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.

Benazepril Hydrochloride and Hydrochlorothiazide Tablets USP are a combination of benazepril hydrochloride USP and hydrochlorothiazide USP. The tablets are formulated for oral administration, containing combinations of 5, 10, or 20 mg of benazepril hydrochloride USP and 6.25, 12.5, or 25 mg of hydrochlorothiazide USP. The inactive ingredients include colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch, titanium dioxide, and triacetin. The 10 mg/12.5 mg tablets also contain FD&C Blue #2 and iron oxide red. The 20 mg/12.5 mg tablets contain FD&C Red #40 and FD&C Yellow #6, while the 20 mg/25 mg tablets include FD&C Blue #2 and FD&C Red #40.

Uses and Indications

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

Dosage and Administration

The recommended dosing regimen for benazepril hydrochloride and hydrochlorothiazide tablets 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 benazepril alone or hydrochlorothiazide alone, a switch to combination therapy with benazepril hydrochloride and hydrochlorothiazide tablets is advised. In such cases, the usual starting dose remains at 10/12.5 mg once daily.

Additionally, this combination therapy may be utilized as a replacement for the titrated individual components, ensuring continuity in patient management while optimizing blood pressure control.

Contraindications

Benazepril hydrochloride and hydrochlorothiazide tablets are contraindicated in the following situations:

Patients who are anuric. Use is contraindicated due to the lack of urine production, which may lead to accumulation of the drug and potential toxicity.

Patients with hypersensitivity to benazepril, any other ACE inhibitor, hydrochlorothiazide, or other sulfonamide-derived drugs. 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. The risk of recurrent angioedema is significant in these patients.

Patients receiving a neprilysin inhibitor (e.g., sacubitril). Administration of benazepril hydrochloride and hydrochlorothiazide tablets is contraindicated within 36 hours of switching to or from sacubitril/valsartan.

Patients with diabetes who are coadministered aliskiren with angiotensin receptor blockers or ACE inhibitors, including benazepril hydrochloride and hydrochlorothiazide tablets. This combination may increase the risk of adverse effects.

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 treated with ACE inhibitors. Notably, angioedema associated with laryngeal edema can be fatal. In the event of laryngeal stridor or angioedema, treatment must be discontinued immediately, and appropriate therapy should be initiated. It is important to note that black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblack patients. Additionally, patients receiving a combination of an ACE inhibitor with an mTOR inhibitor or a neprilysin inhibitor may be at an increased risk for angioedema.

Intestinal angioedema has also been reported in patients treated with ACE inhibitors, typically presenting as abdominal pain, with symptoms resolving upon discontinuation of the medication. Life-threatening anaphylactoid reactions have occurred in patients undergoing desensitization treatment while on ACE inhibitors. Furthermore, anaphylactoid reactions have been documented in patients undergoing dialysis with high-flux membranes while receiving ACE inhibitors. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with a history of allergy and asthma.

General Precautions

Healthcare professionals should monitor serum electrolytes periodically, as hydrochlorothiazide can lead to hypokalemia and hyponatremia. Additionally, drugs that inhibit the renin-angiotensin system may cause hyperkalemia. Hydrochlorothiazide may also affect glucose tolerance and elevate serum levels of cholesterol and triglycerides. Furthermore, it can raise serum uric acid levels, potentially precipitating gout in susceptible individuals. It is advised to avoid the use of benazepril hydrochloride and hydrochlorothiazide in patients with hypercalcemia.

Laboratory Tests

The hydrochlorothiazide component may decrease serum protein-bound iodine (PBI) levels without indicating thyroid disturbance. It is recommended that therapy be interrupted for a few days prior to conducting tests of parathyroid function.

Emergency Medical Help

Immediate medical attention is required if laryngeal stridor or angioedema of the face, tongue, or glottis occurs. Treatment should be discontinued, and appropriate therapy must be instituted without delay.

Discontinuation and Medical Follow-Up

Patients should discontinue the ACE inhibitor and seek medical advice if jaundice or significant elevations in hepatic enzymes are observed.

Side Effects

Patients receiving treatment with benazepril hydrochloride and hydrochlorothiazide may experience a range of adverse reactions. Common adverse reactions reported in clinical trials include cough (1.0%), dizziness (1.0%), headache (0.6%), and fatigue (0.6%).

