Benazepril hydrochloride/Hydrochlorothiazide

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.

Limitations of Use

This medication should not be used as the first-line treatment for hypertension.

Dosage and Administration

The recommended dosage of Benazepril Hydrochloride and Hydrochlorothiazide is 10/12.5 mg once daily. This dosage may be increased after 2 to 3 weeks as needed to achieve desired blood pressure goals, with a maximum recommended dose of 20/25 mg once daily.

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 is appropriate. The usual starting dose for this switch is 10/12.5 mg once daily.

The combination may also be used as a replacement therapy for patients who have been titrated on the individual components.

Administration is via the oral route, and the tablets may be taken with or without food.

Contraindications

Benazepril hydrochloride and hydrochlorothiazide is contraindicated in patients who are anuric. It is also contraindicated in individuals who are hypersensitive 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.

Additionally, the medication is contraindicated in patients with a history of angioedema, whether or not they have previously received ACE inhibitor treatment. Co-administration with a neprilysin inhibitor, such as sacubitril, is also contraindicated; benazepril hydrochloride and hydrochlorothiazide should not be administered within 36 hours of switching to or from sacubitril/valsartan.

Furthermore, the use of aliskiren in combination with angiotensin receptor blockers or ACE inhibitors, including benazepril hydrochloride and hydrochlorothiazide, is contraindicated in patients with diabetes.

Warnings and Precautions

Anaphylactoid and Possibly Related Reactions Patients receiving ACE inhibitors, including benazepril hydrochloride and hydrochlorothiazide, may experience a variety of adverse reactions, some of which can be serious. Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported, with the potential for laryngeal edema to be fatal. If laryngeal stridor or angioedema occurs, treatment should be discontinued immediately, and appropriate therapy should be instituted. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks. Additionally, patients receiving coadministration of an ACE inhibitor with an mTOR inhibitor or a neprilysin inhibitor may be at increased risk for angioedema. Intestinal angioedema has also been reported, often presenting with abdominal pain, and symptoms typically resolve after discontinuation of the ACE inhibitor. Life-threatening anaphylactoid reactions have occurred in patients undergoing desensitization while receiving ACE inhibitors, as well as in patients dialyzed with high-flux membranes.

Hypotension Benazepril hydrochloride and hydrochlorothiazide can cause symptomatic hypotension, particularly in patients who are volume and/or salt depleted. Therapy should be initiated under close medical supervision in patients with congestive heart failure, as excessive hypotension may lead to oliguria, azotemia, and, in rare cases, acute renal failure and death. If hypotension occurs, the patient should be placed in a supine position, and intravenous infusion of physiological saline may be necessary.

Impaired Renal Function Renal function should be monitored periodically in patients treated with benazepril hydrochloride and hydrochlorothiazide. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function.

Neutropenia/Agranulocytosis Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if associated with impaired renal function.

Fetal Toxicity The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy can reduce fetal renal function and increase morbidity and mortality. Benazepril hydrochloride and hydrochlorothiazide should be discontinued as soon as pregnancy is detected.

Hepatic Failure Discontinue the ACE inhibitor if jaundice or marked elevations of hepatic enzymes occur, and ensure appropriate medical follow-up.

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

Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide can cause acute transient myopia and angle-closure glaucoma. Discontinue hydrochlorothiazide as rapidly as possible if symptoms occur.

General Precautions Serum electrolytes should be monitored periodically due to the potential for hypokalemia, hyponatremia, and hyperkalemia. Hydrochlorothiazide may also alter glucose tolerance and raise serum cholesterol and triglyceride levels. Avoid using benazepril hydrochloride and hydrochlorothiazide in patients with hypercalcemia. Persistent nonproductive cough has been reported with ACE inhibitors, resolving after discontinuation of therapy.

Laboratory Tests Therapy with benazepril hydrochloride and hydrochlorothiazide should be interrupted for a few days before carrying out tests of parathyroid function. The hydrochlorothiazide component may decrease serum PBI levels without signs of thyroid disturbance.

Emergency Medical Help If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment should be discontinued immediately, and appropriate therapy should be instituted.

Side Effects

Patients in U.S. placebo-controlled studies have reported several adverse reactions associated with the use of Benazepril Hydrochloride and Hydrochlorothiazide. The following sections categorize these reactions by seriousness and frequency.

