Benazepril hydrochloride/Hydrochlorothiazide

Description

Benazepril hydrochloride, USP is a white to off-white crystalline powder with a molecular formula of C24H28N2O5•HCl and a molecular weight of 460.96. It is soluble in water (>100 mg/mL), ethanol, and methanol. The chemical name for benazepril hydrochloride is 3-[1-(ethoxycarbonyl)-3-phenyl-(1S)-propylamino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid monohydrochloride. The active metabolite, benazeprilat, functions as a nonsulfhydryl angiotensin-converting enzyme inhibitor, formed through hepatic cleavage of the ester group.

Hydrochlorothiazide, USP is a white or practically white, practically odorless crystalline powder with a molecular formula of C7H8ClN3O4S2 and a molecular weight of 297.73. 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. The chemical name for hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, and it is classified as a thiazide diuretic.

The tablets are formulated for oral administration and contain a combination of benazepril hydrochloride and hydrochlorothiazide in the following strengths: 5 mg of benazepril hydrochloride with 6.25 mg of hydrochlorothiazide, 10 mg of benazepril hydrochloride with 12.5 mg of hydrochlorothiazide, 20 mg of benazepril hydrochloride with 12.5 mg of hydrochlorothiazide, and 20 mg of benazepril hydrochloride with 25 mg of hydrochlorothiazide.

Inactive ingredients include colloidal silicon dioxide, crospovidone, hydrogenated castor oil, lactose monohydrate, poloxamer, polyethylene glycol, pregelatinized starch (corn), titanium dioxide, and zinc stearate. The 5 mg/6.25 mg tablets also contain polyvinyl alcohol - part hydrolyzed and talc. The 10 mg/12.5 mg tablets contain FD&C red No. 40, FD&C yellow No. 6, polyvinyl alcohol, and talc. The 20 mg/12.5 mg tablets include FD&C blue No. 2, FD&C red No. 40, hypromellose, and polysorbate, while the 20 mg/25 mg tablets contain FD&C red No. 40, hypromellose, and polysorbate. This product meets USP Dissolution Test 2.

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 starting dose for the management of blood pressure is 10/12.5 mg administered once daily. After an initial period of 2 to 3 weeks, the dosage may be increased as necessary to achieve desired blood pressure goals. The maximum recommended dose should not exceed 20/25 mg per day.

Healthcare professionals should ensure that the medication is taken consistently at the same time each day to maintain stable blood levels. Adjustments to the dosage should be made based on the patient's response and tolerability.

Contraindications

Benazepril hydrochloride 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. 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.

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

Coadministration of aliskiren with angiotensin receptor blockers or ACE inhibitors, including benazepril hydrochloride 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 Angioedema Reactions Anaphylactoid reactions, including angioedema affecting the face, extremities, lips, tongue, glottis, and larynx, have been reported. In cases of laryngeal stridor or significant angioedema, treatment must be discontinued immediately, and appropriate therapy should be initiated. It is important to note that black patients have a higher incidence of angioedema. Additionally, intestinal angioedema has been observed in patients treated with ACE inhibitors, often presenting with abdominal pain. Diagnosis may necessitate imaging or surgical intervention, with symptoms typically resolving upon discontinuation of the ACE inhibitor.

Desensitization and Membrane Exposure Risks Life-threatening anaphylactoid reactions have occurred in patients undergoing desensitization treatment while on ACE inhibitors. Furthermore, reactions have been reported in patients undergoing dialysis with high-flux membranes while receiving these medications.

Hypotension and Renal Function Monitoring ACE inhibitors can lead to symptomatic hypotension, particularly in patients who are volume- or salt-depleted. Caution is advised when administering these agents to patients on other antihypertensives. Regular monitoring of renal function is essential, as acute renal failure may occur in patients whose renal function is dependent on the renin-angiotensin system.

Hematological Monitoring 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 Benazepril hydrochloride and hydrochlorothiazide should be discontinued as soon as pregnancy is detected, as drugs affecting the renin-angiotensin system can cause injury or death to the developing fetus. If jaundice or significant elevations in hepatic enzymes occur, the medication should be discontinued.

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

General Precautions Serum electrolytes should be monitored periodically due to the potential for hypokalemia, hyponatremia, and hyperkalemia. Hydrochlorothiazide may also affect glucose tolerance and elevate serum cholesterol and triglycerides. It is advised to avoid the use of benazepril hydrochloride and hydrochlorothiazide in patients with hypercalcemia.