In a study involving 665 participants, reactions that were possibly or probably drug-related included fatigue (6.3%), postural dizziness (5.2%), headache (3.5%), cough (3.1%), hypertonia (2.1%), vertigo (1.5%), nausea (1.5%), impotence (1.4%), somnolence (1.2%), and dizziness (1.2%).

Other adverse reactions occurring at frequencies between 0.3% and 1.0% encompass various systems: cardiovascular reactions such as palpitations and flushing; gastrointestinal issues including vomiting, diarrhea, dyspepsia, anorexia, and constipation; neurologic and psychiatric effects like insomnia, nervousness, paresthesia, decreased libido, dry mouth, taste perversion, and tinnitus; dermatologic reactions such as rash and sweating; and miscellaneous reactions including urinary frequency, arthralgia, myalgia, asthenia, and pain (including chest and abdominal pain).

Postmarketing experience has revealed additional serious adverse reactions. For benazepril, these include Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, thrombocytopenia, and eosinophilic pneumonitis. Hydrochlorothiazide has been associated with a variety of adverse reactions, including digestive issues such as pancreatitis, small bowel angioedema, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, and anorexia. Neurologic reactions may include vertigo, lightheadedness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, and restlessness. Musculoskeletal reactions such as muscle spasm, hematologic issues including aplastic anemia, agranulocytosis, leukopenia, neutropenia, and thrombocytopenia, as well as metabolic disturbances like hyperglycemia, glycosuria, hyperuricemia, pyrexia, asthenia, and parathyroid gland changes with hypercalcemia and hypophosphatemia have also been reported. Hypersensitivity reactions can manifest as anaphylactoid reactions, necrotizing angiitis, respiratory distress (including pneumonitis and pulmonary edema), purpura, urticaria, rash, and photosensitivity. Skin reactions may include erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, and toxic epidermal necrolysis.

Warnings associated with the use of these medications include fetal toxicity, as drugs acting on the renin-angiotensin system can cause injury and death to the developing fetus. Anaphylactoid reactions, including angioedema of the face, extremities, lips, tongue, glottis, and larynx, have been reported, with laryngeal edema potentially being fatal. Symptomatic hypotension may occur, particularly in patients who are volume and/or salt depleted. Monitoring of white blood cell counts is advised in patients with collagen-vascular disease due to the risk of neutropenia and agranulocytosis.

Additionally, hydrochlorothiazide may cause acute myopia and secondary angle-closure glaucoma as an idiosyncratic reaction. Thiazide diuretics have also been reported to exacerbate or activate systemic lupus erythematosus.

Drug Interactions

Patients taking neprilysin inhibitors concurrently may experience an increased risk of angioedema. Caution is advised when combining these agents.

The coadministration of benazepril hydrochloride and hydrochlorothiazide may influence potassium levels; therefore, periodic monitoring of potassium is recommended. Additionally, patients receiving both ACE inhibitors and mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus) are at an elevated risk for angioedema.

Thiazide diuretics, such as hydrochlorothiazide, can reduce the renal clearance of lithium, thereby increasing the risk of lithium toxicity. Monitoring of lithium levels is advised when these medications are used together. Furthermore, the dual blockade of the renin-angiotensin system (RAS) with ACE inhibitors or aliskiren is associated with heightened risks of hypertension, hyperkalemia, and alterations in renal function; thus, the combined use of RAS inhibitors should be avoided. Specifically, aliskiren should not be coadministered with benazepril hydrochloride 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. Additionally, the antihypertensive effect 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.

When administering hydrochlorothiazide with ion exchange resins, it is recommended to stagger the dosages, giving 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. Additionally, hydrochlorothiazide may enhance responsiveness to muscle relaxants, such as curare derivatives.

Dosage adjustments of antidiabetic medications may be necessary when using hydrochlorothiazide. The use of thiazide diuretics may also reduce the renal excretion of antineoplastic agents, potentially enhancing their myelosuppressive effects. The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents due to decreased gastrointestinal motility.

Finally, concomitant treatment with diuretics may elevate the risk of hyperuricemia and gout-type complications when used with cyclosporin. The combination of thiazide diuretics with alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension. Hydrochlorothiazide may diminish the response to pressor amines such as noradrenaline; however, 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

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 until further data is available.

Geriatric Use

In clinical studies involving benazepril hydrochloride and hydrochlorothiazide, 19% of the total patient population were elderly patients aged 65 years or older, with approximately 1.5% being 75 years or older. Despite the inclusion of these geriatric patients, no overall differences in effectiveness or safety were observed when compared to younger patients.

