Vaseretic

Description

VASERETIC® is a pharmaceutical formulation that combines enalapril maleate, an angiotensin converting enzyme inhibitor, and hydrochlorothiazide, a diuretic. Enalapril maleate is the maleate salt of enalapril, which is the ethyl ester of enalaprilat, a long-acting angiotensin converting enzyme inhibitor. It is chemically described as (S)-1-[N-1-(ethoxycarbonyl)-3-phenylpropyl-L-alanyl]-L-proline, (Z)-2-butenedioate salt (1:1), with an empirical formula of C20H28N2O5 • C4H4O4 and a molecular weight of 492.53. This compound appears as a white to off-white crystalline powder, exhibiting sparing solubility in water, solubility in ethanol, and free solubility in methanol. Enalapril acts as a pro-drug, which is bioactivated to enalaprilat following oral administration through hydrolysis of the ethyl ester.

Hydrochlorothiazide is identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with an empirical formula of C7H8ClN3O4S2 and a molecular weight of 297.74. It is a white or practically white crystalline powder that is slightly soluble in water and freely soluble in sodium hydroxide solution.

VASERETIC is available in tablet form, specifically as VASERETIC 10-25 mg, which contains 10 mg of enalapril maleate and 25 mg of hydrochlorothiazide. The formulation includes inactive ingredients such as iron oxide, lactose, magnesium stearate, sodium bicarbonate, and starch.

Uses and Indications

VASERETIC is indicated for the treatment of hypertension. This fixed-dose combination is not indicated for initial treatment.

Dosage and Administration

The usual dosage range of enalapril is 10 to 40 mg per day, which may be administered as a single dose or divided into two doses. Hydrochlorothiazide is typically effective at doses ranging from 12.5 to 50 mg daily. For patients whose blood pressure remains inadequately controlled with either enalapril or hydrochlorothiazide monotherapy, VASERETIC may be prescribed at a dosage of 10-25 mg.

Adjustments to the doses of enalapril, hydrochlorothiazide, or both should be made based on the clinical response of the patient. It is recommended that the hydrochlorothiazide dose not be increased until a period of 2 to 3 weeks has elapsed to adequately assess the patient's response. Generally, patients do not require doses exceeding 20 mg of enalapril or 50 mg of hydrochlorothiazide.

The maximum daily dosage of VASERETIC should not exceed two tablets of 10-25 mg.

Contraindications

VASERETIC is contraindicated in patients with hypersensitivity to any component of the product. It is also contraindicated in individuals with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor, as well as in those with hereditary or idiopathic angioedema.

Patients with anuria or hypersensitivity to other sulfonamide-derived drugs should not use VASERETIC due to the hydrochlorothiazide component. Additionally, VASERETIC is contraindicated in combination with neprilysin inhibitors, such as sacubitril; administration should not occur within 36 hours of switching to or from sacubitril/valsartan.

Co-administration of aliskiren with VASERETIC is contraindicated in patients with diabetes.

Warnings and Precautions

Excessive hypotension may occur in patients treated with enalapril, particularly in those who are severely salt or volume depleted, such as individuals receiving aggressive diuretic therapy or those on dialysis. While excessive hypotension is rarely observed in uncomplicated hypertensive patients, vigilance is warranted in these populations.

Syncope has been reported in 1.3% of patients receiving VASERETIC, compared to an incidence of 0.5% in patients taking enalapril alone. In patients with severe congestive heart failure, excessive hypotension can lead to oliguria, progressive azotemia, and, in rare cases, acute renal failure or death.

Angioedema, which may involve the face, extremities, lips, tongue, glottis, and/or larynx, has been documented in patients treated with angiotensin-converting enzyme (ACE) inhibitors, including enalapril. This reaction can occur at any point during treatment and may be life-threatening if laryngeal edema leads to airway obstruction. In such cases, immediate intervention with subcutaneous epinephrine (1:1000 solution, 0.3 mL to 0.5 mL) and measures to ensure airway patency are critical. Additionally, intestinal angioedema has been reported in patients receiving ACE inhibitors. Patients with a history of angioedema unrelated to ACE inhibitor therapy may have an increased risk of developing angioedema while on these medications. Anaphylactoid reactions have also been noted in patients undergoing dialysis with high-flux membranes while concurrently treated with an ACE inhibitor. Rarely, ACE inhibitors have been associated with a syndrome characterized by cholestatic jaundice that can progress to fulminant hepatic necrosis and, in some cases, death.

