Benazepril hydrochloride/Hydrochlorothiazide

Description

Benazepril hydrochloride, USP is a white to off-white crystalline powder, highly 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 a molecular formula of C24H28N2O5·HCl and a molecular weight of 460.96 g/mol. 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, practically 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. Its chemical name is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular formula of C7H8ClN3O4S2 and a molecular weight of 297.74 g/mol. Hydrochlorothiazide is classified as a thiazide diuretic.

Benazepril hydrochloride and hydrochlorothiazide tablets, USP are formulated for oral administration, combining benazepril hydrochloride, USP in strengths of 5, 10, or 20 mg with hydrochlorothiazide, USP in strengths of 6.25, 12.5, or 25 mg. The tablets contain inactive ingredients including black iron oxide (20 mg/12.5 mg), crospovidone, colloidal silicon dioxide, ferric oxide (10 mg/12.5 mg, 20 mg/12.5 mg, and 20 mg/25 mg), hypromellose, hydroxypropyl cellulose, microcrystalline cellulose, polyethylene glycol, titanium dioxide, and zinc stearate.

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.

Dosage and Administration

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

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

Co-administration of aliskiren with angiotensin receptor blockers or ACE inhibitors, including benazepril hydrochloride and hydrochlorothiazide tablets, is contraindicated in patients with diabetes due to the increased risk of renal impairment.

Warnings and Precautions

Anaphylactoid and Possibly Related Reactions Angioedema, including swelling of the face, extremities, lips, tongue, glottis, and larynx, has been reported in patients treated with angiotensin-converting enzyme (ACE) inhibitors. Notably, angioedema associated with laryngeal edema can be fatal. In the event of laryngeal stridor or angioedema affecting the face, tongue, or glottis, treatment with benazepril hydrochloride and hydrochlorothiazide tablets must be discontinued immediately, and appropriate therapy should be initiated. It is important to note that black patients receiving ACE inhibitors have been observed to have a higher incidence of angioedema compared to nonblack patients. Additionally, patients receiving coadministration of ACE inhibitors with mTOR inhibitors or neprilysin inhibitors may be at an increased risk for angioedema. Intestinal angioedema has also been reported in patients treated with ACE inhibitors, with symptoms resolving upon discontinuation of the medication. Life-threatening anaphylactoid reactions have occurred in patients undergoing desensitization treatment while on ACE inhibitors, as well as in patients dialyzed with high-flux membranes.

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, while drugs that inhibit the renin-angiotensin system may cause hyperkalemia. Hydrochlorothiazide may also affect glucose tolerance and elevate serum cholesterol and triglyceride levels. Thiazides are known to decrease urinary calcium excretion, potentially causing mild elevations in serum calcium; therefore, benazepril hydrochloride and hydrochlorothiazide tablets should be avoided in patients with hypercalcemia. A persistent nonproductive cough has been reported with all ACE inhibitors, which typically resolves after discontinuation of therapy. In patients undergoing surgery or anesthesia with agents that induce hypotension, benazepril may inhibit the formation of angiotensin II that would otherwise occur due to compensatory renin release.

Laboratory Tests The hydrochlorothiazide component may decrease serum protein-bound iodine (PBI) levels without indicating thyroid disturbance. It is recommended that therapy with benazepril hydrochloride and hydrochlorothiazide tablets be interrupted for several days prior to conducting tests of parathyroid function.

Emergency Medical Help Instructions In cases of laryngeal stridor or angioedema affecting the face, tongue, or glottis, immediate discontinuation of benazepril hydrochloride and hydrochlorothiazide tablets is essential, along with the initiation of appropriate therapy.

Stop Taking and Call Your Doctor Instructions If hypotension occurs, the patient should be placed in a supine position, and if necessary, treated with intravenous infusion of physiological saline. Treatment with benazepril hydrochloride and hydrochlorothiazide tablets can typically be resumed following the restoration of blood pressure and volume.

Side Effects

Patients may experience a range of adverse reactions while receiving treatment. Common adverse reactions, occurring in 1% or more of participants, 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, with frequencies ranging from 0.3% to 1.0%, encompass cardiovascular effects such as palpitations and flushing; gastrointestinal issues including vomiting, diarrhea, dyspepsia, anorexia, and constipation; and neurologic and psychiatric symptoms like insomnia, nervousness, paresthesia, decreased libido, dry mouth, taste perversion, and tinnitus. Dermatologic reactions may include rash and sweating, while other reported effects involve urinary frequency, arthralgia, myalgia, asthenia, and various types of pain, including chest and abdominal pain.

Serious adverse reactions have also been reported. Cardiovascular events such as syncope, peripheral vascular disorder, and tachycardia have been noted. Additionally, patients may experience systemic reactions including infection, back pain, flu syndrome, fever, chills, and neck pain. Dermatologic concerns may involve photosensitivity and pruritus, while gastrointestinal reactions can include gastroenteritis, flatulence, and tooth disorder. Neurologic and psychiatric effects may manifest as hypesthesia, abnormal vision, abnormal dreams, and retinal disorders. Respiratory issues such as upper respiratory infections, epistaxis, bronchitis, rhinitis, sinusitis, and voice alteration have also been documented. Other reactions include conjunctivitis, arthritis, urinary tract infections, alopecia, and urinary frequency.