Common Adverse Reactions

• 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%

• Somnolence: 1.2%

Other Adverse Reactions (0.3% to 1.0%)

• Cardiovascular: Palpitations, flushing, hypotension (0.6%), postural hypotension (0.3%), syncope, peripheral vascular disorder, tachycardia.

• Gastrointestinal: Vomiting, diarrhea, dyspepsia, anorexia, constipation, gastroenteritis, flatulence, tooth disorder.

• Neurologic and Psychiatric: Insomnia, nervousness, paresthesia, libido decrease, dry mouth, taste perversion, tinnitus, lightheadedness, transient blurred vision, abnormal vision, abnormal dreams, retinal disorder.

• Dermatologic: Rash, sweating, photosensitivity, pruritus.

• Other: Urinary frequency, arthralgia, myalgia, asthenia, pain (including chest pain and abdominal pain), infection, back pain, flu syndrome, fever, chills, neck pain, conjunctivitis, arthritis, urinary tract infection, alopecia.

Serious Adverse Reactions

• Angioedema: Edema of the face, extremities, lips, tongue, glottis, and larynx has been reported, with the potential for fatal laryngeal edema.

• Neutropenia/Agranulocytosis: Monitoring of white blood cell counts is recommended in patients with collagen-vascular disease, especially if associated with impaired renal function.

• Fetal Toxicity: Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus; discontinuation is advised as soon as pregnancy is detected.

• Hepatic Failure: Rarely associated with a syndrome that begins with cholestatic jaundice and can progress to fulminant hepatic necrosis and death.

Postmarketing Experience

• Benazepril: Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, thrombocytopenia, eosinophilic pneumonitis.

• Hydrochlorothiazide:

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

  • Neurologic: Vertigo, weakness, restlessness, muscle spasm.

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

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

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

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

Additional Notes

• Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, predominantly squamous cell carcinoma (SCC).

• Acute myopia and secondary angle-closure glaucoma have been reported as idiosyncratic reactions to Hydrochlorothiazide.

Monitoring and management of these adverse reactions are essential for patient safety and effective treatment.

Drug Interactions

Patients taking concomitant neprilysin inhibitors, such as sacubitril, may be at increased risk for angioedema. Additionally, the use of benazepril hydrochloride and hydrochlorothiazide with potassium supplements or potassium-sparing diuretics may affect potassium levels; therefore, potassium should be monitored periodically.

The renal clearance of lithium is reduced by thiazides, which increases the risk of lithium toxicity. Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. Monitoring of lithium levels is advised when used concomitantly with benazepril hydrochloride and hydrochlorothiazide.

Dual blockade of the renin-angiotensin system (RAS) with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypertension, hyperkalemia, and changes in renal function, including acute renal failure. It is generally recommended to avoid the combined use of RAS inhibitors, particularly in patients with diabetes or renal impairment (GFR < 60 mL/min).

Coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors may result in deterioration of renal function, especially in elderly patients, those who are volume-depleted, or those with compromised renal function. These effects are usually reversible, but renal function should be monitored periodically. Furthermore, the antihypertensive effect of benazepril and hydrochlorothiazide may be attenuated by NSAIDs.

Interaction studies have shown that benazepril does not have clinically important effects on the serum concentrations or clinical effects of anticoagulants such as warfarin and acenocoumarol. However, nitritoid reactions have been reported rarely in patients receiving injectable gold (sodium aurothiomalate) in conjunction with ACE inhibitors.

For hydrochlorothiazide, it is important to stagger the dosage with ion exchange resins, administering hydrochlorothiazide at least 4 hours before or 4 to 6 hours after the resins to avoid reduced absorption. Thiazide-induced hypokalemia or hypomagnesemia may predispose patients to digoxin toxicity, and there may be increased responsiveness to muscle relaxants such as curare derivatives.

Dosage adjustments of antidiabetic drugs may be necessary when using hydrochlorothiazide. Additionally, the concomitant use of thiazide diuretics with antineoplastic agents (e.g., cyclophosphamide, methotrexate) may reduce renal excretion and enhance myelosuppressive effects. The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents due to decreased gastrointestinal motility, while pro-kinetic drugs may decrease their bioavailability.

Concomitant treatment with diuretics may increase the risk of hyperuricemia and gout-type complications when using cyclosporin. Furthermore, the administration of thiazide diuretics with alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension. Hydrochlorothiazide may also reduce the response to pressor amines such as noradrenaline, although the clinical significance of this effect is not sufficient to preclude their use.