It is important to note that a limited amount of data indicates that the systemic clearance of hydrochlorothiazide may be reduced in both healthy and hypertensive elderly subjects compared to younger healthy volunteers. This finding suggests that careful consideration should be given to potential dose adjustments and monitoring in geriatric patients to ensure optimal therapeutic outcomes and minimize the risk of adverse effects.

Pregnancy

There is no specific information available regarding the use of this medication during pregnancy, including safety concerns, dosage modifications, or special precautions that should be taken. Healthcare professionals are advised to consider the lack of data when prescribing this medication to pregnant patients and to weigh the potential benefits against any unknown risks to fetal outcomes. Women of childbearing potential should be counseled accordingly.

Lactation

Nursing mothers should be aware of the potential for excretion of benazepril hydrochloride and hydrochlorothiazide in breast milk. There is a lack of data on the effects of benazepril hydrochloride and hydrochlorothiazide on nursing infants. Caution should be exercised when administering benazepril hydrochloride and hydrochlorothiazide to nursing mothers.

Renal Impairment

Patients with renal impairment should be monitored for renal function periodically while receiving benazepril hydrochloride and hydrochlorothiazide. The use of drugs that inhibit the renin-angiotensin system and diuretics can lead to changes in renal function, including the potential for acute renal failure.

Particular caution is warranted 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, as they may be at an increased risk for developing acute renal failure when treated with benazepril hydrochloride and hydrochlorothiazide.

In cases where a clinically significant decrease in renal function occurs, it may be necessary to consider withholding or discontinuing therapy. 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.

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. It is essential for healthcare providers to exercise caution and closely monitor liver function in patients with compromised liver function while on ACE inhibitor therapy.

Overdosage

In cases of overdosage with benazepril hydrochloride and hydrochlorothiazide, specific treatment information is limited. Management should primarily focus on symptomatic and supportive care.

Clinical Manifestations of Overdosage

In animal studies, single oral doses of benazepril at 1 g/kg resulted in reduced activity, while doses of 3 g/kg were linked to significant lethality. Human data regarding benazepril overdose are sparse; 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 could theoretically act as a specific antagonist-antidote, it is largely unavailable outside of research settings.

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 potential complications.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. At doses ranging from 50 to 500 mg/kg/day, which corresponds to 6 to 61 times the maximum recommended dose based on body-surface area, benazepril did not adversely affect the reproductive performance of male and female rats.

In terms of carcinogenicity, no evidence was found when benazepril was administered to rats and mice for a duration of 104 weeks at doses up to 150 mg/kg/day. Additionally, no mutagenic activity was detected in the Ames test conducted in bacteria, whether with or without metabolic activation, nor in an in vitro test for forward mutations in cultured mammalian cells, or in a nucleus anomaly test.

Under the National Toxicology Program, studies involving hydrochlorothiazide were conducted in rats and mice over a period of 2 years, with doses reaching 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 also found to be non-genotoxic in various in vitro assays, including the Ames test using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium, as well as in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. In vivo assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene also indicated a lack of genotoxicity.

Positive results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma Cell (mutagenicity) assays with hydrochlorothiazide concentrations ranging from 43 to 1300 µg/mL. Furthermore, positive results were also observed in the Aspergillus nidulans nondisjunction assay, although the concentration of hydrochlorothiazide used in this test was unspecified.

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), as observed 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, with a higher risk in white patients taking cumulative doses of ≥50,000 mg, where the risk increased to approximately 1 additional case per 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 System: Vertigo, lightheadedness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, and restlessness.

Musculoskeletal System: Muscle spasm.

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

Metabolic Effects: 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 reflect the ongoing monitoring of the safety profile of these medications in the postmarketing setting.

Patient Counseling

Patients should be informed about the risk of angioedema, including laryngeal edema, which can occur at any time during treatment with ACE inhibitors such as benazepril hydrochloride 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 hydrochloride 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 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. 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, resulting in lightheadedness and potential syncope.

Patients receiving benazepril hydrochloride and hydrochlorothiazide should be instructed not to use potassium supplements or salt substitutes containing potassium without prior consultation with their prescribing physician, as this may lead to hyperkalemia.

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 essential 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 defined by the United States Pharmacopeia (USP). It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Care must be taken to protect the product from moisture and light to ensure its integrity and efficacy.

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.

FDA Insert (PDF)

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

View full prescribing information (PDF)