Enalapril should be administered with caution to patients who have left ventricular outflow tract obstruction. Changes in renal function may be expected in susceptible individuals, particularly in those with severe congestive heart failure, where treatment with ACE inhibitors may lead to oliguria, progressive azotemia, and, rarely, acute renal failure or death. Therefore, renal function assessment should be included in the evaluation of hypertensive patients. Elevated serum potassium levels (greater than 5.7 mEq/L) have been observed in approximately 1% of hypertensive patients treated with enalapril alone.

Periodic monitoring of white blood cell counts is advisable for patients with collagen vascular disease and renal disease. Renal function should be closely monitored during the initial weeks of therapy in patients with unilateral or bilateral renal artery stenosis. Additionally, periodic determination of serum electrolytes is recommended to detect potential electrolyte imbalances in patients receiving thiazide therapy.

In the event of hypotension, the patient should be positioned supine, and if necessary, an intravenous infusion of normal saline should be administered. Should angioedema occur, VASERETIC must be discontinued immediately, and appropriate therapy and monitoring should be instituted until complete and sustained resolution of symptoms is achieved.

Side Effects

Patients receiving VASERETIC may experience a range of adverse reactions. The most common adverse reactions, occurring in more than 2% of patients, include dizziness (8.6%, with 0.7% discontinuation), headache (5.5%, with 0.4% discontinuation), and fatigue (3.9%, with 0.8% discontinuation). Other common reactions include cough (3.5%, with 0.4% discontinuation), muscle cramps (2.7%, with 0.2% discontinuation), nausea (2.5%, with 0.4% discontinuation), asthenia (2.4%, with 0.3% discontinuation), orthostatic effects (2.3%, with less than 0.1% discontinuation), impotence (2.2%, with 0.5% discontinuation), and diarrhea (2.1%, with less than 0.1% discontinuation).

Clinical adverse experiences occurring in 0.5% to 2.0% of patients include syncope, chest pain, and abdominal pain. Cardiovascular effects such as orthostatic hypotension, palpitation, and tachycardia have also been reported. Digestive system reactions include vomiting, dyspepsia, constipation, flatulence, and dry mouth. Nervous and psychiatric effects may manifest as insomnia, nervousness, paresthesia, somnolence, and vertigo. Skin reactions such as pruritus and rash, as well as other adverse reactions including dyspnea, gout, back pain, arthralgia, diaphoresis, decreased libido, tinnitus, and urinary tract infections, have been noted.

Serious adverse reactions include angioedema, which has been reported in patients receiving VASERETIC, with a higher incidence observed in black patients. Angioedema associated with laryngeal edema may be fatal; therefore, VASERETIC should be discontinued immediately, and appropriate therapy should be provided if angioedema occurs. Hypotension has been reported in 0.9% of patients, with orthostatic hypotension occurring in 1.5% and syncope in 1.3%. A persistent nonproductive cough may occur, typically resolving after discontinuation of therapy.

Additional serious reactions include neutropenia and agranulocytosis, particularly in patients with renal impairment or collagen vascular disease. Rare cases of hepatic failure associated with cholestatic jaundice progressing to fulminant hepatic necrosis have been documented. Furthermore, hydrochlorothiazide, a component of VASERETIC, is associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma in white patients taking large cumulative doses.

It is important to note that drugs affecting the renin-angiotensin system, such as VASERETIC, can cause injury and death to the developing fetus. Therefore, VASERETIC should be discontinued as soon as pregnancy is detected.

Drug Interactions

Patients taking neprilysin inhibitors concurrently may experience an increased risk of angioedema.

