Lotensin Hct

Description

Benazepril hydrochloride USP is a white to off-white crystalline powder, soluble in water (>100 mg/mL), ethanol, and methanol. Its chemical name is 3-[1-(ethoxycarbonyl)-3-phenyl-(1S)-propyl amino]-2,3,4,5-tetrahydro-2-oxo-1 H-1-(3S)-benzazepine-1-acetic acid monohydrochloride, with an empirical formula of C24H28N2O5·HCl and a molecular weight of 460.96. Hydrochlorothiazide USP is a white or practically white, practically odorless crystalline powder. It is slightly soluble in water, freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide, sparingly soluble in methanol, and insoluble in ether, chloroform, and dilute mineral acids. Hydrochlorothiazide’s chemical name is 6-chloro-3,4-dihydro-2 H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with an empirical formula of C7H8ClN3O4S2 and a molecular weight of 297.73. Lotensin HCT is a combination of benazepril and hydrochlorothiazide USP, formulated as tablets for oral administration containing either 10 or 20 mg of benazepril and 12.5 or 25 mg of hydrochlorothiazide USP. The inactive ingredients in the tablets include cellulose compounds, crospovidone, hydrogenated castor oil, iron oxides (in the 10/12.5 mg, 20/12.5 mg, and 20/25 mg tablets), lactose, polyethylene glycol, talc, and titanium dioxide.

Uses and Indications

Lotensin HCT USP is indicated for the treatment of hypertension. This fixed combination drug is not indicated for the initial therapy of hypertension.

Dosage and Administration

The recommended dosage of Lotensin HCT is once daily. Initial therapy should begin with a dose of 10/12.5 mg. After 2 to 3 weeks, the dosage may be increased as necessary to achieve desired blood pressure goals, with a maximum recommended dose of 20/25 mg.

For patients whose blood pressure is not adequately controlled with benazepril alone or hydrochlorothiazide alone, a switch to Lotensin HCT combination therapy is advised. In such cases, the usual starting dose remains 10/12.5 mg once daily.

Lotensin HCT may also be used as a replacement therapy, substituting the combination for the titrated individual components as clinically appropriate.

Contraindications

Lotensin HCT 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, regardless of previous ACE inhibitor treatment.

Concurrent use with a neprilysin inhibitor (e.g., sacubitril) is contraindicated. Lotensin HCT should not be administered within 36 hours of switching to or from sacubitril/valsartan.

Coadministration of aliskiren with angiotensin receptor blockers or ACE inhibitors, including Lotensin HCT, is contraindicated in patients with diabetes.

Warnings and Precautions

Patients treated with Lotensin HCT should be closely monitored for several serious adverse reactions and conditions that may arise during therapy.

Anaphylactoid and Possibly Related Reactions

Angioedema, including swelling of the face, extremities, lips, tongue, glottis, and larynx, has been reported in patients receiving angiotensin-converting enzyme (ACE) inhibitors. Notably, angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with Lotensin HCT must be discontinued immediately, and appropriate therapy should be initiated. It is important to note that black patients have a higher incidence of angioedema when treated with ACE inhibitors compared to nonblack patients. Additionally, patients receiving a combination of an ACE inhibitor with an mTOR inhibitor or a neprilysin inhibitor may be at an increased risk for angioedema. Intestinal angioedema has also been reported, with symptoms resolving upon discontinuation of the ACE inhibitor. Anaphylactoid reactions have been observed in patients undergoing dialysis with high-flux membranes while concurrently treated with an ACE inhibitor. Furthermore, hypersensitivity reactions to hydrochlorothiazide are more likely in patients with a history of allergy and asthma.

Hypotension

Lotensin HCT may cause symptomatic hypotension, particularly in patients who are volume- or salt-depleted. 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 receiving Lotensin HCT. If a clinically significant decrease in renal function is observed, consideration should be given to withholding or discontinuing therapy.

Neutropenia/Agranulocytosis

Monitoring of white blood cell counts is advisable in patients with collagen-vascular disease, especially those with concurrent impaired renal function.

