Benazepril hydrochloride/Hydrochlorothiazide

Description

Benazepril hydrochloride 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. The active metabolite, benazeprilat, functions as a nonsulfhydryl angiotensin-converting enzyme inhibitor, formed through hepatic cleavage of the ester group from benazepril.

Hydrochlorothiazide USP is a white or practically white, odorless crystalline powder, slightly soluble in water and freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide. It is sparingly soluble in methanol and insoluble in ether, chloroform, and dilute mineral acids. The chemical name for hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular formula of C7H8ClN3O4S2 and a molecular weight of 297.73. Hydrochlorothiazide acts as a thiazide diuretic.

The combination tablets of benazepril hydrochloride and hydrochlorothiazide are formulated for oral administration, containing 5, 10, or 20 mg of benazepril hydrochloride and 6.25, 12.5, or 25 mg of hydrochlorothiazide USP. Inactive ingredients include crospovidone, hydrogenated castor oil, hypromellose, iron oxide (black), iron oxide (red), lactose monohydrate, magnesium stearate, polyethylene glycol, talc, and titanium dioxide.

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 of benazepril and 12.5 mg of hydrochlorothiazide. 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 mg of benazepril and 25 mg of hydrochlorothiazide.

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 appropriate. In such cases, the usual recommended starting dose remains at 10/12.5 mg once daily.

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

Contraindications

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

Patients who are anuric. The use of this medication in such patients may lead to further renal complications.

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, regardless of previous ACE inhibitor treatment, due to the risk of exacerbating this condition.

Co-administration of aliskiren with angiotensin receptor blockers or ACE inhibitors, including benazepril hydrochloride and hydrochlorothiazide tablets, is contraindicated in patients with diabetes, as it 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 Angioedema Reactions Anaphylactoid reactions, including angioedema affecting the face, extremities, lips, tongue, glottis, and larynx, have been reported. In cases of laryngeal stridor or angioedema, it is imperative to discontinue treatment immediately and initiate appropriate therapy. Additionally, intestinal angioedema may present with abdominal pain, with symptoms resolving upon cessation of the ACE inhibitor. Life-threatening anaphylactoid reactions have also occurred in patients undergoing desensitization while on ACE inhibitors, as well as in those dialyzed with high-flux membranes.

Hypotension Benazepril can lead to symptomatic hypotension, particularly in patients who are volume and/or salt depleted. It is essential to correct any volume and/or salt depletion prior to initiating therapy. Should hypotension occur, the patient should be placed in a supine position, and if necessary, treated with intravenous infusion of physiological saline.

Renal Function Monitoring Periodic monitoring of renal function is recommended, and therapy should be withheld or discontinued in patients who exhibit a clinically significant decrease in renal function.

Neutropenia and Agranulocytosis Patients with collagen-vascular disease, especially those with impaired renal function, should have their white blood cell counts monitored due to the risk of neutropenia or agranulocytosis.

Fetal Toxicity The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy can adversely affect fetal renal function, leading to increased morbidity and mortality. Therefore, benazepril hydrochloride and hydrochlorothiazide should be discontinued as soon as pregnancy is detected.

Hepatic Function In the event of jaundice or significant elevations in hepatic enzymes, the ACE inhibitor should be discontinued, and appropriate medical follow-up should be sought.

Systemic Lupus Erythematosus Thiazide diuretics, such as hydrochlorothiazide, may exacerbate or activate systemic lupus erythematosus.

Ocular Effects Hydrochlorothiazide has been associated with acute transient myopia and secondary angle-closure glaucoma. If these symptoms occur, discontinuation of hydrochlorothiazide should be undertaken as rapidly as possible.

Laboratory Tests It is advised to interrupt therapy with benazepril hydrochloride and hydrochlorothiazide for a few days prior to conducting tests of parathyroid function to ensure accurate results.

Healthcare professionals should remain vigilant for these potential adverse effects and monitor patients accordingly to ensure safe and effective use of these medications.

Side Effects

Patients in U.S. placebo-controlled studies have reported various adverse reactions, with the most common being dizziness (6.3%), fatigue (5.2%), and postural dizziness (3.5%). Other frequently observed reactions include headache (3.1%), cough (2.1%), hypertonia (1.5%), vertigo (1.5%), nausea (1.4%), impotence (1.2%), and somnolence (1.2%).

Additional side effects occurring in 0.3% to 1% of patients encompass cardiovascular issues such as palpitations and flushing, gastrointestinal disturbances including vomiting, diarrhea, dyspepsia, anorexia, and constipation, as well as 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.