Pediatric Use

Neonates with a history of in utero exposure to benazepril hydrochloride and hydrochlorothiazide may require special attention. If oliguria or hypotension occurs, it is essential to support blood pressure and renal perfusion. Exchange transfusions or dialysis may be necessary to reverse hypotension and/or substitute for disordered renal function. Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; however, there are only occasional reports of benefit from these maneuvers with another ACE inhibitor, and experience is limited.

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

In U.S. clinical studies involving benazepril hydrochloride and hydrochlorothiazide, 19% of patients were aged 65 or older, with approximately 1.5% being 75 or older. No overall differences in effectiveness or safety were observed between elderly patients and younger patients. However, 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.

Given that benazepril and its active metabolite, benazeprilat, are substantially excreted by the kidneys, caution is advised in dose selection for elderly patients, who are more likely to have decreased renal function. It may be beneficial to monitor renal function in this population to ensure appropriate dosing and minimize the risk of adverse effects. While clinical experience has not identified significant differences in responses between elderly and younger patients, the potential for greater sensitivity in some older individuals cannot be ruled out.

Pregnancy

Benazepril Hydrochloride and Hydrochlorothiazide is classified as Pregnancy Category D, indicating that there is positive evidence of human fetal risk based on data from investigational or marketing experience or studies in humans. Healthcare professionals should be aware of the potential for fetal/neonatal morbidity and mortality associated with the use of this medication during pregnancy.

Animal studies have shown that benazepril and hydrochlorothiazide, either alone or in combination, did not adversely affect fertility or conception. However, there are no available human fertility data for hydrochlorothiazide. Additionally, no evidence of carcinogenicity was observed when benazepril was administered to rats and mice for 104 weeks at doses up to 150 mg/kg/day, and hydrochlorothiazide was not found to be genotoxic in various in vitro assays.

Given the potential risks, healthcare providers are advised to carefully consider the benefits and risks of prescribing this medication to pregnant patients. It is recommended that alternative therapies be considered, especially during the second and third trimesters, when the risk of adverse fetal outcomes may be heightened.

Lactation

Minimal amounts of unchanged benazepril and its active metabolite, benazeprilat, are excreted into the breast milk of lactating women, with breastfed infants receiving less than 0.1% of the maternal doses. In contrast, hydrochlorothiazide, a thiazide diuretic, is definitively excreted into breast milk.

Due to the potential for serious adverse reactions in nursing infants from hydrochlorothiazide and the unknown effects of benazepril, healthcare providers should carefully consider whether to discontinue breastfeeding or to stop the use of benazepril hydrochloride and hydrochlorothiazide. This decision should take into account the importance of the medication to the mother’s health. Caution is advised when administering these medications to nursing mothers, given the lack of data on their effects on breastfed infants.

Renal Impairment

Patients with renal impairment should be closely monitored when treated with benazepril hydrochloride and hydrochlorothiazide. Periodic assessment of renal function is essential, as changes, 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 compromised by the activity of the renin-angiotensin system, such as those with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion. These patients are at an increased risk of developing acute renal failure while on therapy. In cases where a clinically significant decrease in renal function is observed, it may be necessary to withhold or discontinue treatment.

In a small study involving hypertensive patients with unilateral or bilateral renal artery stenosis, treatment with benazepril was associated with reversible increases in blood urea nitrogen and serum creatinine levels. Monitoring should be particularly vigilant during the initial weeks of therapy in these patients. Additionally, some patients without pre-existing renal vascular disease have experienced minor and transient increases in these parameters, especially when benazepril is administered alongside a diuretic, which may necessitate a dosage adjustment.

For patients with severe renal disease, the use of benazepril hydrochloride and hydrochlorothiazide should be approached with caution, as thiazides can precipitate azotemia, and the cumulative effects of repeated dosing may pose additional risks. Monitoring of white blood cell counts is also advisable in patients with collagen-vascular diseases, particularly if renal function is impaired.

Overall, careful evaluation of renal function is critical in the management of patients receiving benazepril hydrochloride and hydrochlorothiazide to mitigate potential adverse effects.

