Benazepril hydrochloride/Hydrochlorothiazide

Description

Benazepril hydrochloride is a white to off-white crystalline powder, exhibiting solubility greater than 100 mg/mL in water, 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. The active metabolite, benazeprilat, functions as a nonsulfhydryl angiotensin-converting enzyme inhibitor, formed through hepatic cleavage of the ester group from benazepril.

Hydrochlorothiazide USP is a white or practically white, odorless crystalline powder, slightly soluble in water and freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide. It is sparingly soluble in methanol and insoluble in ether, chloroform, and dilute mineral acids. The chemical name for hydrochlorothiazide 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. Hydrochlorothiazide acts as a thiazide diuretic.

The tablets are a combination of benazepril hydrochloride and hydrochlorothiazide USP, formulated for oral administration. They are available in strengths of 5 mg, 10 mg, or 20 mg of benazepril hydrochloride combined with 6.25 mg, 12.5 mg, or 25 mg of hydrochlorothiazide USP. Inactive ingredients include colloidal silicon dioxide, crospovidone, hydrogenated castor oil, hypromellose, lactose monohydrate, poloxamer, polyethylene glycol, polysorbate, pregelatinized starch, titanium dioxide, and zinc stearate. The 10 mg/12.5 mg tablets contain D&C red No. 27 and FD&C blue No. 1, while the 20 mg/12.5 mg tablets include FD&C blue No. 2 and FD&C red No. 40. The 20 mg/25 mg tablets also contain FD&C red No. 40.

Uses and Indications

Benazepril hydrochloride and hydrochlorothiazide tablets are indicated for the treatment of hypertension. This fixed combination drug is not indicated for the initial therapy of hypertension.

There are no teratogenic or nonteratogenic effects mentioned in the provided data.

Dosage and Administration

Benazepril is administered orally at a dosage range of 10 mg to 80 mg once daily. Hydrochlorothiazide is also given orally, with a recommended daily dosage of 12.5 mg to 50 mg.

For patients requiring combination therapy with benazepril and hydrochlorothiazide, the dosages are as follows: benazepril should be administered at 5 mg to 20 mg, and hydrochlorothiazide at 6.25 mg to 25 mg, both taken once daily.

Healthcare professionals should ensure that the medications are taken consistently at the same time each day to maintain optimal therapeutic levels.

Contraindications

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

Warnings and Precautions

Patients receiving ACE inhibitors may experience a range of adverse reactions, some of which can be serious. Anaphylactoid and possibly related reactions have been reported, necessitating careful monitoring.

Angioedema Angioedema affecting the face, extremities, lips, tongue, glottis, and larynx has been documented. In cases where laryngeal stridor or angioedema occurs, it is imperative to discontinue treatment immediately and initiate appropriate therapy.

Intestinal Angioedema Patients may present with abdominal pain attributed to intestinal angioedema while on ACE inhibitors. Symptoms typically resolve upon discontinuation of the medication.

Anaphylactoid Reactions During Desensitization Life-threatening anaphylactoid reactions have been observed in patients undergoing desensitization therapy while receiving ACE inhibitors.

Anaphylactoid Reactions During Membrane Exposure Patients undergoing dialysis with high-flux membranes while on ACE inhibitors have reported anaphylactoid reactions.

Hypotension Symptomatic hypotension may occur, particularly in patients who are volume and/or salt depleted. Initiation of therapy should occur under close medical supervision in patients with congestive heart failure.

Impaired Renal Function Caution is advised when using ACE inhibitors in patients with severe renal disease. Renal function should be monitored during the initial weeks of therapy.

Neutropenia/Agranulocytosis Monitoring of white blood cell counts is recommended for patients with collagen-vascular disease, especially those with concurrent impaired renal function.

Fetal/Neonatal Morbidity and Mortality ACE inhibitors pose a risk of fetal and neonatal morbidity and mortality when administered to pregnant women. Discontinuation is advised as soon as pregnancy is confirmed.

