Enalapril maleate/Hydrochlorothiazide

Uses and Indications

Enalapril maleate and hydrochlorothiazide is indicated for the treatment of hypertension. This fixed dose combination is not indicated for initial treatment.

Dosage and Administration

The recommended dosage of Enalapril Maleate and Hydrochlorothiazide is as follows:

Dosage of Enalapril: The usual dosage range is 10 to 40 mg per day, which may be administered in a single dose or divided into two doses.

Dosage of Hydrochlorothiazide: Effective doses range from 12.5 to 50 mg daily.

Combination Therapy: For patients whose blood pressure is not adequately controlled with either enalapril or hydrochlorothiazide monotherapy, combination therapy with Enalapril Maleate and Hydrochlorothiazide may be initiated using the following formulations:

• Enalapril maleate and hydrochlorothiazide 5 mg/12.5 mg

• Enalapril maleate and hydrochlorothiazide 10 mg/25 mg

The daily dosage should not exceed:

• Four tablets of enalapril maleate and hydrochlorothiazide 5 mg/12.5 mg

• Two tablets of enalapril maleate and hydrochlorothiazide 10 mg/25 mg

Dose Titration: Further increases in the dosages of enalapril, hydrochlorothiazide, or both should be based on clinical response. It is recommended that the hydrochlorothiazide dose not be increased until 2 to 3 weeks have elapsed.

Renal Impairment: The usual regimens of therapy need not be adjusted as long as the patient's creatinine clearance is greater than 30 mL/min/1.73 m² (serum creatinine approximately less than or equal to 3 mg/dL or 265 µmol/L).

Contraindications

Enalapril maleate and hydrochlorothiazide is contraindicated in patients who are hypersensitive to any component of this 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 patients with hereditary or idiopathic angioedema.

Due to the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Additionally, enalapril maleate and hydrochlorothiazide should not be administered in combination with a neprilysin inhibitor (e.g., sacubitril), and it is advised to avoid administration within 36 hours of switching to or from sacubitril/valsartan.

Co-administration of aliskiren with enalapril maleate and hydrochlorothiazide is contraindicated in patients with diabetes.

Warnings and Precautions

Excessive hypotension may occur in patients treated with enalapril maleate and hydrochlorothiazide, particularly in those who are severely salt/volume depleted, such as individuals receiving vigorous diuretic therapy or those on dialysis. Syncope has been reported in 1.3% of patients taking VASERETIC, while the incidence is 0.5% in those receiving 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

Angioedema affecting the face, extremities, lips, tongue, glottis, and/or larynx has been documented in patients treated with angiotensin-converting enzyme (ACE) inhibitors, including enalapril. This condition may occur at any time during treatment and can be fatal if associated with laryngeal edema. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk. Intestinal angioedema has also been reported. In cases of angioedema involving the tongue, glottis, or larynx, immediate medical intervention is required, including the administration of subcutaneous epinephrine (1:1000 solution, 0.3 mL to 0.5 mL) and measures to ensure airway patency.

Anaphylactoid Reactions

Anaphylactoid reactions have been observed in patients undergoing dialysis with high-flux membranes while concurrently treated with an ACE inhibitor. Rarely, ACE inhibitors have been linked to a syndrome that begins with cholestatic jaundice and can progress to fulminant hepatic necrosis, sometimes resulting in death. Additionally, another ACE inhibitor, captopril, has been associated with agranulocytosis and bone marrow depression.

General Precautions

Enalapril should be administered with caution to patients with left ventricular outflow tract obstruction. Changes in renal function may be expected in susceptible individuals, particularly those with severe congestive heart failure. Evaluation of renal function is essential in hypertensive patients. Elevated serum potassium levels (greater than 5.7 mEq/L) have been noted in approximately 1% of patients treated with enalapril alone. Periodic monitoring of serum electrolytes is recommended to detect potential imbalances, especially in patients receiving thiazide therapy.

Laboratory Tests

Regular monitoring of white blood cell counts is advisable for patients with collagen vascular disease and renal disease. Renal function should be closely observed during the initial weeks of therapy in patients with renal artery stenosis. Serum and urine electrolyte determinations are particularly critical for patients experiencing excessive vomiting or receiving parenteral fluids.

