Enalapril maleate/Hydrochlorothiazide

Description

Enalapril maleate-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 a molecular formula of C20H28N2O5 • C4H4O4 and a molecular weight of 492.53. Enalapril maleate appears as a white to off-white crystalline powder, which is sparingly soluble in water, soluble in ethanol, and freely soluble in methanol. As a pro-drug, enalapril is bioactivated following oral administration through hydrolysis of the ethyl ester to enalaprilat, the active angiotensin converting enzyme inhibitor.

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

Enalapril maleate and hydrochlorothiazide tablets are available in two combinations: 5 mg of enalapril maleate with 12.5 mg of hydrochlorothiazide, and 10 mg of enalapril maleate with 25 mg of hydrochlorothiazide. The inactive ingredients include lactose monohydrate, pregelatinized starch, corn starch, zinc stearate, and purified water.

Uses and Indications

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

Dosage and Administration

Enalapril may be administered at a dosage range of 10 to 40 mg per day, which can be given as a single dose or divided into two doses. Hydrochlorothiazide is typically prescribed at a daily dosage of 12.5 to 50 mg.

For patients whose blood pressure is not adequately controlled with monotherapy, combination therapy with enalapril maleate and hydrochlorothiazide tablets is indicated. These combination tablets are available in two strengths: 5 mg/12.5 mg and 10 mg/25 mg. The total daily dosage should not exceed four tablets of the 5 mg/12.5 mg formulation or two tablets of the 10 mg/25 mg formulation.

Dose titration for enalapril, hydrochlorothiazide, or both should be based on the clinical response of the patient. It is recommended that the hydrochlorothiazide dosage not be increased until a period of 2 to 3 weeks has elapsed to adequately assess the patient's response.

In patients with renal impairment, usual regimens of therapy do 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 ≤3 mg/dL or 265 µmol/L.

Contraindications

Enalapril maleate and hydrochlorothiazide tablets are contraindicated in patients with a known hypersensitivity to any component of the formulation. The use of this product is also contraindicated in individuals with a history of angioedema associated with prior treatment using an angiotensin-converting enzyme inhibitor, as well as in patients with hereditary or idiopathic angioedema. Additionally, due to the presence of hydrochlorothiazide, this medication is contraindicated in patients with anuria or those who exhibit hypersensitivity to other sulfonamide-derived drugs.

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 rare in uncomplicated hypertensive patients, this risk necessitates careful monitoring. Syncope has been reported in 1.3% of patients receiving enalapril maleate and hydrochlorothiazide, with an incidence of 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, 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 fatal. Additionally, intestinal angioedema has been reported in patients receiving ACE inhibitors. Anaphylactoid reactions have been observed in patients undergoing dialysis with high-flux membranes while concurrently treated with an ACE inhibitor. Captopril, another ACE inhibitor, has been linked to agranulocytosis and bone marrow depression. Rarely, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice and can progress to fulminant hepatic necrosis, and in some cases, death.

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. Clinical studies have shown that 20% of patients with renal artery stenosis experienced increases in blood urea nitrogen and serum creatinine. Therefore, evaluation of renal function is essential in 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 determination of serum electrolytes is recommended to detect potential electrolyte imbalances.

Laboratory tests should include periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease. Renal function should be closely monitored during the initial weeks of therapy in patients with renal artery stenosis. 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, immediate medical intervention is required. 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.

Patients should discontinue enalapril maleate and hydrochlorothiazide tablets and seek medical attention if they experience angioedema, ensuring appropriate therapy and monitoring until complete and sustained resolution of symptoms occurs. Additionally, patients receiving ACE inhibitors who develop jaundice or significant elevations in hepatic enzymes should stop the medication and obtain appropriate medical follow-up.

Side Effects

Common adverse reactions observed in clinical trials include dizziness (8.6%, with a discontinuation rate of 0.7%), headache (5.5%, 0.4% discontinuation), and fatigue (3.9%, 0.8% discontinuation). Other frequently reported reactions are 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), and diarrhea (2.1%, <0.1% discontinuation).