Hepatic Failure Discontinuation of therapy is warranted if jaundice or significant elevations in hepatic enzymes occur.

Impaired Hepatic Function Use with caution in patients with impaired hepatic function or progressive liver disease.

Systemic Lupus Erythematosus Thiazide diuretics may exacerbate or activate systemic lupus erythematosus.

Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide has been associated with acute transient myopia and acute angle-closure glaucoma.

General Precautions Initial and periodic assessments of serum electrolytes are recommended to identify potential electrolyte imbalances. Thiazide diuretics may also reduce glucose tolerance and elevate serum levels of cholesterol, triglycerides, and uric acid. A persistent nonproductive cough has been reported with ACE inhibitors, typically resolving after discontinuation. During surgical procedures or anesthesia, benazepril may inhibit angiotensin II formation, potentially leading to hypotension.

Laboratory Tests The hydrochlorothiazide component may lower serum PBI levels without indicating thyroid disturbance. It is advisable to interrupt therapy for several days prior to conducting tests of parathyroid function.

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. If hypotension occurs, the patient should be positioned supine, and intravenous infusion of physiological saline may be necessary for treatment.

Side Effects

Patients may experience a range of adverse reactions while receiving treatment. Common adverse reactions observed in clinical trials include 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%).

Other adverse reactions, occurring at frequencies between 0.3% and 1%, include angioedema, which presents as edema of the lips or face without other manifestations (0.3%). Cardiovascular effects such as hypotension (0.6%), postural hypotension (0.3%), palpitations, and flushing have also been reported. Gastrointestinal disturbances may manifest as vomiting, diarrhea, dyspepsia, anorexia, and constipation. Neurologic and psychiatric reactions include insomnia, nervousness, paresthesia, decreased libido, dry mouth, taste perversion, and tinnitus. Dermatologic reactions may consist of rash and sweating. Additional reactions reported include gout, urinary frequency, arthralgia, myalgia, asthenia, and various types of pain, including chest and abdominal pain.

Serious adverse reactions warranting attention include angioedema affecting the face, extremities, lips, tongue, glottis, and larynx, which can be fatal if associated with laryngeal edema. Symptomatic hypotension may occur, particularly in patients who are volume and/or salt depleted. There is a risk of fetal and neonatal morbidity and mortality when ACE inhibitors are administered to pregnant women. Rarely, hepatic failure has been associated with a syndrome that begins with cholestatic jaundice and can progress to fulminant hepatic necrosis and, in some cases, death. Additionally, neutropenia and agranulocytosis have been noted, and monitoring of white blood cell counts is advised for patients with collagen-vascular disease, especially if renal function is impaired.

Other adverse reactions of note include syncope, peripheral vascular disorder, tachycardia, infections, back pain, flu syndrome, fever, chills, neck pain, photosensitivity, pruritus, gastroenteritis, flatulence, tooth disorder, hypesthesia, abnormal vision, abnormal dreams, retinal disorder, upper respiratory infections, epistaxis, bronchitis, rhinitis, sinusitis, voice alteration, conjunctivitis, arthritis, urinary tract infections, alopecia, and urinary frequency.

Drug Interactions

Concomitant use of potassium supplements and potassium-sparing diuretics may elevate the risk of hyperkalemia. It is advised to monitor serum potassium levels frequently in patients receiving these combinations.

The use of ACE inhibitors alongside lithium has been associated with increased serum lithium levels and symptoms indicative of lithium toxicity. Caution is warranted when co-administering these agents, and frequent monitoring of serum lithium levels is recommended.

Rare instances of nitritoid reactions, such as facial flushing, nausea, vomiting, and hypotension, have been reported with the use of injectable gold (sodium aurothiomalate) in conjunction with ACE inhibitors.

Non-steroidal anti-inflammatory agents (NSAIDs), including COX-2 inhibitors, may lead to a deterioration of renal function, particularly in elderly patients, those who are volume-depleted, or individuals with pre-existing renal impairment. Additionally, the antihypertensive effects of ACE inhibitors and thiazide diuretics may be diminished by NSAID use. Periodic monitoring of renal function is recommended for patients on these combinations.