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

Postmarketing experience has revealed serious adverse reactions associated with benazepril, including Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, thrombocytopenia, and eosinophilic pneumonitis. For hydrochlorothiazide, notable digestive issues include pancreatitis, small bowel angioedema, and jaundice, alongside neurologic symptoms such as vertigo and transient blurred vision. Musculoskeletal reactions like muscle spasm, hematologic concerns including aplastic anemia and agranulocytosis, and metabolic disturbances such as hyperglycemia and hyperuricemia have also been reported. Hypersensitivity reactions may include anaphylactoid responses, necrotizing angiitis, and various skin reactions, including erythema multiforme and exfoliative dermatitis.

Warnings associated with the use of these medications include the potential for anaphylactoid reactions, which can lead to angioedema affecting the face, extremities, and larynx, with the latter being potentially fatal. Symptomatic hypotension may occur, particularly in patients who are volume or salt depleted. Changes in renal function, including acute renal failure, can also arise, necessitating monitoring of renal status. Additionally, neutropenia and agranulocytosis have been observed, warranting consideration of white blood cell count monitoring in patients with collagen-vascular diseases.

A boxed warning highlights the risk of fetal toxicity, indicating that drugs acting directly on the renin-angiotensin system can cause injury or death to a developing fetus. It is advised to discontinue benazepril hydrochloride and hydrochlorothiazide as soon as pregnancy is detected.

Drug Interactions

Concomitant use of benazepril hydrochloride and hydrochlorothiazide with potassium supplements or potassium-sparing diuretics may lead to alterations in potassium levels. It is advisable to monitor potassium levels periodically in patients receiving this combination.

The renal clearance of lithium is decreased by thiazide diuretics, which increases the risk of lithium toxicity. Patients receiving benazepril hydrochloride and hydrochlorothiazide alongside lithium should have their lithium levels monitored closely due to the potential for increased serum lithium concentrations and associated toxicity symptoms.

The dual blockade of the renin-angiotensin system (RAS) through the 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. Most patients do not experience additional benefits from the combination of two RAS inhibitors compared to monotherapy. Therefore, the combined use of RAS inhibitors should generally be avoided. Patients on benazepril hydrochloride and hydrochlorothiazide, along with other RAS-affecting agents, should be closely monitored for blood pressure, renal function, and electrolyte levels. Specifically, aliskiren should not be co-administered with benazepril hydrochloride and hydrochlorothiazide in patients with diabetes or renal impairment (GFR < 60 ml/min).

In elderly patients, those who are volume-depleted, or individuals with compromised renal function, the co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors such as benazepril may lead to renal function deterioration, potentially resulting in acute renal failure. These effects are typically reversible; however, 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.

Benazepril has been used safely in conjunction with beta-adrenergic blockers, calcium channel blockers, cimetidine, diuretics, digoxin, hydralazine, and naproxen without significant adverse interactions. Interaction studies with anticoagulants such as 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 avoid 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 (e.g., cyclophosphamide, methotrexate): The use of thiazide diuretics may reduce the renal excretion of these agents and enhance 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 hyperuricemia and gout-type complications may be increased 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 such as noradrenaline, although this effect is not 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

Pediatric patients, particularly neonates with a history of in utero exposure to benazepril hydrochloride and hydrochlorothiazide, may experience complications such as oliguria or hypotension. In such cases, it is crucial to provide support for blood pressure and renal perfusion. Interventions such as exchange transfusions or dialysis may be necessary to address hypotension and/or to compensate for impaired renal function. Although benazepril can cross the placenta and may theoretically be removed from the neonatal circulation through these procedures, reports of benefit from similar interventions with other ACE inhibitors are limited.

The safety and effectiveness of benazepril hydrochloride and hydrochlorothiazide in pediatric patients have not been established, and caution is advised when considering its use in this population.

Geriatric Use

Elderly patients represent a significant portion of the population receiving benazepril hydrochloride and hydrochlorothiazide, with 19% of participants in U.S. clinical studies being 65 years of age or older, and approximately 1.5% being 75 years or older. Clinical findings indicate that there were no overall differences in effectiveness or safety between these 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 while minimizing the risk of adverse effects.

Pregnancy

There are no adequate and well-controlled studies of benazepril and hydrochlorothiazide in pregnant patients. Animal studies have shown no evidence of carcinogenicity for benazepril when administered to rats and mice for 104 weeks at doses up to 150 mg/kg/day. Additionally, hydrochlorothiazide was not found to be genotoxic in in vitro assays using various strains of Salmonella typhimurium.