Post-marketing experience has revealed additional serious adverse reactions associated with specific medications. For instance, benazepril has been linked to Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, thrombocytopenia, and eosinophilic pneumonitis. Hydrochlorothiazide has been associated with pancreatitis, small bowel angioedema, jaundice (intrahepatic cholestatic), sialadenitis, and gastrointestinal disturbances such as 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. Musculoskeletal effects such as muscle spasms, hematologic issues including aplastic anemia, agranulocytosis, leukopenia, neutropenia, and thrombocytopenia, as well as metabolic disturbances like hyperglycemia, glycosuria, hyperuricemia, pyrexia, and parathyroid gland changes with hypercalcemia and hypophosphatemia have also been observed.

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

Drug Interactions

Patients taking neprilysin inhibitors may experience an increased risk of angioedema when used concomitantly with benazepril hydrochloride and hydrochlorothiazide tablets.

Pharmacodynamic Interactions

Potassium Supplements and Potassium-Sparing Diuretics Concomitant use of benazepril hydrochloride and hydrochlorothiazide tablets with potassium supplements or potassium-sparing diuretics may lead to alterations in potassium levels. Periodic monitoring of potassium is advised.

mTOR Inhibitors The coadministration of ACE inhibitors, including benazepril, with mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus) may increase the risk of angioedema.

Lithium Thiazide diuretics can reduce the renal clearance of lithium, increasing the risk of lithium toxicity. Patients receiving benazepril hydrochloride and hydrochlorothiazide tablets alongside lithium should have their lithium levels monitored closely.

Dual Blockade of the Renin-Angiotensin System (RAS) The combination of RAS inhibitors, such as angiotensin receptor blockers, ACE inhibitors, or aliskiren, is associated with heightened risks of hypertension, hyperkalemia, and renal function changes, including acute renal failure. It is generally recommended to avoid the combined use of RAS inhibitors. Patients on benazepril hydrochloride and hydrochlorothiazide tablets should have their blood pressure, renal function, and electrolytes closely monitored. Aliskiren should not be coadministered with these tablets in patients with diabetes or renal impairment (GFR < 60 mL/min).

NSAIDs and COX-2 Selective Agents In elderly patients, those who are volume-depleted, or individuals with compromised renal function, the coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors may lead to renal function deterioration, potentially resulting in acute renal failure. These effects are typically reversible. Renal function should be monitored periodically in patients receiving benazepril and NSAID therapy. Additionally, the antihypertensive effect of benazepril and hydrochlorothiazide may be diminished by NSAIDs.

Pharmacokinetic Interactions

Hydrochlorothiazide and Ion Exchange Resins To minimize interaction, hydrochlorothiazide should be administered at least 4 hours before or 4 to 6 hours after ion exchange resins, as these resins can significantly reduce the absorption of hydrochlorothiazide.

Digitalis Glycosides Thiazide-induced hypokalemia or hypomagnesemia may increase the risk of digoxin toxicity.

Skeletal Muscle Relaxants There may be an increased responsiveness to muscle relaxants, such as curare derivatives, when used with thiazide diuretics.

Antidiabetic Agents Dosage adjustments of antidiabetic medications may be necessary when used in conjunction with benazepril hydrochloride and hydrochlorothiazide tablets.

Antineoplastic Agents The concomitant use of thiazide diuretics with antineoplastic agents (e.g., cyclophosphamide, methotrexate) may reduce the renal excretion of these cytotoxic agents and enhance their myelosuppressive effects.

Drugs that Alter Gastrointestinal Motility Anticholinergic agents may increase the bioavailability of thiazide-type diuretics due to decreased gastrointestinal motility. Conversely, prokinetic drugs may decrease the bioavailability of thiazide diuretics.

Cyclosporin Concomitant treatment with diuretics may elevate the risk of hyperuricemia and gout-type complications.

Alcohol, Barbiturates, or Narcotics The use of thiazide diuretics alongside alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension.

Pressor Amines Hydrochlorothiazide may diminish the response to pressor amines such as noradrenaline; however, the clinical significance of this effect does not preclude 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. Special attention may be necessary for neonates with a history of exposure to benazepril hydrochloride and hydrochlorothiazide tablets. In cases of oliguria or hypotension in neonates, it is crucial to provide direct support for blood pressure and renal perfusion, as exchange transfusions or dialysis may be required.

Geriatric Use

In clinical studies involving benazepril hydrochloride and hydrochlorothiazide tablets, 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 younger 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

There are no available human fertility data for hydrochlorothiazide. In animal studies, both benazepril and hydrochlorothiazide, administered alone or in combination, demonstrated no adverse effects on fertility and conception.

Healthcare professionals should consider the lack of human data when prescribing hydrochlorothiazide to pregnant patients. The potential risks and benefits should be carefully evaluated, particularly in women of childbearing potential.