Renin-Angiotensin System (RAS) Inhibitors The combined use of angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with heightened risks of hypotension, hyperkalemia, and alterations in renal function, including acute renal failure, compared to monotherapy. Therefore, the concomitant use of RAS inhibitors is not recommended. Specifically, aliskiren should not be coadministered with VASERETIC in patients with diabetes or those with renal impairment (GFR <60 mL/min).

Patients on diuretics may experience an excessive reduction in blood pressure upon initiation of enalapril therapy. The antihypertensive effect of enalapril may be enhanced by antihypertensive agents that promote renin release, such as diuretics. However, caution is advised as the coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors like enalapril may lead to renal function deterioration, including potential acute renal failure. Additionally, NSAIDs may reduce the antihypertensive efficacy of ACE inhibitors.

Enalapril can be safely used with beta adrenergic-blocking agents, methyldopa, nitrates, calcium channel blockers, hydralazine, and prazosin without significant adverse interactions. It also mitigates potassium loss induced by diuretics; however, the use of potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes may result in significant serum potassium increases.

Lithium toxicity has been observed in patients receiving lithium alongside drugs that promote sodium elimination, including ACE inhibitors. Therefore, serum lithium levels should be closely monitored when enalapril is administered with lithium. Rare instances of nitritoid reactions have been reported in patients receiving injectable gold in conjunction with ACE inhibitors. Furthermore, patients receiving both an ACE inhibitor and mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus) may be at an increased risk for angioedema.

Diuretics The concurrent use of thiazide diuretics with alcohol, barbiturates, or narcotics may enhance the risk of orthostatic hypotension. Dosage adjustments of anti-diabetic medications may be necessary when thiazide diuretics are used. Additionally, thiazide diuretics may have an additive effect with other antihypertensive agents.

The absorption of hydrochlorothiazide can be impaired by cholestyramine and colestipol resins. Intensified electrolyte depletion, particularly hypokalemia, may occur when thiazide diuretics are administered with corticosteroids or ACTH. There may be a reduced response to pressor amines (e.g., norepinephrine) when thiazide diuretics are used, although this does not preclude their use. Conversely, there may be an increased responsiveness to nondepolarizing skeletal muscle relaxants (e.g., tubocurarine) when thiazide diuretics are administered.

Diuretic agents can decrease the renal clearance of lithium, significantly increasing the risk of lithium toxicity; thus, they should generally not be coadministered. Additionally, the administration of non-steroidal anti-inflammatory agents can diminish the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics.

Packaging & NDC

The table below lists all NDC Code configurations of Vaseretic (enalapril maleate 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 VASERETIC, may experience complications such as oliguria or hypotension. In such cases, it is crucial to support blood pressure and renal perfusion. Interventions such as exchange transfusions or dialysis may be necessary to address hypotension and manage renal function. Notably, enalapril, which can cross the placenta, has been effectively removed from neonatal circulation through peritoneal dialysis, suggesting potential benefit, although there is no clinical experience with its removal via exchange transfusion.

The safety and effectiveness of VASERETIC in pediatric patients have not been established, necessitating caution when considering its use in this population.

Geriatric Use

Clinical studies of VASERETIC did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experiences have not identified significant differences in responses between elderly and younger patients.

In general, dose selection for geriatric patients should be approached with caution. It is advisable to start at the low end of the dosing range, taking into account the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies. Given that VASERETIC is substantially excreted by the kidneys, the risk of toxic reactions may be heightened in patients with impaired renal function.

Elderly patients are more prone to renal function decline; therefore, careful consideration should be given to dose selection in this population. Additionally, the evaluation of hypertensive patients should always include an assessment of renal function to ensure appropriate management and minimize potential risks.

Pregnancy

The safety of this drug during pregnancy has not been established, as there are no specific warnings or contraindications related to its use in pregnant patients. Currently, there is a lack of data regarding potential risks to the fetus or any recommended dosage modifications for women who are pregnant. Healthcare professionals should consider the absence of information when prescribing this medication to women of childbearing potential and weigh the potential benefits against any unknown risks. It is advisable to monitor pregnant patients closely and to discuss any concerns regarding the use of this drug during pregnancy.