Benazepril has been administered with beta-adrenergic-blocking agents, calcium-blocking agents, cimetidine, diuretics, digoxin, and hydralazine without evidence of clinically significant adverse interactions.

Interaction studies have not demonstrated any clinically important effects of benazepril on the serum concentrations or clinical effects of anticoagulants such as warfarin and acenocoumarol.

In diabetic patients, insulin requirements may vary; they may be increased, decreased, or remain unchanged when used in conjunction with ACE inhibitors.

Thiazide diuretics may reduce arterial responsiveness to norepinephrine, although this effect does not compromise their efficacy. They may also enhance responsiveness to tubocurarine.

The absorption of hydrochlorothiazide is significantly impaired when administered with anionic exchange resins such as cholestyramine and colestipol, leading to a reduction in gastrointestinal absorption by up to 85% and 43%, respectively.

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. Therefore, the use of this medication in children, infants, and adolescents should be approached with caution, as there is insufficient data to support its use in these populations. Healthcare professionals are advised to consider the potential risks and benefits before prescribing this medication to pediatric patients.

Geriatric Use

In clinical studies involving benazepril hydrochloride and hydrochlorothiazide, 19% of the participants were aged 65 years or older, with approximately 1.5% being 75 years or older. Overall, no significant differences in effectiveness or safety were observed between elderly patients and their younger counterparts. However, it is important to note that while clinical experience has not identified distinct differences in responses between these age groups, a greater sensitivity to the medication in some older individuals cannot be excluded.

Given that benazepril and its active metabolite, benazeprilat, are primarily excreted by the kidneys, caution is warranted in the selection of dosages for geriatric patients. This population is more likely to experience decreased renal function, which may necessitate dose adjustments. Therefore, it may be beneficial to monitor renal function in elderly patients to ensure safe and effective use of the medication.

Pregnancy

Pregnant patients are advised that this medication is classified as Pregnancy Category D, indicating evidence of risk to the fetus based on human data. Healthcare professionals should consider the potential benefits and risks when prescribing this medication to pregnant patients. It is essential to monitor fetal outcomes closely, as there may be implications for fetal and neonatal morbidity and mortality. Women of childbearing potential should be counseled regarding the risks associated with the use of this medication during pregnancy and should be informed about effective contraceptive measures if applicable.

Lactation

Minimal amounts of unchanged benazepril and its active metabolite, benazeprilat, are excreted into the breast milk of lactating mothers treated with benazepril. A breastfed infant receiving only breast milk would ingest less than 0.1% of the maternal doses of benazepril and benazeprilat.

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 whether to discontinue breastfeeding or to discontinue benazepril hydrochloride and hydrochlorothiazide. This decision should take into account the importance of the medication to the mother.

Renal Impairment

Patients with renal impairment should be treated with caution when using benazepril hydrochloride and hydrochlorothiazide, particularly in cases of severe renal disease, as thiazides may precipitate azotemia and the effects of repeated dosing can be cumulative.

In individuals with severe congestive heart failure, where renal function may be reliant on the renin-angiotensin-aldosterone system, inhibition by benazepril may lead to anticipated changes in renal function. This treatment may result in oliguria, progressive azotemia, and, in rare instances, acute renal failure or death.

Monitoring of renal function is essential during the initial weeks of therapy in hypertensive patients with unilateral or bilateral renal artery stenosis, as a small study indicated that benazepril treatment was associated with increases in blood urea nitrogen and serum creatinine, which were reversible upon discontinuation of therapy or concomitant diuretic use.

Additionally, some hypertensive patients treated with benazepril, even without pre-existing renal vascular disease, have experienced minor and transient increases in blood urea nitrogen and serum creatinine, particularly when benazepril is administered alongside a diuretic. In such cases, a dosage reduction of benazepril hydrochloride and hydrochlorothiazide may be necessary.