Emergency Instructions

In the event of hypotension, patients should be placed in a supine position and may require intravenous normal saline infusion. If angioedema occurs, VASERETIC should be discontinued immediately, and appropriate therapy and monitoring should be initiated until complete resolution of symptoms is achieved. Patients receiving ACE inhibitors who develop jaundice or significant elevations in hepatic enzymes should discontinue the medication and seek medical follow-up.

Side Effects

Common adverse reactions occurring in ≥2% of patients include:

• Dizziness: 8.6% (0.7% discontinuation)

• Headache: 5.5% (0.4% discontinuation)

• Fatigue: 3.9% (0.8% discontinuation)

• Cough: 3.5% (0.4% discontinuation)

• Muscle Cramps: 2.7% (0.2% discontinuation)

• Nausea: 2.5% (0.4% discontinuation)

• Asthenia: 2.4% (0.3% discontinuation)

• Orthostatic Effects: 2.3% (<0.1% discontinuation)

• Impotence: 2.2% (0.5% discontinuation)

• Diarrhea: 2.1% (<0.1% discontinuation)

Clinical adverse experiences occurring in 0.5% to 2.0% of patients include:

• Body as a Whole: Syncope, chest pain, abdominal pain

• Cardiovascular: Orthostatic hypotension, palpitation, tachycardia

• Digestive: Vomiting, dyspepsia, constipation, flatulence, dry mouth

• Nervous/Psychiatric: Insomnia, nervousness, paresthesia, somnolence, vertigo

• Skin: Pruritus, rash

• Other: Dyspnea, gout, back pain, arthralgia, diaphoresis, decreased libido, tinnitus, urinary tract infection

Angioedema has been reported in patients receiving enalapril maleate and hydrochlorothiazide, with a higher incidence in black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis, and/or larynx occurs, treatment should be discontinued immediately, and appropriate therapy instituted.

Hypotension-related adverse effects in clinical trials were reported as follows: hypotension (0.9%), orthostatic hypotension (1.5%), and syncope (1.3%).

Additional adverse reactions or important notes include:

• Enalapril Maleate:

  • Anaphylactoid reactions, cardiac arrest, myocardial infarction or cerebrovascular accident, pulmonary embolism and infarction, pulmonary edema, rhythm disturbances including atrial tachycardia and bradycardia, angina pectoris, Raynaud's phenomenon, ileus, pancreatitis, hepatic failure, hepatitis, melena, anorexia, glossitis, stomatitis, dry mouth, rare cases of neutropenia, thrombocytopenia, bone marrow depression, hemolytic anemia, depression, confusion, ataxia, peripheral neuropathy, renal failure, oliguria, flank pain, gynecomastia, pulmonary infiltrates, eosinophilic pneumonitis, bronchospasm, pneumonia, bronchitis, rhinorrhea, sore throat, hoarseness, asthma, upper respiratory infection, exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, herpes zoster, erythema multiforme, urticaria, pemphigus, alopecia, flushing, photosensitivity, blurred vision, taste alteration, anosmia, conjunctivitis, dry eyes, tearing.

• Hydrochlorothiazide:

  • Weakness, pancreatitis, jaundice, sialadenitis, cramping, gastric irritation, anorexia, aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia, purpura, photosensitivity, urticaria, necrotizing angiitis, fever, respiratory distress, muscle spasm, restlessness, renal failure, renal dysfunction, interstitial nephritis, erythema multiforme, exfoliative dermatitis, toxic epidermal necrolysis, alopecia, transient blurred vision, xanthopsia.

Postmarketing experience has indicated an increased risk of non-melanoma skin cancer associated with hydrochlorothiazide, particularly for squamous cell carcinoma in white patients taking large cumulative doses.

Drug Interactions

Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema when using enalapril maleate and hydrochlorothiazide or Vaseretic. The dual blockade of the renin-angiotensin system (RAS) with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy. Therefore, the combined use of RAS inhibitors should be avoided. Specifically, aliskiren should not be coadministered with either enalapril maleate and hydrochlorothiazide or Vaseretic in patients with diabetes or renal impairment (GFR <60 mL/min).