Laboratory Testing Considerations The hydrochlorothiazide component may decrease serum protein-bound iodine (PBI) levels without causing signs of thyroid disturbance. Therapy should be interrupted for several days prior to conducting tests of parathyroid function.

Emergency Situations In the event of laryngeal stridor or angioedema affecting the face, tongue, or glottis, treatment must be discontinued immediately, and appropriate medical intervention should be sought. If hypotension occurs, the patient should be placed in a supine position, and intravenous infusion of physiological saline may be necessary.

Side Effects

Patients may experience a range of adverse reactions while using this medication, which can be categorized by frequency and seriousness.

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 1.0%, encompass a variety of systems. Cardiovascular effects may include palpitations and flushing. Gastrointestinal reactions can manifest as vomiting, diarrhea, dyspepsia, anorexia, and constipation. Neurologic and psychiatric effects may present as insomnia, nervousness, paresthesia, decreased libido, dry mouth, taste perversion, and tinnitus. Dermatologic reactions include rash and sweating. Additional reactions reported involve urinary frequency, arthralgia, myalgia, asthenia, and various types of pain, including chest and abdominal pain.

Postmarketing experience has revealed further adverse reactions associated with the components of the medication. Notably, benazepril has been linked to serious conditions such as 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 symptoms including vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, and anorexia. Cardiovascular issues such as syncope, peripheral vascular disorder, and tachycardia have also been reported. Other systemic reactions include 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.

Warnings associated with this medication include the potential for fetal toxicity, as drugs acting on the renin-angiotensin system may cause injury or death to a developing fetus. Anaphylactoid reactions, including angioedema affecting the face, extremities, lips, tongue, glottis, and larynx, have been reported, with laryngeal edema posing a risk of fatality. Symptomatic hypotension may occur, particularly in patients who are volume and/or salt depleted. Additionally, neutropenia or agranulocytosis may necessitate monitoring of white blood cell counts in patients with collagen-vascular disease.

Other important notes include the potential for hydrochlorothiazide to 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. Rarely, hepatic failure may occur, beginning with cholestatic jaundice and potentially progressing to fulminant hepatic necrosis.

Drug Interactions

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

When potassium supplements or potassium-sparing diuretics are used alongside benazepril hydrochloride and hydrochlorothiazide, there may be alterations in potassium levels. It is advisable to monitor potassium levels periodically in these patients.

The coadministration of ACE inhibitors with mTOR inhibitors, such as temsirolimus, sirolimus, or everolimus, may elevate the risk of angioedema.

Thiazide diuretics, including hydrochlorothiazide, can reduce the renal clearance of lithium, leading to an increased risk of lithium toxicity. Patients receiving both lithium and benazepril hydrochloride and hydrochlorothiazide should have their lithium levels monitored closely.

The dual blockade of the renin-angiotensin system (RAS) through the combined use of angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with heightened risks of hypertension, hyperkalemia, and renal function changes, including acute renal failure. It is recommended to avoid the combined use of RAS inhibitors. Patients on benazepril hydrochloride and hydrochlorothiazide, along with other RAS-affecting agents, should have their blood pressure, renal function, and electrolytes closely monitored. Additionally, aliskiren should not be coadministered with benazepril hydrochloride and hydrochlorothiazide in patients with diabetes or renal impairment (GFR <60 mL/min).

In elderly or volume-depleted patients, particularly those on diuretic therapy or with compromised renal function, the coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors like benazepril may lead to renal function deterioration, potentially resulting in acute renal failure. Renal function should be monitored periodically in patients receiving benazepril and NSAID therapy, as the antihypertensive effect of benazepril and hydrochlorothiazide may be diminished by NSAIDs.

Benazepril has been used safely with beta-adrenergic-blocking agents, calcium-blocking agents, cimetidine, diuretics, digoxin, hydralazine, and naproxen without significant adverse interactions. Interaction studies with warfarin and acenocoumarol have not demonstrated clinically important effects on serum concentrations or clinical outcomes.

Rare nitritoid reactions, characterized by facial flushing, nausea, vomiting, and hypotension, have been reported in patients receiving injectable gold (sodium aurothiomalate) alongside ACE inhibitors.