It is imperative that the evaluation of hypertensive patients includes a thorough assessment of renal function.

Hepatic Impairment

Patients with hepatic impairment should use benazepril hydrochloride and hydrochlorothiazide with caution, particularly those with impaired hepatic function or progressive liver disease. Minor alterations in fluid and electrolyte balance in these patients may precipitate hepatic coma.

In individuals with hepatic dysfunction due to cirrhosis, the levels of benazeprilat remain essentially unaltered; however, no formal pharmacokinetic studies have been conducted in hypertensive patients with impaired liver function.

It is important to note that ACE inhibitors, including benazepril, have been rarely associated with a syndrome that begins with cholestatic jaundice and can progress to fulminant hepatic necrosis, and in some cases, death. The underlying mechanism of this syndrome remains unclear.

Patients receiving ACE inhibitors who develop jaundice or significant elevations in hepatic enzyme levels should discontinue the ACE inhibitor and receive appropriate medical follow-up to ensure safety and monitor liver function.

Overdosage

Overdosage of benazepril hydrochloride and hydrochlorothiazide can result in significant adverse effects, primarily severe hypotension. This condition may manifest with symptoms including dizziness, fainting, or shock, necessitating immediate medical attention.

In the event of an overdose, it is crucial to place the patient in a supine position to facilitate blood flow and minimize the risk of further complications. If indicated, treatment may involve the administration of intravenous infusion of physiological saline to help restore blood volume and stabilize blood pressure.

Continuous monitoring of blood pressure and renal function is essential following an overdose to ensure the patient's safety and to guide further management. It is important to note that there is no specific antidote available for the overdose of benazepril hydrochloride and hydrochlorothiazide, underscoring the need for supportive care and vigilant observation.

Nonclinical Toxicology

No evidence of carcinogenicity was observed in studies where benazepril was administered to rats and mice for 104 weeks at doses up to 150 mg/kg/day. This dosage exceeds the maximum recommended human dose by more than 100 times on a body-weight basis and by 18 times in rats and 9 times in mice on a body-surface-area basis. Additionally, no mutagenic activity was detected in the Ames test conducted in bacteria, nor in an in vitro test for forward mutations in cultured mammalian cells, or in a nucleus anomaly test.

In reproductive studies, benazepril was administered at doses ranging from 50 mg/kg/day to 500 mg/kg/day, which corresponds to 38 to 375 times the maximum recommended human dose on a body-weight basis and 6 to 61 times on a body-surface-area basis. These studies indicated no adverse effects on the reproductive performance of both male and female rats.

Under the National Toxicology Program, hydrochlorothiazide was provided in the feed of rats and mice for two years at doses up to 600 mg/kg/day in mice and 100 mg/kg/day in rats. These studies revealed no evidence of carcinogenic potential in rats or female mice; however, equivocal evidence of hepatocarcinogenicity was noted in male mice. Hydrochlorothiazide was not found to be genotoxic in various in vitro assays, including the Ames test with multiple strains of Salmonella typhimurium, the Chinese Hamster Ovary test for chromosomal aberrations, and in vivo assays involving mouse germinal cell chromosomes and Chinese hamster bone marrow chromosomes.

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 µg/mL to 1300 µg/mL. Additionally, positive results were noted in the Aspergillus nidulans nondisjunction assay at an unspecified concentration of hydrochlorothiazide. In fertility studies, hydrochlorothiazide did not adversely affect the reproductive capabilities of mice and rats of either sex when exposed to doses of up to 100 mg/kg/day and 4 mg/kg/day, respectively, prior to mating and throughout gestation.

Postmarketing Experience

Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with angiotensin-converting enzyme (ACE) inhibitors. In U.S. clinical trials, symptoms consistent with angioedema were observed in approximately 0.5% of subjects receiving benazepril, while no such symptoms were reported in subjects receiving placebo. Angioedema associated with laryngeal edema can be fatal; therefore, if laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with benazepril hydrochloride and hydrochlorothiazide should be discontinued immediately, and appropriate therapy should be initiated.