Patients on diuretics may occasionally experience an excessive reduction of blood pressure after initiating therapy with enalapril. The antihypertensive effect of enalapril is augmented by antihypertensive agents that cause renin release, such as diuretics. Coadministration of nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, with ACE inhibitors may result in deterioration of renal function, including possible acute renal failure, and may diminish the antihypertensive effect of ACE inhibitors.

Enalapril has been used safely with beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine, and prazosin without evidence of clinically significant adverse interactions. However, it is important to note that enalapril attenuates diuretic-induced potassium loss, and the use of potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium levels. Therefore, caution and frequent monitoring of serum potassium are recommended when these agents are used concomitantly.

Lithium toxicity has been reported in patients receiving lithium alongside drugs that cause sodium elimination, including ACE inhibitors. It is advised that serum lithium levels be monitored frequently if enalapril is administered with lithium. Additionally, nitritoid reactions have been reported rarely in patients receiving injectable gold (sodium aurothiomalate) with ACE inhibitors.

When hydrochlorothiazide is administered, potentiation of orthostatic hypotension may occur with alcohol, barbiturates, or narcotics. Dosage adjustments of anti-diabetic drugs may be required when used with hydrochlorothiazide. There is potential for additive effects or potentiation with other antihypertensive drugs. The absorption of hydrochlorothiazide can be impaired in the presence of cholestyramine and colestipol resins.

Intensified electrolyte depletion, particularly hypokalemia, may occur with corticosteroids or ACTH when administered with hydrochlorothiazide. There may also be a possible decreased response to pressor amines, although this does not preclude their use. Furthermore, there is a potential for increased responsiveness to nondepolarizing skeletal muscle relaxants when administered with hydrochlorothiazide.

Diuretic agents can reduce the renal clearance of lithium, significantly increasing the risk of lithium toxicity, and should generally not be given with diuretics. Lastly, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics.

Pediatric Use

Safety and effectiveness of Enalapril Maleate and Hydrochlorothiazide, as well as Vaseretic, in pediatric patients have not been established.

In neonates with a history of in utero exposure to these medications, if oliguria or hypotension occurs, it is crucial to provide support for blood pressure and renal perfusion. Exchange transfusions or dialysis may be necessary to reverse hypotension and/or address disordered renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit. Theoretically, it may also be removed by exchange transfusion; however, there is no clinical experience with this procedure.

Geriatric Use

Clinical studies of enalapril maleate and hydrochlorothiazide, as well as Vaseretic, did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience has not identified significant differences in responses between elderly and younger patients.

In general, dose selection for geriatric patients should be approached with caution, typically starting at the low end of the dosing range. This cautious approach is warranted due to the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies in this population.

Both medications are substantially excreted by the kidneys, which raises the risk of toxic reactions, particularly in patients with impaired renal function. Given that elderly patients are more prone to renal impairment, careful consideration should be given to dose selection.

Furthermore, evaluation of hypertensive geriatric patients should always include an assessment of renal function to ensure safe and effective treatment.

Pregnancy

There are no specific statements regarding the use of Enalapril Maleate and Hydrochlorothiazide or Vaseretic during pregnancy, including safety concerns, dosage modifications, or special precautions. However, Enalapril Maleate is classified as Pregnancy Category C during the first trimester and Category D during the second and third trimesters. This indicates that while there may be potential risks, particularly in later stages of pregnancy, the benefits of treatment may outweigh the risks in certain situations.

Healthcare professionals should be aware of the potential for fetal/neonatal morbidity and mortality associated with the use of these medications during pregnancy. It is recommended that pregnant patients be closely monitored, and alternative therapies should be considered when appropriate.

Lactation

Enalapril, enalaprilat, and hydrochlorothiazide have been detected in human breast milk. Due to the potential for serious reactions in breastfed infants from either drug, healthcare providers should carefully consider whether to discontinue breastfeeding or to discontinue the use of enalapril maleate and hydrochlorothiazide, including Vaseretic. This decision should take into account the importance of the medication to the lactating mother.