Hydrochlorothiazide has specific interaction considerations:

• Ion Exchange Resins: Hydrochlorothiazide should be administered at least 4 hours before or 4 to 6 hours after ion exchange resins to prevent significant absorption reduction.

• 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.

• Antidiabetic Agents: Dosage adjustments of antidiabetic medications may be necessary.

• Antineoplastic Agents: The use of thiazide diuretics may decrease the renal excretion of cytotoxic agents, enhancing their myelosuppressive effects.

• Drugs that Alter Gastrointestinal Motility: Anticholinergic agents may increase the bioavailability of thiazide diuretics, while prokinetic drugs may decrease it.

• Cyclosporin: The risk of hyperuricaemia and gout-type complications may be heightened with concomitant diuretic use.

• Alcohol, Barbiturates, or Narcotics: The combination of thiazide diuretics with these substances may potentiate orthostatic hypotension.

• Pressor Amines: Hydrochlorothiazide may diminish the response to pressor amines like noradrenaline, although this effect is not clinically 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. 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

Elderly patients, defined as those aged 65 years and older, comprised 19% of the total population in U.S. clinical studies involving benazepril hydrochloride and hydrochlorothiazide, with approximately 1.5% of patients being 75 years or older. Clinical findings indicate that there were no overall differences in effectiveness or safety between geriatric 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 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 whether to discontinue nursing 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 monitored periodically for changes in renal function while receiving benazepril hydrochloride and hydrochlorothiazide. The use of drugs that inhibit the renin-angiotensin system and diuretics can lead to alterations in renal function, including the risk of 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 acute renal failure when treated with this combination.

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 indicated that treatment with benazepril in hypertensive patients with unilateral or bilateral renal artery stenosis was associated with increases in blood urea nitrogen and serum creatinine; these elevations 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, it is crucial to monitor liver function closely. Should any patient develop jaundice or exhibit marked elevations in hepatic enzyme levels, the ACE inhibitor should be discontinued immediately. Appropriate medical follow-up is essential to manage any potential complications arising from hepatic impairment.

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 necessary, 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 is essential during the management of an overdose to ensure that the patient remains stable and to guide further therapeutic interventions. 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 monitoring.

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 dose corresponds to 18 times the maximum recommended human dose on a body-surface-area basis for rats and 9 times for mice. 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.

In reproductive toxicity studies, benazepril was administered at doses ranging from 50 to 500 mg/kg/day, which is 6 to 61 times the maximum recommended dose 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, rats and mice were fed hydrochlorothiazide for 2 years at doses up to 600 mg/kg/day in mice and up to 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 using strains of Salmonella typhimurium, the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, and in vivo assays involving mouse germinal cell chromosomes and Chinese hamster bone marrow chromosomes.

Conversely, positive results were obtained in the in vitro CHO Sister Chromatid Exchange test and in the Mouse Lymphoma Cell mutagenicity assays at hydrochlorothiazide concentrations ranging from 43 to 1300 mcg/mL. Additionally, positive test results were recorded 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), especially in white patients receiving large cumulative doses. Data from the Sentinel System indicate that the overall risk for SCC is approximately 1 additional case per 16,000 patients per year, with a higher risk of approximately 1 additional case per 6,700 patients per year in white patients taking a cumulative dose of ≥50,000 mg.

Additional adverse events reported with hydrochlorothiazide include:

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

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

Musculoskeletal: Muscle spasm.

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

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

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

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

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

These events highlight the importance of ongoing monitoring and reporting of adverse reactions 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 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. It is important for them to discuss treatment options with their physician if they are planning to become pregnant and to report any pregnancies 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 prescribing physician. In the event of syncope, patients should discontinue the medication and consult with their physician before resuming treatment.

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

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

Patients should be encouraged 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 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 with benazepril hydrochloride and hydrochlorothiazide should be interrupted for a few days before conducting tests of parathyroid function.

Storage and Handling

The product is to be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. It is essential to protect the product from light and moisture to maintain its integrity. The container must be kept tightly closed at all times.

Each strength of the product is supplied in bottles that include a desiccant to help control moisture. When dispensing, it is important to use a tight, light-resistant container as specified by the USP, equipped with a child-resistant closure as required.

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 for 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 Glenmark Pharmaceuticals Inc. , USA. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)