Adverse reactions occurring in 0.5 to 2.0 percent of patients include syncope, chest pain, and abdominal pain. Cardiovascular effects such as orthostatic hypotension, palpitations, and tachycardia have also been reported. Digestive system reactions include vomiting, dyspepsia, constipation, flatulence, and dry mouth. Nervous and psychiatric effects encompass insomnia, nervousness, paresthesia, somnolence, and vertigo. Skin reactions include pruritus and rash, while other notable reactions consist of dyspnea, gout, back pain, arthralgia, diaphoresis, decreased libido, tinnitus, and urinary tract infections.

Angioedema has been reported in patients receiving enalapril maleate and hydrochlorothiazide tablets, with a higher incidence noted in black patients compared to non-black patients. Angioedema associated with laryngeal edema may be fatal; therefore, if symptoms such as swelling of the face, extremities, lips, tongue, glottis, and/or larynx occur, treatment with enalapril maleate and hydrochlorothiazide tablets 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 associated with enalapril maleate include anaphylactoid reactions, cardiac arrest, myocardial infarction, cerebrovascular accidents, pulmonary embolism, 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 infections, 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, and tearing.

Adverse reactions associated with hydrochlorothiazide include 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, and xanthopsia.

Drug Interactions

Patients receiving enalapril may experience significant drug interactions that necessitate careful monitoring and potential dosage adjustments.

Pharmacodynamic Interactions

• Diuretics: The initiation of enalapril therapy in patients on diuretics, particularly those recently started on diuretics, may lead to an excessive reduction in blood pressure. To mitigate the risk of hypotension, it is advisable to either discontinue the diuretic or increase salt intake prior to starting enalapril. Additionally, the antihypertensive effect of enalapril may be enhanced by diuretics, which promote renin release.

• Potassium-Sparing Diuretics and Supplements: Enalapril can attenuate potassium loss induced by diuretics. However, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium levels. If these agents are used together due to hypokalemia, they should be administered with caution and serum potassium levels should be monitored frequently.

• Lithium: The coadministration of enalapril with lithium has been associated with reports of lithium toxicity, which is reversible upon discontinuation of both medications. It is recommended that serum lithium levels be monitored closely in patients receiving this combination.

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): In patients with compromised renal function, the use of NSAIDs alongside enalapril may lead to further deterioration of renal function, although these effects are typically reversible. Additionally, NSAIDs may diminish the antihypertensive effect of enalapril.

• Gold Therapy: Rare instances of nitritoid reactions, characterized by facial flushing, nausea, vomiting, and hypotension, have been reported in patients receiving injectable gold (sodium aurothiomalate) in conjunction with enalapril.

Pharmacokinetic Interactions

• Thiazide Diuretics: When thiazide diuretics are administered concurrently with other medications, several interactions may occur:

  • Alcohol, Barbiturates, or Narcotics: These agents may potentiate orthostatic hypotension.

  • Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be necessary.

  • Other Antihypertensive Agents: There may be an additive effect or potentiation of antihypertensive effects.

  • Cholestyramine and Colestipol Resins: The absorption of hydrochlorothiazide may be impaired in the presence of these anionic exchange resins.

  • Corticosteroids and ACTH: These agents may lead to intensified electrolyte depletion, particularly hypokalemia.

  • Pressor Amines (e.g., Norepinephrine): There may be a decreased response to pressor amines, although this does not preclude their use.

  • Skeletal Muscle Relaxants (e.g., Tubocurarine): There may be an increased responsiveness to nondepolarizing muscle relaxants.

  • Lithium: The combination of diuretics and lithium is generally contraindicated due to the high risk of lithium toxicity.

  • NSAIDs: The administration of NSAIDs can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics.

Healthcare providers should remain vigilant for these interactions and consider appropriate monitoring and dosage adjustments as necessary.

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. Therefore, the use of this medication in children, infants, and adolescents should be approached with caution until further data is available.

Geriatric Use

Clinical studies of enalapril maleate and hydrochlorothiazide tablets did not include a sufficient number of subjects aged 65 and over to determine whether these elderly patients respond differently from younger subjects. 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 this medication 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 have decreased renal function; therefore, careful consideration should be given during dose selection. Additionally, the evaluation of hypertensive elderly patients should always include an assessment of renal function to ensure safe and effective treatment.

Pregnancy

Pregnant patients should be aware that this medication is classified as Category C during the first trimester and Category D during the second and third trimesters. This indicates that there may be potential risks associated with its use in pregnancy.