Renal Impairment

Patients with renal impairment should be closely monitored when using medications that include thiazides and angiotensin-converting enzyme (ACE) inhibitors, such as enalapril maleate and hydrochlorothiazide. Thiazides are contraindicated in severe renal disease due to the risk of precipitating azotemia, and cumulative effects of the drug may develop in those with impaired renal function.

Caution is advised when administering enalapril in this patient population, as it may lead to worsening renal function. In patients with severe congestive heart failure, particularly those with renal insufficiency, there is a risk of excessive hypotension, which may result in oliguria, progressive azotemia, and, in rare cases, acute renal failure or death.

Additionally, patients with renal impairment may be at an increased risk for serious adverse reactions, including neutropenia and agranulocytosis. This risk is particularly pronounced in patients with concurrent collagen vascular diseases. Therefore, periodic monitoring of white blood cell counts is recommended for patients with both renal disease and collagen vascular conditions to detect any potential hematological complications early.

Overall, careful consideration of dosing adjustments and vigilant monitoring are essential for patients with renal impairment receiving these medications.

Hepatic Impairment

Patients with hepatic impairment may experience serious adverse effects when treated with ACE inhibitors, such as a syndrome characterized by cholestatic jaundice that can progress to fulminant hepatic necrosis and, in some cases, death. The underlying mechanism of this syndrome remains unclear.

In the event that patients develop jaundice or significant elevations in hepatic enzyme levels while on ACE inhibitors, it is essential to discontinue the medication and ensure appropriate medical follow-up.

Thiazide diuretics should be administered with caution in patients with impaired hepatic function or progressive liver disease, as even minor changes in fluid and electrolyte balance could precipitate hepatic coma.

Monitoring of liver function tests is recommended for patients receiving these medications, particularly in those with pre-existing hepatic conditions.

Overdosage

In cases of overdosage with enalapril maleate and hydrochlorothiazide or VASERETIC, no specific treatment information is available; therefore, management should be symptomatic and supportive. It is essential to discontinue therapy with the medication and closely observe the patient.

Recommended interventions include the induction of emesis and/or gastric lavage, along with the correction of dehydration, electrolyte imbalances, and hypotension using established medical procedures. The most likely manifestation of overdosage is hypotension, which can be treated with intravenous infusion of normal saline solution.

Animal studies have indicated that single oral doses of enalapril exceeding 1,000 mg/kg in mice and 1,775 mg/kg in rats were associated with lethality. In cases where enalaprilat is present, it may be removed from general circulation through hemodialysis, and it has also been effectively removed from neonatal circulation via peritoneal dialysis. Continuous monitoring of the patient's condition is advised to ensure appropriate management of any arising symptoms.

Nonclinical Toxicology

Teratogenic Effects

No teratogenic effects were reported in the studies conducted with enalapril maleate and hydrochlorothiazide.

Impairment of Fertility

In nonclinical studies, 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. Similarly, hydrochlorothiazide did not impair fertility in mice and rats of either sex when administered 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, respectively, based on body surface area comparisons.

Carcinogenesis and Mutagenesis

Enalapril, in combination with hydrochlorothiazide, was not found to be 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 carcinogenicity studies revealed no evidence of tumorigenic effects 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 mg/kg/day 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.

Hydrochlorothiazide also demonstrated no carcinogenic potential in two-year feeding studies conducted by the National Toxicology Program (NTP) in female mice at doses up to approximately 600 mg/kg/day (53 times the MRHDD) and in male and female rats at doses up to approximately 100 mg/kg/day (18 times the MRHDD). However, the NTP reported equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay using various strains of Salmonella typhimurium and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. In vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene also showed no genotoxicity. Positive results were observed only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays at specific concentrations, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Storage and Handling

Enalapril Maleate and Hydrochlorothiazide and Vaseretic are supplied in tablet form.

Tablets should be stored at a temperature of 20° to 25°C (68° to 77°F) for Enalapril Maleate and Hydrochlorothiazide, and at 25°C (77°F) for Vaseretic, with permissible excursions between 15° to 30°C (59° to 86°F) as per USP Controlled Room Temperature guidelines.

It is essential to keep the container tightly closed to protect the contents from moisture. If the product package is subdivided, it must be dispensed in a tight container in accordance with USP standards.