Hepatic Impairment

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

No adjustment of the initial dose is required for patients with mild to moderate hepatic impairment. However, in patients with hepatic dysfunction due to cirrhosis, levels of benazeprilat are essentially unaltered, and no formal pharmacokinetic studies have been conducted in hypertensive patients with impaired liver function.

Rarely, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice and can progress to fulminant hepatic necrosis and, in some cases, death. The mechanism underlying this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations in hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. Monitoring of liver function tests is recommended in these patients to ensure safety.

Overdosage

In cases of overdosage with benazepril hydrochloride and hydrochlorothiazide, treatment should be symptomatic and supportive, as no specific antidote is available. Therapy with these medications should be discontinued, and the patient should be closely monitored. The most common manifestation of benazepril overdosage in humans is likely to be hypotension, which may present with symptoms such as dizziness, fainting, or shock. In the case of hydrochlorothiazide overdose, signs and symptoms typically include dehydration and electrolyte depletion, specifically hypokalemia, hypochloremia, and hyponatremia. If digitalis has been administered concurrently, hypokalemia may exacerbate the risk of cardiac arrhythmias.

Patients experiencing an overdose should be placed in a supine position, and intravenous infusion of physiological saline may be necessary to manage hypotension. Monitoring of blood pressure and renal function is essential during the management of an overdose. Laboratory determinations of serum levels of benazepril and its metabolites are not widely available and do not play a role in the management of overdose. Additionally, there are no established physiological maneuvers to accelerate the elimination of benazepril and its metabolites, and while benazeprilat is only slightly dialyzable, dialysis may be considered for patients with severely impaired renal function.

Angiotensin II could theoretically serve as a specific antagonist-antidote in the context of benazepril overdose; however, it is largely unavailable outside of specialized research facilities. Therefore, the primary approach to managing an overdose involves supportive care and addressing the symptoms as they arise.

Nonclinical Toxicology

Teratogenic Effects

No teratogenic effects have been reported in the available studies for benazepril hydrochloride and hydrochlorothiazide.

Non-Teratogenic Effects

In animal studies, both benazepril and hydrochlorothiazide, administered alone or in combination, demonstrated no adverse effects on fertility and conception. Specifically, at doses ranging from 50 to 500 mg/kg/day, which corresponds to 6 to 61 times the maximum recommended human dose on a body-surface-area basis, benazepril did not adversely affect the reproductive performance of male and female rats.

Carcinogenesis

No evidence of carcinogenicity was observed when benazepril was administered to rats and mice for 104 weeks at doses up to 150 mg/kg/day, which is 18 times the maximum recommended human dose on a body-surface-area basis for rats and 9 times for mice. Similarly, studies involving hydrochlorothiazide, conducted under the National Toxicology Program, revealed no carcinogenic potential in rats or female mice; however, equivocal evidence of hepatocarcinogenicity was noted in male mice.

Mutagenesis

Benazepril exhibited no mutagenic activity in the Ames test, both with and without metabolic activation, nor in in vitro tests for forward mutations in cultured mammalian cells or in nucleus anomaly tests. Hydrochlorothiazide also showed no genotoxicity in various in vitro assays, including those using strains of Salmonella typhimurium and the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. However, positive results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma Cell (mutagenicity) assays at concentrations ranging from 43 to 1300 µg/mL. Additionally, positive results were noted in the Aspergillus nidulans nondisjunction assay.

Impairment of Fertility

Hydrochlorothiazide did not demonstrate any adverse effects on the fertility of male and female rats in studies where these animals were exposed to doses up to 100 mg/kg/day and 4 mg/kg/day, respectively, prior to mating and throughout gestation.

Animal Toxicology

Benazepril was administered to rats and mice for 104 weeks at doses up to 150 mg/kg/day. Hydrochlorothiazide was given to rats and mice in their feed for 2 years, at doses up to 600 mg/kg/day in mice and up to 100 mg/kg/day in rats.

Storage and Handling

Benazepril Hydrochloride and Hydrochlorothiazide is supplied in tablet form, including both coated and film-coated configurations.

The product should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as per USP Controlled Room Temperature guidelines. It is essential to protect the tablets from moisture and light.

Each strength is provided in bottles that contain a desiccant to maintain product integrity. The tablets must be dispensed in a tight, light-resistant container as defined by the USP, equipped with a child-resistant closure as required.

Additionally, it is crucial to keep this and all medications out of the reach of children.