Lactation

Enalapril, enalaprilat, and hydrochlorothiazide have been detected in human breast milk. Due to the potential for serious reactions in nursing infants from either drug, a decision should be made whether to discontinue nursing or to discontinue VASERETIC, taking into account the importance of the drug to the mother.

Renal Impairment

Patients with renal impairment should be treated with caution, particularly when using thiazides, as these agents may precipitate azotemia in individuals with severe renal disease. The cumulative effects of thiazides can develop in patients with reduced kidney function, necessitating careful monitoring and potential dose adjustments.

Additionally, the use of enalapril in patients with renal impairment requires vigilance due to the risk of neutropenia and agranulocytosis. While the incidence of these adverse effects is rare in uncomplicated patients, they occur more frequently in those with renal impairment, especially if accompanied by a collagen vascular disease. Although clinical trial data for enalapril do not definitively establish a causal relationship with agranulocytosis, marketing experience has documented cases of neutropenia or agranulocytosis where a connection to enalapril cannot be excluded. Therefore, periodic monitoring of white blood cell counts is advisable for patients with both collagen vascular disease and renal disease.

Hepatic Impairment

Patients with hepatic impairment should be monitored closely when receiving treatment with ACE inhibitors. Rarely, these medications have been associated with a syndrome that begins with cholestatic jaundice and can progress to fulminant hepatic necrosis, and in some cases, death. The underlying mechanism of this syndrome remains unclear.

In the event that patients receiving ACE inhibitors develop jaundice or experience marked elevations in hepatic enzymes, it is imperative that the ACE inhibitor be discontinued immediately. Appropriate medical follow-up should be initiated to address any complications arising from these changes in liver function.

Additionally, thiazide diuretics should be used with caution in patients with impaired hepatic function or those with progressive liver disease. Minor alterations in fluid and electrolyte balance in these patients may precipitate hepatic coma, necessitating careful monitoring and potential dosage adjustments.

Overdosage

In the event of an overdosage with VASERETIC, specific treatment information is not available; therefore, management should be symptomatic and supportive. It is imperative that therapy with VASERETIC be discontinued immediately, and the patient should be monitored closely for any adverse effects.

Recommended Actions

Healthcare professionals should consider the following measures in the management of overdosage:

• Induction of Emesis and Gastric Lavage: These procedures may be employed to reduce the absorption of the drug.

• Correction of Dehydration and Electrolyte Imbalance: It is essential to address any dehydration or electrolyte disturbances that may arise as a result of the overdosage.

• Management of Hypotension: The most likely manifestation of overdosage is hypotension. The standard treatment for this condition involves the intravenous infusion of normal saline solution.

Lethality and Toxicity

Animal studies have indicated that lethality is associated with single oral doses of enalapril exceeding 1,000 mg/kg in mice and 1,775 mg/kg in rats. This underscores the potential severity of overdosage and the need for prompt medical intervention.

Removal of Enalaprilat

Enalaprilat, the active metabolite of enalapril, can be removed from the general circulation through hemodialysis. Additionally, it has been effectively removed from neonatal circulation via peritoneal dialysis, which may be considered in specific cases.

In summary, the management of VASERETIC overdosage requires immediate discontinuation of the drug, close observation, and supportive care tailored to the symptoms presented.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. In terms of non-teratogenic effects, enalapril did not adversely affect the reproductive performance of male and female rats treated with doses up to 90 mg/kg/day, which is 26 times the maximum recommended human daily dose (MRHDD) when adjusted for body surface area. Hydrochlorothiazide also demonstrated no adverse effects on fertility in mice and rats of either sex when administered dietary doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation. These doses correspond to 9 times and 0.7 times the MRHDD based on body surface area.

