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 require additional blood pressure reduction.

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. After 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 whose blood pressure is not adequately controlled with either benazepril alone or hydrochlorothiazide alone, a switch to combination therapy with Benazepril HCl and Hydrochlorothiazide is advised.

In cases where patients are transitioning from individual components, the combination therapy may be used as a replacement for the titrated doses of benazepril and hydrochlorothiazide. It is essential to monitor blood pressure regularly to ensure effective management and adjust the dosage accordingly.

Contraindications

Benazepril HCl and Hydrochlorothiazide is contraindicated in the following situations:

Patients who are anuric.

Patients with hypersensitivity to benazepril, any other ACE inhibitor, hydrochlorothiazide, or other sulfonamide-derived drugs, as hypersensitivity reactions are more likely in individuals with a history of allergy or bronchial asthma.

Patients with a history of angioedema, with or without previous ACE inhibitor treatment.

Concurrent use with neprilysin inhibitors, such as sacubitril, is contraindicated. Benazepril HCl and Hydrochlorothiazide should not be administered within 36 hours of switching to or from sacubitril/valsartan.

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 ACE inhibitors, including benazepril, may experience a range of adverse reactions, some of which can be serious.

Anaphylactoid and Possibly Related Reactions

Angioedema, which can affect the face, extremities, lips, tongue, glottis, and larynx, has been reported in patients. In cases of laryngeal stridor or angioedema, it is imperative to discontinue treatment immediately and initiate appropriate therapy. Notably, black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblack patients. Additionally, patients receiving concurrent therapy with an ACE inhibitor and an mTOR inhibitor or a neprilysin inhibitor may be at an increased risk for angioedema. Intestinal angioedema has also been documented in patients treated with ACE inhibitors, often diagnosed through abdominal CT scans, ultrasounds, or surgical procedures.

Anaphylactoid reactions have been observed during desensitization treatments in patients on ACE inhibitors, as well as in those undergoing dialysis with high-flux membranes. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with a history of allergies or asthma.

Hypotension and Renal Function

ACE inhibitors can lead to symptomatic hypotension, particularly in patients who are volume- or salt-depleted. Regular monitoring of renal function is recommended, and therapy should be reconsidered in patients experiencing significant renal function decline.

Hematological Concerns

Patients with collagen vascular disease should have their white blood cell counts monitored due to the risk of neutropenia or agranulocytosis.

Fetal Toxicity and Hepatic Concerns

The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy poses a risk of injury or death to the developing fetus. If jaundice or marked elevations in hepatic enzymes occur, ACE inhibitors should be discontinued.

Systemic Conditions and Ocular Effects

Thiazide diuretics may exacerbate or activate systemic lupus erythematosus. Hydrochlorothiazide has been associated with acute myopia and secondary angle-closure glaucoma, which may occur as an idiosyncratic reaction.

General Precautions

Healthcare professionals should monitor serum electrolytes periodically due to the potential for hypokalemia, hyponatremia, and hyperkalemia. Hydrochlorothiazide may also affect glucose tolerance and increase serum cholesterol and triglyceride levels. It is advised to avoid the use of benazepril HCl and hydrochlorothiazide in patients with hypercalcemia. Additionally, a persistent nonproductive cough has been reported with ACE inhibitors.

Laboratory Tests

The hydrochlorothiazide component may decrease serum PBI levels without indicating thyroid disturbance. It is recommended to interrupt therapy for a few days prior to conducting tests of parathyroid function.

Emergency Medical Help

In the event of laryngeal stridor or angioedema affecting the face, tongue, or glottis, treatment should be discontinued immediately, and appropriate medical intervention should be sought.

Management of Hypotension

If hypotension occurs, the patient should be placed in a supine position, and intravenous infusion of physiological saline should be administered as necessary.

Side Effects

Patients receiving treatment with Benazepril HCl and Hydrochlorothiazide may experience a range of adverse reactions. The most common adverse reactions reported in clinical trials include cough (1.0%), dizziness (1.0%), headache (0.6%), and fatigue (0.6%).

In a clinical trial involving 665 participants treated with Benazepril HCl and Hydrochlorothiazide, the following reactions were observed at higher frequencies: dizziness (6.3%), fatigue (5.2%), postural dizziness (3.5%), headache (3.1%), cough (2.1%), hypertonia (1.5%), vertigo (1.5%), nausea (1.4%), impotence (1.2%), and somnolence (1.2%). In comparison, participants receiving placebo (N = 235) reported dizziness (3.4%), fatigue (2.6%), headache (4.3%), cough (1.3%), and hypertonia (1.3%).