In terms of fertility, animal studies indicate that benazepril and hydrochlorothiazide, either alone or in combination, did not adversely affect fertility and conception. However, there are no human fertility data available for hydrochlorothiazide.

Given the lack of human data and the potential for unknown risks, healthcare professionals should exercise caution when prescribing these medications to pregnant patients. It is recommended that the benefits and risks be carefully weighed in the context of the individual patient's condition.

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. 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.

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.

Furthermore, monitoring of white blood cell counts is advisable in patients with collagen-vascular disease, particularly if the disease is associated with impaired renal function.

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 enzymes, 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 focus on symptomatic and supportive care. It is recommended that therapy with benazepril hydrochloride and hydrochlorothiazide be discontinued, and the patient should be closely monitored. Key considerations include the treatment of dehydration, electrolyte imbalances, and hypotension according to established medical protocols.

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

Human data on benazepril overdose are limited, but hypotension is likely the most common manifestation. In cases of hydrochlorothiazide overdose, dehydration and electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, are frequently observed. 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 commonly available, and such determinations do not have a defined role in the management of 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-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 advisable to manage benazepril overdose with the infusion of normal saline solution to restore hemodynamic stability.

Nonclinical Toxicology

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

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. Similarly, hydrochlorothiazide did not exhibit carcinogenic potential in rats or female mice; however, equivocal evidence of hepatocarcinogenicity was noted in male mice.

In terms of mutagenicity, no mutagenic activity was detected in the Ames test in bacteria, both with and without metabolic activation, nor in an in vitro test for forward mutations in cultured mammalian cells or in a nucleus anomaly test. Hydrochlorothiazide was also not genotoxic in various in vitro assays, including tests 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.

However, positive results were obtained in the in vitro CHO Sister Chromatid Exchange test and in Mouse Lymphoma Cell assays at hydrochlorothiazide concentrations ranging from 43 to 1300 mcg/mL. Additionally, positive results were recorded in the Aspergillus nidulans nondisjunction assay at an unspecified concentration of hydrochlorothiazide.

Benazepril, administered to rats and mice for 104 weeks at doses up to 150 mg/kg/day, and hydrochlorothiazide, given in feed to rats and mice for 2 years at doses up to 600 mg/kg/day in mice and up to 100 mg/kg/day in rats, did not reveal any adverse effects on reproductive performance in 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 on a body-surface-area basis.

Postmarketing Experience

During post-approval use of benazepril and hydrochlorothiazide, various adverse reactions have been reported voluntarily or through surveillance programs. Due to the nature of these reports, which originate from a population of uncertain size, it is not always feasible to estimate their frequency or establish a causal relationship to drug exposure.

For benazepril, the following adverse reactions have been identified: Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, thrombocytopenia, and eosinophilic pneumonitis.

In the case of hydrochlorothiazide, a broader range of adverse reactions has been reported across several categories:

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

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

Musculoskeletal Reactions: Muscle spasm.

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

Metabolic Reactions: 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.

Patient Counseling

Healthcare providers should advise patients that if pregnancy is detected, benazepril hydrochloride and hydrochlorothiazide should be discontinued as soon as possible. It is important to inform patients that medications acting directly on the renin-angiotensin system can cause injury or death to a developing fetus. Female patients of childbearing age should be made aware of the potential consequences of exposure to these medications during pregnancy and should discuss treatment options if they are planning to become pregnant.

Patients should be encouraged to report any pregnancies to their healthcare provider as soon as possible. Additionally, patients receiving benazepril hydrochloride and hydrochlorothiazide should be instructed to report immediately any signs or symptoms of angioedema, such as swelling of the face, eyes, lips, or tongue, or difficulty breathing, and to refrain from taking any further doses until they have consulted with their prescribing physician.

Patients should also be cautioned that lightheadedness may occur, particularly during the initial days of therapy, and this should be reported to the prescribing physician. In the event of syncope, patients should discontinue the medication and seek advice from their physician.

It is essential 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 or syncope. Patients should be advised against using potassium supplements or salt substitutes containing potassium without prior consultation with their prescribing physician.

Finally, patients should be instructed to promptly report any signs of infection, such as a sore throat or fever, as these may indicate neutropenia.

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 to 25° C (68 to 77° F), in accordance with USP Controlled Room Temperature guidelines. It is essential to protect the product from moisture and light to maintain its quality. Additionally, this product, along with all medications, must be kept out of the reach of children to ensure safety.

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 thyroid disturbance in patients. Clinicians are advised to interrupt 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 Ranbaxy Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)