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 benazepril hydrochloride and hydrochlorothiazide tablets, 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 hydrochloride and hydrochlorothiazide tablets. It is important to note that changes in renal function, including acute renal failure, may occur due to the effects of drugs that inhibit the renin-angiotensin system and diuretics.

Particular caution is warranted for 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 of developing acute renal failure when receiving benazepril hydrochloride and hydrochlorothiazide tablets.

In cases where a clinically significant decrease in renal function is observed, consideration should be given to withholding or discontinuing therapy. Additionally, 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 that begins with cholestatic jaundice and can progress to fulminant hepatic necrosis, which may result in death. The underlying mechanism of this syndrome remains unclear.

In patients receiving ACE inhibitors, it is crucial to monitor liver function closely. If jaundice or significant elevations in hepatic enzymes are observed, the ACE inhibitor should be discontinued immediately. Appropriate medical follow-up is essential to manage any potential complications arising from hepatic impairment.

Overdosage

In the event of an overdosage with benazepril hydrochloride and hydrochlorothiazide tablets, specific treatment information is limited. Management should be primarily symptomatic and supportive. It is recommended that therapy with the tablets be discontinued, and the patient should be closely monitored. Key concerns during management include addressing dehydration, electrolyte imbalances, and hypotension, which should be treated according to established medical procedures.

Toxicological studies indicate that single oral doses of benazepril at 1 g/kg resulted in reduced activity in mice, while doses of 3 g/kg were associated with significant lethality. In rats, reduced activity was not observed until doses reached 5 g/kg, and doses of 6 g/kg were not lethal. For hydrochlorothiazide, single-dose studies showed that most rats survived doses up to 2.75 g/kg.

Human data on benazepril overdose are limited, but hypotension is likely the most common manifestation. In cases of hydrochlorothiazide overdose, symptoms typically include dehydration and electrolyte depletion, such as hypokalemia, hypochloremia, and hyponatremia. If digitalis has been administered concurrently, hypokalemia may exacerbate the risk of cardiac arrhythmias.

Laboratory assessments of serum levels of benazepril and its metabolites are not routinely available, and such determinations do not have a defined role in managing benazepril overdose. Furthermore, there is no evidence to support the use of physiological maneuvers, such as altering urine pH, to enhance the elimination of benazepril and its metabolites. Although benazeprilat is only slightly dialyzable, dialysis may be considered for patients with severely impaired renal function.

While angiotensin II could theoretically act as a specific antagonist or antidote in cases of benazepril overdose, it is largely unavailable outside of specialized research settings. Given that the hypotensive effects of benazepril result from vasodilation and effective hypovolemia, it is reasonable to manage benazepril overdose with the infusion of normal saline solution to restore fluid balance.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted.

In terms of non-teratogenic effects, benazepril did not demonstrate any evidence of carcinogenicity when administered to rats and mice over a period of 104 weeks at doses up to 150 mg/kg/day. Additionally, no mutagenic activity was detected in the Ames test, which included both bacterial assays with and without metabolic activation, as well as in vitro tests for forward mutations in cultured mammalian cells and nucleus anomaly tests. Furthermore, benazepril did not adversely affect the reproductive performance of male and female rats 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.

Hydrochlorothiazide 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.

However, positive test 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 mcg/mL. Additionally, positive results were noted in the Aspergillus nidulans nondisjunction assay, although the concentration of hydrochlorothiazide used in this test was unspecified.

No specific details regarding animal pharmacology and toxicology were provided in the available data.

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

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

Musculoskeletal Disorders: Muscle spasm.

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

Metabolic Disorders: 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.

Benazepril has been associated with serious adverse events, including 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. They should be advised to report any signs or symptoms suggesting angioedema, such as swelling of the face, eyes, lips, or tongue, or difficulty in breathing, immediately. Patients should be instructed to refrain from taking any other 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 tablets during pregnancy. It is important for them to discuss treatment options with their physician if they are planning to become pregnant and to report any pregnancies to their physician as soon as possible.

Patients should be cautioned that lightheadedness can occur, particularly during the initial days of therapy. They should report any instances of lightheadedness to their physician. In the event of syncope, patients should discontinue the medication and consult their physician before resuming treatment.

Patients should be advised that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to a significant drop in blood pressure, resulting in lightheadedness and potential syncope.

It is essential for patients to consult their physician before using potassium supplements or salt substitutes containing potassium, as this may lead to hyperkalemia.

Patients should be instructed 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 protect their skin from sun exposure and to undergo regular skin cancer screenings due to an increased risk of non-melanoma skin cancer.

Additionally, patients should be informed that the hydrochlorothiazide component may decrease serum PBI levels without signs of thyroid disturbance. Therefore, therapy should be interrupted for a few days prior to conducting tests of parathyroid function.

Storage and Handling

The product is supplied in a tight, light-resistant container to ensure its integrity and efficacy. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as outlined by USP Controlled Room Temperature guidelines. It is essential to protect the product from moisture and light to maintain its quality.

Additional Clinical Information

The hydrochlorothiazide component of benazepril hydrochloride and hydrochlorothiazide tablets 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 hydrochloride and hydrochlorothiazide tablets 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 Apotex Corp.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)