Other adverse reactions occurring in 0.3% to 1.0% of patients include cardiovascular effects such as palpitations and flushing; gastrointestinal issues like vomiting, diarrhea, dyspepsia, anorexia, and constipation; neurologic and psychiatric symptoms including insomnia, nervousness, paresthesia, decreased libido, dry mouth, taste perversion, and tinnitus; dermatologic reactions such as rash and sweating; and various other effects including urinary frequency, arthralgia, myalgia, asthenia, and pain (including chest and abdominal pain).

Additional adverse reactions noted include cardiovascular events such as syncope, peripheral vascular disorder, and tachycardia; systemic reactions like infection, back pain, flu syndrome, fever, chills, and neck pain; dermatologic issues including photosensitivity and pruritus; gastrointestinal disturbances such as gastroenteritis, flatulence, and tooth disorder; neurologic and psychiatric effects like hypesthesia, abnormal vision, abnormal dreams, and retinal disorder; respiratory issues including upper respiratory infection, epistaxis, bronchitis, rhinitis, sinusitis, and voice alteration; and other reactions such as conjunctivitis, arthritis, urinary tract infection, alopecia, and urinary frequency.

Post-marketing experience has revealed additional serious adverse reactions associated with Benazepril, including Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, thrombocytopenia, and eosinophilic pneumonitis. Hydrochlorothiazide has been associated with pancreatitis, small bowel angioedema, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, and anorexia.

Neurologic adverse reactions reported post-marketing include vertigo, lightheadedness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, and restlessness. Hematologic reactions such as aplastic anemia, agranulocytosis, leukopenia, neutropenia, and thrombocytopenia have also been noted. Metabolic effects include hyperglycemia, glycosuria, hyperuricemia, pyrexia, asthenia, and parathyroid gland changes with hypercalcemia and hypophosphatemia.

Hypersensitivity reactions may occur, including anaphylactoid reactions, necrotizing angiitis, respiratory distress (including pneumonitis and pulmonary edema), purpura, urticaria, rash, and photosensitivity. Skin reactions can include erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, and toxic epidermal necrolysis.

Drug Interactions

Patients receiving concomitant therapy with neprilysin inhibitors may experience an increased risk of angioedema.

When Benazepril HCl and Hydrochlorothiazide are used together with potassium supplements or potassium-sparing diuretics, there is a potential for altered potassium levels; therefore, periodic monitoring of potassium is advised. Additionally, the coadministration of ACE inhibitors and mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus) may also elevate the risk of angioedema.

Thiazide diuretics, such as Hydrochlorothiazide, can reduce the renal clearance of lithium, which may lead to lithium toxicity; thus, monitoring of lithium levels is recommended when these medications are used together. Furthermore, the dual blockade of the renin-angiotensin system (RAS) with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with heightened risks of hypertension, hyperkalemia, and alterations in renal function; combined use 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).

The use of NSAIDs, including selective COX-2 inhibitors, in conjunction with ACE inhibitors may lead to deterioration of renal function; renal function should be monitored periodically. Additionally, the antihypertensive effects of Benazepril and Hydrochlorothiazide may be diminished by NSAID use.

Interaction studies have not demonstrated 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.

To avoid reduced absorption, it is recommended to stagger the administration of Hydrochlorothiazide and ion exchange resins, taking 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. There may also 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.

Coadministration of thiazide diuretics with antineoplastic agents (e.g., cyclophosphamide, methotrexate) may reduce renal excretion and enhance myelosuppressive effects. The bioavailability of thiazide diuretics may be increased by anticholinergic agents due to decreased gastrointestinal motility, while prokinetic drugs may decrease their bioavailability.

Finally, the concomitant use of diuretics may elevate the risk of hyperuricemia and gout-type complications when used with cyclosporin. Additionally, thiazide diuretics may potentiate orthostatic hypotension when administered with alcohol, barbiturates, or narcotics. Hydrochlorothiazide may also diminish the response to pressor amines such as noradrenaline, although this effect is not significant enough 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

Safety and effectiveness in pediatric patients have not been established. In neonates with a history of in utero exposure to Benazepril HCl and Hydrochlorothiazide, if oliguria or hypotension occurs, it is crucial to provide support for blood pressure and renal perfusion. In such cases, exchange transfusions or dialysis may be necessary to reverse hypotension and/or address impaired renal function. Benazepril, which crosses the placenta, may theoretically be removed from the neonatal circulation through these interventions. However, reports of benefit from similar maneuvers with other ACE inhibitors are limited, and clinical experience is sparse.

Geriatric Use

In clinical studies involving Benazepril HCl and Hydrochlorothiazide, 19% of the total patient population was aged 65 years or older, with approximately 1.5% of patients 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 finding 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. Specifically, studies conducted over 104 weeks in rats and mice at doses up to 150 mg/kg/day did not reveal any carcinogenic effects associated with benazepril. Additionally, hydrochlorothiazide has shown no genotoxicity in in vitro assays using various strains of Salmonella typhimurium.

