Enalapril maleate/Hydrochlorothiazide

Description

Enalapril maleate and hydrochlorothiazide is a combination of an angiotensin converting enzyme inhibitor, enalapril maleate, and a diuretic, hydrochlorothiazide. Enalapril maleate is the maleate salt of enalapril, which is the ethyl ester of the long-acting angiotensin converting enzyme inhibitor, enalaprilat. 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, is sparingly soluble in water, soluble in ethanol, and freely soluble in methanol. Enalapril acts as a pro-drug, which is bioactivated following oral administration through hydrolysis of the ethyl ester to enalaprilat, the active angiotensin converting enzyme inhibitor.

Hydrochlorothiazide is chemically 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.

The combination is available in two tablet formulations: enalapril maleate and hydrochlorothiazide 5/12.5 mg, which contains 5 mg of enalapril maleate and 12.5 mg of hydrochlorothiazide, and enalapril maleate and hydrochlorothiazide 10/25 mg, which contains 10 mg of enalapril maleate and 25 mg of hydrochlorothiazide. The inactive ingredients for the 5/12.5 mg formulation include ferric oxide black, ferric oxide yellow, lactose monohydrate, magnesium stearate, pregelatinized starch, purified water, and sodium bicarbonate. The 10/25 mg formulation contains ferric oxide yellow, ferric oxide red, lactose monohydrate, magnesium stearate, pregelatinized starch, purified water, and sodium bicarbonate.

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 usual dosage of Enalapril ranges from 10 to 40 mg per day, which may be administered as a single dose or divided into two doses. Hydrochlorothiazide is effective at doses between 12.5 mg and 50 mg daily.

For patients whose blood pressure is not adequately controlled with either enalapril or hydrochlorothiazide monotherapy, combination therapy may be considered. This includes the administration of Enalapril maleate and hydrochlorothiazide in the following formulations: 5/12.5 mg or 10/25 mg. Adjustments to the doses of enalapril, hydrochlorothiazide, or both should be based on the clinical response of the patient. It is recommended that the hydrochlorothiazide dose not be increased until 2 to 3 weeks have passed.

The maximum daily dosage should not exceed four tablets of enalapril maleate and hydrochlorothiazide 5/12.5 mg or two tablets of enalapril maleate and hydrochlorothiazide 10/25 mg.

Administration of the usual regimens of therapy with enalapril maleate and hydrochlorothiazide does not require adjustment as long as the patient's creatinine clearance remains greater than 30 mL/min/1.73 m², corresponding to a serum creatinine level of approximately less than or equal to 3 mg/dL (265 μmol/L).

Contraindications

Enalapril maleate and hydrochlorothiazide is contraindicated in patients with hypersensitivity to any component of the formulation. It is also contraindicated in individuals with a history of angioedema associated with prior treatment using an angiotensin-converting enzyme inhibitor, as well as in those with hereditary or idiopathic angioedema.

The presence of hydrochlorothiazide contraindicates its use in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Additionally, this product should not be used in conjunction with a neprilysin inhibitor, such as sacubitril. Administration of enalapril maleate and hydrochlorothiazide should not occur 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 due to the potential for adverse effects.

Warnings and Precautions

Excessive hypotension may occur in patients using enalapril, particularly in those who are severely salt or volume depleted, such as individuals undergoing vigorous diuretic therapy or those on dialysis. While this adverse effect is rarely seen in uncomplicated hypertensive patients, vigilance is warranted.

Syncope has been reported in 1.3% of patients receiving enalapril maleate in combination with hydrochlorothiazide, and in 0.5% of patients 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, 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. Laryngeal edema associated with angioedema can be life-threatening. Additionally, intestinal angioedema has been reported in patients receiving ACE inhibitors. Anaphylactoid reactions have also been noted in patients undergoing dialysis with high-flux membranes while concurrently treated with an ACE inhibitor.

There is a rare association between ACE inhibitors and a syndrome that begins with cholestatic jaundice and can progress to fulminant hepatic necrosis, and in some cases, death. Captopril, another ACE inhibitor, has been linked to agranulocytosis and bone marrow depression, highlighting the need for caution.

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. 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. It is recommended that periodic serum electrolyte determinations be conducted at appropriate intervals for patients receiving thiazide therapy to monitor for potential electrolyte imbalances.