Fetal Toxicity

The use of medications that act on the renin-angiotensin system during the second and third trimesters of pregnancy is associated with reduced fetal renal function and increased morbidity and mortality in both the fetus and neonate. Lotensin HCT should be discontinued as soon as pregnancy is detected.

Hepatic Failure

Patients receiving ACE inhibitors who develop jaundice or significant elevations in hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Systemic Lupus Erythematosus

Thiazide diuretics, such as hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus erythematosus.

Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide may cause an idiosyncratic reaction leading to acute transient myopia and acute angle-closure glaucoma. The primary treatment for this condition is the rapid discontinuation of hydrochlorothiazide.

General Precautions

Serum electrolytes should be monitored periodically, as hydrochlorothiazide can induce hypokalemia and hyponatremia, while drugs that inhibit the renin-angiotensin system may lead to hyperkalemia. Hydrochlorothiazide may also affect glucose tolerance and elevate serum cholesterol and triglyceride levels. Lotensin HCT should be avoided in patients with hypercalcemia. Additionally, ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. In surgical settings or during anesthesia with agents that induce hypotension, benazepril may inhibit the formation of angiotensin II, which could otherwise occur due to compensatory renin release.

Laboratory Tests

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

In the event of laryngeal stridor or angioedema of the face, tongue, or glottis, immediate discontinuation of Lotensin HCT and initiation of appropriate therapy is essential.

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 occurring in approximately 1% of patients include cough (1.0%), dizziness (1.0%), headache (0.6%), and fatigue (0.6%). In U.S. placebo-controlled studies, reactions that were possibly or probably drug-related were reported with higher frequencies: 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 observed in 0.3% to 1.0% of patients include cardiovascular effects such as palpitations and flushing; gastrointestinal issues like vomiting, diarrhea, dyspepsia, anorexia, and constipation; neurologic and psychiatric symptoms including insomnia, nervousness, paresthesia, decreased libido, dry mouth, taste perversion, and tinnitus; dermatologic reactions such as rash and sweating; and various other effects including urinary frequency, arthralgia, myalgia, asthenia, and pain (including chest and abdominal pain).

Additional adverse reactions noted include cardiovascular events such as syncope, peripheral vascular disorder, and tachycardia; systemic reactions like infection, back pain, flu syndrome, fever, chills, and neck pain; dermatologic issues including photosensitivity and pruritus; gastrointestinal disturbances such as gastroenteritis, flatulence, and tooth disorder; neurologic and psychiatric effects like hypesthesia, abnormal vision, abnormal dreams, and retinal disorder; respiratory issues including upper respiratory infection, epistaxis, bronchitis, rhinitis, sinusitis, and voice alteration; and other reactions such as conjunctivitis, arthritis, urinary tract infection, alopecia, and urinary frequency.

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

A boxed warning highlights the potential for fetal toxicity; when pregnancy is detected, it is advised to discontinue the medication as soon as possible, as drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Drug Interactions

Patients taking neprilysin inhibitors concurrently may experience an increased risk of angioedema. Similarly, the concomitant use of Lotensin HCT with potassium supplements or potassium-sparing diuretics can affect potassium levels; therefore, periodic monitoring of potassium is advised.

The combination of ACE inhibitors and mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus) may also elevate the risk of angioedema. Additionally, renal clearance of lithium is diminished by thiazide diuretics, which raises the potential for lithium toxicity; monitoring of lithium levels is recommended when Lotensin HCT is used in conjunction with lithium.

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 alterations in renal function; therefore, combined use should be avoided. Specifically, aliskiren should not be coadministered with Lotensin HCT in patients with diabetes or renal impairment (GFR < 60 mL/min).

Coadministration of nonsteroidal anti-inflammatory drugs (NSAIDs) with ACE inhibitors, including benazepril, may lead to renal function deterioration; renal function should be monitored periodically. Furthermore, the antihypertensive effect of benazepril and hydrochlorothiazide may be diminished by NSAIDs.

