapeutic decisions.

Overdosage

In cases of overdosage with Benazepril HCl and Hydrochlorothiazide, specific treatment information is limited. Management should focus on symptomatic and supportive care.

Clinical Manifestations of Overdosage

In animal studies, single oral doses of 1 g/kg of benazepril resulted in reduced activity, while doses of 3 g/kg were linked to significant lethality. In humans, the most frequently observed symptom of benazepril overdose is hypotension. For hydrochlorothiazide, common signs and symptoms include dehydration and electrolyte imbalances, particularly hypokalemia, hypochloremia, and hyponatremia. It is important to note that if digitalis has been administered concurrently, hypokalemia may exacerbate the risk of cardiac arrhythmias.

Management Strategies

Due to the lack of widely available laboratory determinations for serum levels of benazepril and its metabolites, these tests do not play a significant role in the management of overdose. Although benazeprilat is only slightly dialyzable, dialysis may be considered for patients with severely impaired renal function.

In the context of benazepril overdose, the infusion of normal saline solution is a reasonable approach to manage fluid balance. While angiotensin II could theoretically act as a specific antagonist-antidote in cases of benazepril overdose, it is generally unavailable outside of research settings.

Healthcare professionals should remain vigilant for the signs of dehydration and electrolyte depletion in patients who have overdosed on hydrochlorothiazide, and appropriate corrective measures should be taken.

Nonclinical Toxicology

No relevant information was found regarding teratogenic effects. In studies assessing non-teratogenic effects, there were no human fertility data available for hydrochlorothiazide. However, animal studies indicated that benazepril and hydrochlorothiazide, either alone or in combination, did not affect fertility or conception.

In terms of carcinogenicity, no evidence of carcinogenic potential was observed when benazepril was administered to rats and mice for 104 weeks at doses up to 150 mg/kg/day. This dose corresponds to 18 times the maximum recommended human dose for rats and 9 times for mice, based on body-surface-area calculations. Similarly, hydrochlorothiazide was evaluated in long-term studies conducted by the National Toxicology Program, where rats and mice received the compound in their feed for 2 years at doses up to 600 mg/kg/day in mice and 100 mg/kg/day in rats. These studies revealed no evidence of carcinogenicity in rats or female mice, although equivocal evidence of hepatocarcinogenicity was noted in male mice.

Regarding mutagenicity, no mutagenic activity was detected in the Ames test using bacteria, both with and without metabolic activation, nor in an in vitro test for forward mutations in cultured mammalian cells or in a nucleus anomaly test. However, positive results were obtained in the in vitro CHO Sister Chromatid Exchange test and in Mouse Lymphoma Cell assays at hydrochlorothiazide concentrations ranging from 43 to 1300 μg/mL. Additionally, positive results were observed in the Aspergillus nidulans nondisjunction assay at an unspecified concentration of hydrochlorothiazide.

In reproductive performance assessments, benazepril administered at doses of 50-500 mg/kg/day, which is 6 to 61 times the maximum recommended dose on a body-surface-area basis, did not adversely affect the reproductive performance of male and female rats. Hydrochlorothiazide was found to be non-genotoxic in various in vitro assays, including tests using strains of Salmonella typhimurium and the Chinese Hamster Ovary test for chromosomal aberrations, as well as in vivo assays involving mouse germinal cell chromosomes and Chinese hamster bone marrow chromosomes.

Postmarketing Experience

Postmarketing experience has identified several adverse events associated with the use of hydrochlorothiazide and benazepril, reported voluntarily or through surveillance programs.

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), especially in white patients receiving large cumulative doses. In a study conducted within the Sentinel System, the overall risk for SCC was estimated at approximately 1 additional case per 16,000 patients per year. For white patients taking a cumulative dose of ≥50,000 mg, the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

Additional adverse events reported with hydrochlorothiazide include:

Digestive System: Pancreatitis, small bowel angioedema, intrahepatic cholestatic jaundice, sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, and anorexia.

Neurologic: Vertigo, lightheadedness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, and restlessness.

Musculoskeletal: Muscle spasm.

Hematologic: Aplastic anemia, agranulocytosis, leukopenia, neutropenia, and thrombocytopenia.

Metabolic: Hyperglycemia, glycosuria, hyperuricemia, pyrexia, asthenia, and parathyroid gland changes associated with hypercalcemia and hypophosphatemia.

Hypersensitivity Reactions: Anaphylactoid reactions, necrotizing angiitis, respiratory distress (including pneumonitis and pulmonary edema), purpura, urticaria, rash, and photosensitivity.

Skin Reactions: Erythema multiforme, including Stevens-Johnson syndrome, and exfoliative dermatitis, including toxic epidermal necrolysis.

Benazepril has been associated with Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, thrombocytopenia, and eosinophilic pneumonitis.

These events highlight the importance of ongoing monitoring and reporting in the postmarketing phase to ensure patient safety.

Patient Counseling

Patients should be informed about the risk of angioedema, including laryngeal edema, which can occur at any time during treatment with Benazepril HCl and Hydrochlorothiazide. They should be advised to report immediately any signs or symptoms of angioedema, such as swelling of the face, eyes, lips, or tongue, or difficulty in breathing. Patients must be instructed to refrain from taking any additional medications until they have consulted with their prescribing physician.

Female patients of childbearing age should be made aware of the potential consequences of exposure to Benazepril HCl and Hydrochlorothiazide during pregnancy. Healthcare providers should discuss treatment options with women who are planning to become pregnant and encourage patients to report any pregnancies to their physicians as soon as possible.

Patients receiving Benazepril HCl and Hydrochlorothiazide should be cautioned about the possibility of symptomatic hypotension, particularly during the initial days of therapy. They should be advised to report any episodes of lightheadedness to their prescribing physician. In the event of syncope, patients should discontinue the medication and consult their physician. Additionally, patients should be informed that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting may lead to a significant drop in blood pressure, resulting in lightheadedness and potential syncope.

Patients should be instructed not to use potassium supplements or salt substitutes containing potassium without prior consultation with their prescribing physician, as hyperkalemia may occur.

Patients should also be advised to promptly report any signs of infection, such as a sore throat or fever, as these may indicate neutropenia.

For those taking hydrochlorothiazide, it is important to instruct patients to protect their skin from sun exposure and to undergo regular skin cancer screenings, as there is an increased risk of non-melanoma skin cancer associated with this medication.

Storage and Handling

The product is supplied in a tight, light-resistant container as per USP standards. It is essential to store the product in a location where the temperature does not exceed 86°F (30°C). Additionally, the product must be protected from moisture and light to maintain its integrity and efficacy.

Additional Clinical Information

The hydrochlorothiazide component of Benazepril HCl and Hydrochlorothiazide may lead to a decrease in serum protein-bound iodine (PBI) levels, although this effect does not indicate any thyroid disturbance in patients. Clinicians are advised to interrupt therapy with Benazepril HCl and Hydrochlorothiazide for several days prior to conducting tests to assess parathyroid function to ensure accurate results.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Benazepril Hydrochloride and Hydrochlorothiazide as submitted by Padagis US LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)