Laboratory monitoring is essential for certain patient populations. Periodic white blood cell count assessments should be considered for patients with collagen vascular disease and renal disease. In patients with renal artery stenosis, renal function should be closely monitored during the initial weeks of therapy. Serum and urine electrolyte determinations are particularly critical in patients experiencing excessive vomiting or receiving parenteral fluids.

In cases of angioedema involving the tongue, glottis, or larynx, which may lead to airway obstruction, immediate medical intervention is necessary. Appropriate therapy, such as subcutaneous epinephrine solution (1:1000, 0.3 mL to 0.5 mL), and measures to ensure a patent airway should be promptly administered.

If hypotension occurs, the patient should be placed in a supine position, and intravenous infusion of normal saline may be required. For patients receiving enalapril maleate and hydrochlorothiazide, treatment should be discontinued immediately, and appropriate therapy and monitoring should be instituted until complete and sustained resolution of signs and symptoms is achieved.

Side Effects

Adverse reactions associated with the use of enalapril maleate and hydrochlorothiazide have been observed in clinical trials and postmarketing experiences. These reactions can be categorized based on their frequency and seriousness.

Common adverse reactions, occurring in 2% or more of patients, include dizziness (8.6%), headache (5.5%), fatigue (3.9%), cough (3.5%), muscle cramps (2.7%), nausea (2.5%), asthenia (2.4%), orthostatic effects (2.3%), impotence (2.2%), and diarrhea (2.1%).

Clinical adverse experiences with an incidence of 0.5% to 2.0% encompass a range of symptoms across various systems. These include syncope, chest pain, and abdominal pain (body as a whole); orthostatic hypotension, palpitation, and tachycardia (cardiovascular); vomiting, dyspepsia, constipation, flatulence, and dry mouth (digestive); insomnia, nervousness, paresthesia, somnolence, and vertigo (nervous/psychiatric); pruritus and rash (skin); as well as dyspnea, gout, back pain, arthralgia, diaphoresis, decreased libido, tinnitus, and urinary tract infection (other).

Serious adverse reactions include angioedema, which has been reported in patients receiving enalapril maleate and hydrochlorothiazide, with a higher incidence noted in black patients compared to non-black patients. Angioedema associated with laryngeal edema can be fatal; therefore, if symptoms such as swelling of the face, extremities, lips, tongue, glottis, or larynx occur, treatment should be discontinued immediately, and appropriate therapy should be initiated.

Hypotension-related adverse effects were noted in clinical trials, with hypotension occurring in 0.9% of patients, orthostatic hypotension in 1.5%, and other orthostatic effects in 2.3%. Additionally, syncope was reported in 1.3% of patients.

Further adverse reactions include anaphylactoid reactions, cardiac arrest, myocardial infarction, cerebrovascular accidents possibly secondary to excessive hypotension, pulmonary embolism, pulmonary edema, rhythm disturbances, angina pectoris, and Raynaud's phenomenon (cardiovascular). Digestive issues such as ileus, pancreatitis, hepatic failure, hepatitis, melena, glossitis, stomatitis, and dry mouth have also been reported. Hematologic reactions include rare cases of neutropenia, thrombocytopenia, bone marrow depression, and hemolytic anemia. Neurological and psychiatric effects may include depression, confusion, ataxia, and peripheral neuropathy. Renal complications such as renal failure, oliguria, and renal dysfunction have been observed, along with respiratory issues like pulmonary infiltrates, eosinophilic pneumonitis, bronchospasm, pneumonia, bronchitis, rhinorrhea, sore throat, hoarseness, asthma, and upper respiratory infections. Skin reactions can include exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, herpes zoster, erythema multiforme, urticaria, pemphigus, alopecia, flushing, and photosensitivity. Special senses may be affected, leading to blurred vision, taste alteration, anosmia, conjunctivitis, dry eyes, and tearing. Miscellaneous reactions may present as a symptom complex including positive ANA, elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, and eosinophilia.

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

Drug Interactions

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

Renin-Angiotensin System (RAS) Inhibitors The dual blockade of the RAS, involving 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 combined use of RAS inhibitors should be avoided. Specifically, aliskiren should not be coadministered with enalapril maleate and hydrochlorothiazide in patients with diabetes or those with renal impairment (GFR <60 mL/min).

Patients on diuretics may occasionally experience an excessive reduction in blood pressure following the initiation of therapy with enalapril. The antihypertensive effect of enalapril may be enhanced by antihypertensive agents that promote renin release, such as diuretics.

Coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors like enalapril may lead to renal function deterioration, potentially resulting in acute renal failure. It is advisable to monitor renal function periodically in patients receiving both enalapril and NSAID therapy. Additionally, NSAIDs may diminish the antihypertensive effect of ACE inhibitors.

Enalapril has been used safely with beta-adrenergic blockers, methyldopa, nitrates, calcium channel blockers, hydralazine, and prazosin without significant adverse interactions. However, enalapril can attenuate potassium loss induced by diuretics. Caution is warranted when using potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or potassium-containing salt substitutes, as these may lead to significant increases in serum potassium levels.

Lithium toxicity has been reported in patients receiving lithium alongside drugs that promote sodium elimination, including ACE inhibitors. Therefore, it is recommended that serum lithium levels be monitored frequently when enalapril is administered with lithium.

Nitritoid reactions have been reported rarely in patients receiving injectable gold (sodium aurothiomalate) in conjunction with ACE inhibitors, including enalapril maleate and hydrochlorothiazide tablets. Furthermore, patients receiving both an ACE inhibitor and mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus) may be at an increased risk for angioedema.

Hydrochlorothiazide Interactions Coadministration of hydrochlorothiazide with alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension. Dosage adjustments of anti-diabetic medications may be necessary when hydrochlorothiazide is administered. Additionally, an additive effect or potentiation may occur with other antihypertensive drugs.

The absorption of hydrochlorothiazide can be impaired by cholestyramine and colestipol resins. Intensified electrolyte depletion, particularly hypokalemia, may occur when corticosteroids or ACTH are administered alongside hydrochlorothiazide.

There may be a possible decreased response to pressor amines, although this does not preclude their use with hydrochlorothiazide. Conversely, there may be an increased responsiveness to nondepolarizing skeletal muscle relaxants (e.g., tubocurarine) when administered with hydrochlorothiazide.

Diuretic agents can reduce the renal clearance of lithium, significantly increasing the risk of lithium toxicity when used with hydrochlorothiazide. Furthermore, the administration of a non-steroidal anti-inflammatory agent can diminish the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics when used with hydrochlorothiazide.

Packaging & NDC

The table below lists all NDC Code configurations of Enalapril Maleate and Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. In neonates with a history of in utero exposure to enalapril maleate and hydrochlorothiazide, if oliguria or hypotension occurs, 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 substitute for impaired renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation through peritoneal dialysis with some clinical benefit. Although theoretically, it may also be removed by exchange transfusion, there is currently no clinical experience to support this procedure.

Geriatric Use

Elderly patients, defined as those aged 65 and older, were not adequately represented in clinical studies of enalapril maleate and hydrochlorothiazide, making it difficult to ascertain whether they respond differently compared to younger patients. However, available clinical experience has not indicated any significant differences in responses between geriatric and younger patients.

In general, dose selection for elderly patients should be approached with caution. It is advisable to initiate treatment at the lower end of the dosing range, taking into account the increased likelihood of diminished hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies. Given that this medication is primarily excreted by the kidneys, there is an elevated risk of toxic reactions in patients with impaired renal function.

Therefore, careful consideration must be given to dose selection in elderly patients, particularly due to their propensity for decreased renal function. It is essential that the evaluation of hypertensive elderly patients includes a thorough assessment of renal function to ensure safe and effective treatment.

Pregnancy

There are no specific statements regarding the use of this drug during pregnancy, including any safety concerns, dosage modifications, or special precautions regarding use during pregnancy. Healthcare professionals should consider the lack of data when prescribing this medication to pregnant patients and 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.

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, lactating mothers should consider whether to discontinue nursing or to discontinue enalapril maleate and hydrochlorothiazide. This decision should take into account the importance of the medication to the mother.

Renal Impairment

Thiazides should be used with caution in patients with severe renal disease, as they may precipitate azotemia and lead to cumulative effects due to impaired renal function. Periodic monitoring of white blood cell counts is recommended for patients with collagen vascular disease and renal disease. In patients with severe congestive heart failure, whether or not associated with renal insufficiency, excessive hypotension has been observed, which may result in oliguria, progressive azotemia, and, in rare cases, acute renal failure or death.

Patients receiving ACE inhibitors, including enalapril maleate and hydrochlorothiazide, may experience a range of adverse reactions, particularly those with renal impairment. Caution is advised when administering enalapril to patients with reduced kidney function, as it may exacerbate renal issues. Additionally, there have been reports of exacerbation or activation of systemic lupus erythematosus in patients with renal impairment.