Benazepril has been used safely with beta-adrenergic-blocking agents and calcium channel blockers without clinically significant adverse interactions. Interaction studies have not revealed clinically important effects of benazepril on anticoagulants such as warfarin and acenocoumarol. However, nitritoid reactions have been reported infrequently in patients receiving injectable gold alongside ACE inhibitors.

When administering hydrochlorothiazide with ion exchange resins, it is recommended to stagger the dosages, giving hydrochlorothiazide at least 4 hours before or 4 to 6 hours after the resins. Thiazide-induced hypokalemia or hypomagnesemia may increase the risk of digoxin toxicity, and dosage adjustments of antidiabetic medications may be necessary when used with hydrochlorothiazide.

Concomitant use of thiazide diuretics may reduce the renal excretion of antineoplastic agents, thereby enhancing their myelosuppressive effects. The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents due to decreased gastrointestinal motility. Additionally, the use of diuretics may elevate the risk of hyperuricemia and gout-type complications when used with cyclosporin.

Finally, the concomitant 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; however, the clinical significance of this interaction is not sufficient to contraindicate their use.

Packaging & NDC

The table below lists all NDC Code configurations of Lotensin Hct (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 Lotensin HCT, 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 manage 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 Lotensin HCT in pediatric patients have not been established, and caution is advised when considering its use in this population.

Geriatric Use

In clinical studies of Lotensin HCT, 19% of the patients were aged 65 years or older, and approximately 1.5% were aged 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 that the systemic clearance of hydrochlorothiazide may be reduced in both healthy and hypertensive elderly subjects when compared to young healthy volunteers. This reduction in clearance may necessitate careful consideration of dosage adjustments and close monitoring of therapeutic response and potential adverse effects in geriatric patients.

Pregnancy

There is no specific information available regarding the use of this medication during pregnancy, including safety concerns, dosage modifications, or special precautions that should be taken. Healthcare professionals are advised to consider the lack of data when prescribing this medication to pregnant patients and to weigh the potential benefits against any unknown risks to fetal outcomes. Women of childbearing potential should be counseled on the importance of effective contraception during treatment and the need to inform their healthcare provider if they become pregnant or plan to become pregnant while on this medication.

Lactation

Minimal amounts of unchanged benazepril and benazeprilat are excreted into the breast milk of lactating mothers treated with benazepril. A breastfed infant receiving only breast milk would ingest less than 0.1% of the maternal doses of benazepril and benazeprilat.

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 Lotensin HCT, weighing the importance of the medication to the mother against the potential risks to the breastfed infant.

Renal Impairment

Patients with severe renal impairment (creatinine clearance CrCL ≤ 30 mL/min) have not had the safety and effectiveness of Lotensin HCT established. For patients with mild (CrCL 60 to 90 mL/min) or moderate (CrCL 30 to 60 mL/min) renal impairment, no dose adjustment is required.

It is recommended to monitor renal function periodically in patients treated with Lotensin HCT, as changes in renal function, including acute renal failure, can occur due to drugs that inhibit the renin-angiotensin system and diuretics. 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—are at particular risk for developing acute renal failure while on Lotensin HCT.

In cases where a clinically significant decrease in renal function occurs, consideration should be given to withholding or discontinuing therapy. Additionally, 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, which were reversible upon discontinuation of benazepril therapy, concomitant diuretic therapy, or both.

Monitoring of white blood cell counts should also be considered in patients with collagen-vascular disease, particularly if the disease is associated with impaired renal function.

Hepatic Impairment

Patients with mild to moderate hepatic impairment do not require an adjustment of the initial dose. However, it is important to note that minor alterations in fluid and electrolyte balance may precipitate hepatic coma in individuals with impaired hepatic function or progressive liver disease.