It is important to note that 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 discuss the potential risks and benefits with their patients.

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 breastfeeding or to discontinue 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 dependent on the activity of the renin-angiotensin system. This includes individuals with conditions such as renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion, who may be at an increased risk of developing acute renal failure.

In cases where a clinically significant decrease in renal function occurs, it is advisable to consider withholding or discontinuing therapy with Benazepril HCl and Hydrochlorothiazide. Clinical findings from 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 associated with agranulocytosis and bone marrow depression more frequently 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 the disease is 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, if jaundice or significant elevations in hepatic enzymes are observed, it is imperative to discontinue the ACE inhibitor immediately. Appropriate medical follow-up should be initiated to monitor liver function and manage any complications that may arise. Regular assessment of liver enzymes is recommended for patients with compromised liver function to ensure timely intervention if abnormalities occur.

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

Animal studies indicate that single oral doses of 1 g/kg of benazepril resulted in reduced activity in mice, while doses of 3 g/kg were linked to significant lethality. In humans, data on benazepril overdosage is scarce; however, hypotension is likely the most common manifestation observed.

For hydrochlorothiazide overdose, the predominant signs and symptoms include dehydration and electrolyte imbalances, such as 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 treatment. While angiotensin II has been proposed as a potential specific antagonist-antidote, it remains largely unavailable outside of specialized research facilities.

Overall, the management of overdosage with these agents should be tailored to the individual patient's clinical presentation, with a focus on supportive care and monitoring for complications.

Nonclinical Toxicology

There is no relevant information regarding teratogenic effects associated with the compounds under investigation.

In terms of non-teratogenic effects, available animal studies indicate that benazepril and hydrochlorothiazide, either alone or in combination, did not adversely affect fertility or conception. However, there are no human fertility data for hydrochlorothiazide.

Carcinogenicity studies conducted over a period of 104 weeks in rats and mice revealed no evidence of carcinogenicity for benazepril at doses up to 150 mg/kg/day. This dosage 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 administered to rats and mice for 2 years at doses of up to 600 mg/kg/day in mice and 100 mg/kg/day in rats, with no evidence of carcinogenic potential observed in rats or female mice. However, equivocal evidence of hepatocarcinogenicity was noted in male mice.

Mutagenicity assessments demonstrated no mutagenic activity for benazepril in the Ames test, in vitro tests for forward mutations in cultured mammalian cells, or in tests for nuclear anomalies. Hydrochlorothiazide also showed no genotoxic effects in various in vitro assays, including those using Salmonella typhimurium strains and the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, as well as in vivo assays involving mouse germinal cell chromosomes and Chinese hamster bone marrow chromosomes.

Nonetheless, positive results were observed in the in vitro CHO Sister Chromatid Exchange test and the Mouse Lymphoma Cell assays, indicating mutagenicity at hydrochlorothiazide concentrations ranging from 43 to 1300 μg/mL. Additionally, positive results were recorded in the Aspergillus nidulans nondisjunction assay, although the concentration of hydrochlorothiazide used in this test was not specified.

Overall, at doses ranging from 50 to 500 mg/kg/day, which equates to 6 to 61 times the maximum recommended dose on a body-surface-area basis, benazepril did not adversely affect the reproductive performance of male and female rats.

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. Data from the Sentinel System indicate that the overall risk for SCC is approximately one additional case per 16,000 patients per year, with a higher risk of one additional case per 6,700 patients per year for white patients taking a cumulative dose of 50,000 mg or more.

Additional adverse events reported with hydrochlorothiazide include:

Digestive System: Pancreatitis, small bowel angioedema, jaundice (intrahepatic cholestatic), 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 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.

For benazepril, postmarketing reports have included Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, thrombocytopenia, and eosinophilic pneumonitis.

Patient Counseling

Patients should be informed that angioedema, including laryngeal edema, can occur at any time during treatment with ACE inhibitors such as Benazepril HCl and Hydrochlorothiazide. They should be advised to report immediately any signs or symptoms of angioedema, including 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 that lightheadedness may occur, 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 before resuming treatment.

It is important to inform all patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to a significant drop in blood pressure, which may result in lightheadedness and possible syncope.

Patients should also be cautioned against using potassium supplements or salt substitutes containing potassium without prior consultation with their prescribing physician.

Patients must be instructed to promptly report any signs of infection, such as sore throat or fever, as these may indicate neutropenia.

For those taking hydrochlorothiazide, it is essential to advise patients to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Storage and Handling

The product is supplied in a tight, light-resistant container, in accordance with USP standards. It is essential to store the product at temperatures not exceeding 86°F (30°C) to maintain its integrity. Additionally, the product must be protected from moisture and light to ensure optimal stability 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 Advagen Pharma Ltd. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)