Hepatic Impairment

Patients with hepatic impairment should be monitored closely when receiving ACE inhibitors due to the rare association of these medications with a syndrome that begins with cholestatic jaundice and may 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 significant elevations in hepatic enzymes, it is imperative to discontinue the ACE inhibitor and ensure appropriate medical follow-up is provided.

Thiazide diuretics should be administered with caution in patients with impaired hepatic function or 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 cases of overdosage with enalapril maleate and hydrochlorothiazide, specific treatment information is limited. Management is primarily symptomatic and supportive. It is recommended that therapy with enalapril maleate and hydrochlorothiazide be discontinued immediately, and the patient should be closely monitored.

Recommended Actions

In the event of an overdose, healthcare professionals should consider the following measures:

• Induction of emesis and/or gastric lavage may be appropriate to reduce the absorption of the drug.

• Correction of dehydration, electrolyte imbalances, and hypotension should be conducted using established medical procedures.

Potential Symptoms

The most likely manifestation of an overdose is hypotension. In animal studies, single oral doses exceeding 1,000 mg/kg in mice and 1,775 mg/kg in rats have been associated with lethality, underscoring the seriousness of potential overdose scenarios.

Management Procedures

For the management of hypotension resulting from an overdose, intravenous infusion of normal saline solution is the usual treatment. Additionally, enalaprilat can be removed from the general circulation through hemodialysis. In cases involving neonates, peritoneal dialysis has been shown to effectively remove enalaprilat from circulation.

Healthcare professionals should remain vigilant and prepared to implement these interventions in the event of an overdose.

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. Similarly, hydrochlorothiazide did not demonstrate any adverse effects on the fertility of 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 with 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) found no evidence of 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 report equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was also shown to be non-genotoxic in vitro in the Ames mutagenicity assay using various Salmonella typhimurium strains and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, as well as 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 specific concentrations, 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 more pronounced 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, the risk escalates to approximately 1 additional case of SCC for every 6,700 patients per year.

Patient Counseling

Patients should be advised to discontinue enalapril maleate and hydrochlorothiazide as soon as pregnancy is detected. It is important for patients to report immediately any signs or symptoms suggesting angioedema, such as swelling of the face, extremities, eyes, lips, or tongue, as well as difficulty in swallowing or breathing. Patients should be instructed to refrain from taking any additional doses until they have consulted with their prescribing physician.

Patients should be cautioned about the potential for lightheadedness, particularly during the initial days of therapy. If actual syncope occurs, patients should discontinue the medication and seek guidance from their physician. Additionally, patients should be informed not to use salt substitutes that contain potassium without prior consultation with their healthcare provider.

Prompt reporting of any indications of infection, such as sore throat or fever, is essential, as these may signal neutropenia. Female patients of childbearing age should be made aware of the risks associated with exposure to enalapril maleate and hydrochlorothiazide during pregnancy. It is advisable to discuss treatment options with women who are planning to become pregnant, and patients should be encouraged to inform their physicians of any pregnancies as soon as possible.

For patients taking hydrochlorothiazide, it is important 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 temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. It is essential to keep the container tightly closed and to protect the product from moisture. In cases where 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 medication 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. Clinicians should inform patients that excessive perspiration and dehydration can lead to significant drops in blood pressure, and other causes of volume depletion, such as vomiting or diarrhea, may also contribute to this risk. Patients are cautioned against using potassium-containing salt substitutes without prior consultation with their physician and should promptly report any signs of infection, such as sore throat or fever, which may indicate neutropenia.

Female patients of childbearing age should be made aware of the potential consequences of exposure to enalapril maleate and hydrochlorothiazide during pregnancy and should discuss treatment options with their healthcare provider if planning to conceive. Additionally, patients taking hydrochlorothiazide should be instructed to protect their skin from sun exposure and to undergo regular skin cancer screenings. Postmarketing experience has indicated that hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), especially in white patients receiving high cumulative doses. The overall risk for SCC is approximately one additional case per 16,000 patients per year, with a significantly higher risk of one additional case for every 6,700 patients per year among white patients taking a cumulative dose of 50,000 mg or more.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Enalapril Maleate and Hydrochlorothiazide as submitted by Taro Pharmaceuticals U. S. A. , Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)