In nonclinical toxicology assessments, enalapril in combination with hydrochlorothiazide was found to be non-mutagenic in the Ames microbial mutagen test, both with and without metabolic activation. Additionally, enalapril-hydrochlorothiazide did not induce DNA single strand breaks in an in vitro alkaline elution assay using rat hepatocytes, nor did it cause chromosomal aberrations in an in vivo mouse bone marrow assay. Long-term studies revealed no evidence of tumorigenicity when enalapril was administered to male and female rats for 106 weeks at doses up to 90 mg/kg/day, or to male and female mice for 94 weeks at doses up to 90 and 180 mg/kg/day, respectively. These doses are 26 times (in rats and female mice) and 13 times (in male mice) the MRHDD when adjusted for body surface area.

Neither enalapril maleate nor its active diacid exhibited mutagenic properties in the Ames microbial mutagen test. Enalapril also tested negative in various genotoxicity studies, including the rec-assay, reverse mutation assay with E. coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test in mice, as well as in an in vivo cytogenic study using mouse bone marrow.

Two-year feeding studies conducted by the National Toxicology Program (NTP) indicated no carcinogenic potential for hydrochlorothiazide in female mice at doses up to approximately 600 mg/kg/day (53 times the MRHDD) or in male and female rats at doses up to approximately 100 mg/kg/day (18 times the MRHDD). However, the NTP did find equivocal evidence of hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay using various Salmonella typhimurium strains or in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, nor in vivo in assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive results were noted only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays at concentrations ranging from 43 to 1300 mcg/mL, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Postmarketing Experience

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data from a study conducted within the Sentinel System indicate that this increased risk is predominantly observed in white patients who have received large cumulative doses of the medication. Specifically, the overall population exhibits an approximate risk of 1 additional case of SCC per 16,000 patients per year. For white patients who have taken a cumulative dose of 50,000 mg or more, the risk escalates to approximately 1 additional case of SCC for every 6,700 patients per year.

Patient Counseling

Healthcare providers should advise patients to discontinue VASERETIC as soon as pregnancy is detected. It is important to inform patients that drugs acting directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Patients should be instructed to report immediately any signs or symptoms of angioedema, which may include swelling of the face, extremities, eyes, lips, or tongue, as well as difficulty in swallowing or breathing. They should be advised to refrain from taking any additional doses of the medication until they have consulted with their prescribing physician.

Caution should be given to patients regarding the potential for lightheadedness, particularly during the initial days of therapy. If patients experience actual syncope, they should be instructed to discontinue the medication and seek guidance from their physician.

Patients must be informed not to use salt substitutes that contain potassium without prior consultation with their physician. Additionally, they should be encouraged to report any signs of infection, such as a sore throat or fever, as these may indicate neutropenia.

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

For patients taking hydrochlorothiazide, it is essential to instruct them to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Storage and Handling

The product is supplied in a tightly sealed container to ensure integrity and stability. It should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15° to 30°C (59° to 86°F) in accordance with USP guidelines.

To maintain product quality, it is essential to keep the container tightly closed and protect it from moisture. If the product package is subdivided, it must be dispensed in a tight container as specified by USP standards.

Additional Clinical Information

Patients should be advised to report any signs or symptoms of angioedema, such as swelling of the face, extremities, eyes, lips, or tongue, as well as difficulty in swallowing or breathing, and to refrain from taking additional doses until consulting their prescribing physician. Lightheadedness, particularly during the initial days of therapy, should also be reported, and if syncope occurs, patients should discontinue the drug and seek medical advice.

Excessive perspiration and dehydration may lead to significant drops in blood pressure due to reduced fluid volume; thus, patients should consult their physician if they experience vomiting or diarrhea. It is important for patients to avoid potassium-containing salt substitutes without prior consultation. Any signs of infection, such as sore throat or fever, should be reported promptly, as they may indicate neutropenia. Female patients of childbearing age should be informed about the risks associated with VASERETIC during pregnancy and discuss treatment options with their healthcare provider, reporting any pregnancies as soon as possible. Additionally, patients taking hydrochlorothiazide should be instructed to protect their skin from sun exposure and to undergo regular skin cancer screenings, as hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma in white patients receiving high cumulative doses.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Vaseretic as submitted by Bausch Health US, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)