Intestinal angioedema has also been reported in patients treated with ACE inhibitors, presenting with abdominal pain (with or without nausea or vomiting). In some cases, there was no prior history of facial angioedema, and C-1 esterase levels were normal. Diagnosis was made through abdominal CT scan, ultrasound, or surgical intervention, with symptoms resolving after discontinuation of the ACE inhibitor.

Anaphylactoid reactions have been documented in patients undergoing dialysis with high-flux membranes while being treated with an ACE inhibitor, as well as in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

The most common reasons for discontinuation of therapy with benazepril hydrochloride and hydrochlorothiazide in U.S. studies included cough (1%), dizziness (1%), headache (0.6%), and fatigue (0.6%). Other adverse experiences reported in 0.3% or more of patients in U.S. controlled clinical trials, along with rarer events observed in post-marketing experience, included angioedema, syncope, peripheral vascular disorder, tachycardia, infection, back pain, flu syndrome, fever, chills, neck pain, photosensitivity, pruritus, gastroenteritis, flatulence, tooth disorder, hypesthesia, abnormal vision, abnormal dreams, retinal disorder, upper respiratory infection, epistaxis, bronchitis, rhinitis, sinusitis, voice alteration, conjunctivitis, arthritis, urinary tract infection, alopecia, and urinary frequency.

In post-marketing experience with benazepril, rare reports of Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, and thrombocytopenia have been noted. Additionally, eosinophilic pneumonitis has been associated with other ACE inhibitors.

Adverse reactions of unknown frequency include small bowel angioedema, anaphylactoid reactions, hyperkalemia, agranulocytosis, and neutropenia. Rarely, ACE inhibitors have been linked to a syndrome that begins with cholestatic jaundice and can progress to fulminant hepatic necrosis and, in some cases, death, although the mechanism of this syndrome remains unclear.

Fetal and neonatal morbidity and mortality have been reported in association with the use of ACE inhibitors during pregnancy.

Patient Counseling

Patients should be informed that angioedema, including laryngeal edema, can occur at any time during treatment with ACE inhibitors. They should be advised to report immediately any signs or symptoms suggesting 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 medication until they have consulted with their prescribing physician.

Female patients of childbearing age should be made aware of the potential consequences of exposure to ACE inhibitors. Healthcare providers should discuss alternative treatment options with women who are planning to become pregnant. Patients should be encouraged to report any pregnancies to their physicians as soon as possible.

Patients should be cautioned that lightheadedness may occur, particularly during the initial days of therapy. They should be advised to report this symptom to their prescribing physician. In the event of syncope, patients should discontinue the use of benazepril hydrochloride and hydrochlorothiazide until they have consulted with their physician.

All patients should be warned 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 be instructed not to use potassium supplements or salt substitutes containing potassium without prior consultation with their prescribing physician.

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

Finally, therapy with benazepril hydrochloride and hydrochlorothiazide should be interrupted for a few days before conducting tests of parathyroid function.

Storage and Handling

The product is supplied in bottles that contain a desiccant to ensure stability. Each strength is packaged to maintain integrity and protect against light and moisture.

Storage conditions require the product to be kept at a temperature range of 20º to 25ºC (68º to 77ºF), in accordance with USP Controlled Room Temperature guidelines. It is essential to dispense the contents into a tight, light-resistant container that meets USP specifications, equipped with a child-resistant closure as mandated.

Additional Clinical Information

The hydrochlorothiazide component of benazepril hydrochloride and hydrochlorothiazide may lead to a decrease in serum protein-bound iodine (PBI) levels, although this effect does not indicate any signs of thyroid disturbance. Clinicians should consider interrupting therapy with benazepril hydrochloride and hydrochlorothiazide for several days prior to conducting tests to assess parathyroid function in patients.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Benazepril Hydrochloride and Hydrochlorothiazide as submitted by H. J. Harkins Company, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)