Additionally, there is a rare association between ACE inhibitors and a syndrome that begins with cholestatic jaundice and can progress to fulminant hepatic necrosis, which may result in death. The mechanism underlying this syndrome remains unclear. Therefore, patients receiving ACE inhibitors who develop jaundice or significant elevations in hepatic enzymes should discontinue the medication and receive appropriate medical follow-up to ensure their safety and well-being.

Overdosage

In cases of overdosage with Lotensin HCT, specific treatment information is limited; therefore, management should focus on symptomatic and supportive care.

Benazepril Overdosage Animal 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 linked to significant lethality. In humans, the predominant manifestation of benazepril overdose is likely to be hypotension.

Hydrochlorothiazide Overdosage In instances of hydrochlorothiazide overdose, the most frequently observed signs and symptoms include dehydration and electrolyte imbalances, such as hypokalemia, hypochloremia, and hyponatremia. It is important to note that if digitalis has been administered concurrently, hypokalemia may exacerbate the risk of cardiac arrhythmias.

Management Considerations Laboratory assessments of serum levels of benazepril and its metabolites are not commonly available and do not play a significant role in the management of benazepril overdose. Although benazeprilat is only slightly dialyzable, dialysis may be considered for patients with severely impaired renal function.

In the context of benazepril overdose, angiotensin II has been proposed as a potential specific antagonist-antidote; however, it is primarily accessible only within research settings. A reasonable approach to managing benazepril overdose includes the infusion of normal saline solution to address hypotension and maintain hydration.

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 for a duration of 104 weeks at doses up to 150 mg/kg/day. Additionally, no mutagenic activity was detected in the Ames test 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. 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, the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, and in vivo assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene.

Under the National Toxicology Program, rats and mice were administered hydrochlorothiazide in their feed for two years at doses up to 600 mg/kg/day in mice and up to 100 mg/kg/day in rats. Positive results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma Cell (mutagenicity) assays, with hydrochlorothiazide concentrations ranging from 43 to 1300 µg/mL. Additionally, positive results were recorded in the Aspergillus nidulans nondisjunction assay, although the concentration of hydrochlorothiazide used in this test was not specified.

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 System: Pancreatitis, small bowel angioedema, jaundice (intrahepatic cholestatic), 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 with hypercalcemia and hypophosphatemia.

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

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

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

These events reflect the ongoing monitoring of the safety profile of these medications in the postmarketing setting.

Patient Counseling

Patients receiving Lotensin HCT should be informed about the potential risk of angioedema, including laryngeal edema, which can occur at any time during treatment. They should be advised to report immediately any signs or symptoms of angioedema, such as swelling of the face, eyes, lips, or tongue, or difficulty breathing. Patients must be instructed to refrain from taking any additional medications until they have consulted with their prescribing physician.

Female patients of childbearing age should be made aware of the risks associated with exposure to Lotensin HCT during pregnancy. Healthcare providers should discuss treatment options with women who are planning to become pregnant and encourage patients to report any pregnancies to their physicians as soon as possible.

Patients should be cautioned that lightheadedness may occur, particularly during the initial days of therapy. They should be advised to report any episodes of lightheadedness to their prescribing physician. In the event of syncope, patients must discontinue Lotensin HCT and consult their physician before resuming treatment. Additionally, all patients should be informed that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to a significant drop in blood pressure, resulting in lightheadedness and potential syncope.

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

It is important for patients to promptly report any signs of infection, such as a sore throat or fever, as these may indicate neutropenia.

For those taking hydrochlorothiazide, patients should be advised to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Storage and Handling

The product is supplied in a tight, light-resistant container, in accordance with USP standards. It is essential to store the product in a location where the temperature does not exceed 86°F (30°C). Additionally, the product must be protected from moisture and light to maintain its integrity and efficacy.

Additional Clinical Information

The hydrochlorothiazide component of Lotensin HCT may lead to a decrease in serum protein-bound iodine (PBI) levels; however, this effect does not indicate any signs of thyroid disturbance in patients. Clinicians are advised to interrupt therapy with Lotensin HCT 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 Lotensin Hct as submitted by Validus Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)