In animal studies, adverse effects on fetal outcomes have been observed, and there is a potential for fetal/neonatal morbidity and mortality. Therefore, healthcare professionals are advised to carefully consider the benefits and risks of this medication when prescribing to women of childbearing potential, particularly during the later stages of pregnancy.

It is recommended that alternative therapies be considered for pregnant patients, especially during the second and third trimesters, to mitigate potential risks to the developing fetus.

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

In the case of angiotensin converting enzyme inhibitors, such as captopril, there is an increased risk of agranulocytosis and bone marrow depression in patients with renal impairment, especially those with concurrent collagen vascular diseases. Although clinical trial data for enalapril are insufficient to definitively rule out a similar risk of agranulocytosis, marketing experience has indicated cases of neutropenia or agranulocytosis where a causal relationship to enalapril cannot be excluded. Therefore, periodic monitoring of white blood cell counts is advisable for patients with both collagen vascular disease and renal impairment.

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 cases of overdosage with enalapril maleate and hydrochlorothiazide tablets, specific treatment information is limited. Management is primarily symptomatic and supportive.

Discontinuation of therapy with enalapril maleate and hydrochlorothiazide tablets is recommended, followed by close observation of the patient. Healthcare professionals should consider the following suggested 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.

It is important to note that single oral doses of enalapril exceeding 1,000 mg/kg in mice and 1,775 mg/kg in rats have been associated with lethality. The most common clinical manifestation of overdosage is likely to be hypotension. In such cases, the standard treatment involves the intravenous infusion of normal saline solution to stabilize blood pressure.

Additionally, enalaprilat, the active metabolite of enalapril, can be removed from systemic circulation through hemodialysis. In neonates, peritoneal dialysis has been shown to effectively remove enalaprilat from circulation.

Healthcare professionals should remain vigilant and implement these management strategies promptly 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 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.

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 cytogenetic 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 find equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was also 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 and Chinese hamster bone marrow chromosomes. 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

Angioedema has been reported in patients receiving enalapril maleate and hydrochlorothiazide tablets, with a higher incidence observed in black patients compared to non-black patients. Angioedema associated with laryngeal edema may be fatal. In cases of angioedema affecting the face, extremities, lips, tongue, glottis, and/or larynx, discontinuation of enalapril maleate and hydrochlorothiazide tablets and immediate initiation of appropriate therapy is recommended.

Syncope has been reported in 1.3% of patients taking enalapril maleate and hydrochlorothiazide tablets, while the incidence of syncope in patients receiving enalapril alone is 0.5%.

Marketing experience has revealed cases of neutropenia or agranulocytosis, where a causal relationship to enalapril cannot be excluded. It is advisable to consider periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease.

Rarely, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice and may progress to fulminant hepatic necrosis, and in some cases, death. The mechanism underlying this syndrome remains unclear. Patients developing jaundice or significant elevations in hepatic enzymes while on ACE inhibitors should discontinue the medication and receive appropriate medical follow-up.

Adverse reactions observed with enalapril have also been reported with enalapril maleate and hydrochlorothiazide tablets. Since the marketing of enalapril, additional adverse reactions have been documented, including anaphylactoid reactions, cardiac arrest, myocardial infarction, cerebrovascular accident, pulmonary embolism and infarction, pulmonary edema, rhythm disturbances, hypotension, angina pectoris, and various skin reactions.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been linked to fetal and neonatal injury, which may include hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably due to decreased fetal renal function.

Infants with a history of in utero exposure to ACE inhibitors should be closely monitored for hypotension, oliguria, and hyperkalemia. In cases of oliguria, attention should be directed toward supporting blood pressure and renal perfusion.

Patient Counseling

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

Patients should be cautioned to report any experiences of lightheadedness, particularly during the initial days of therapy. In the event of actual syncope, patients should be advised to discontinue the medication and seek guidance from their prescribing physician.

It is important to inform all patients that excessive perspiration and dehydration can lead to a significant drop in blood pressure due to reduced fluid volume. They should also be made aware that other factors contributing to volume depletion, such as vomiting or diarrhea, may similarly result in decreased blood pressure. Patients should be encouraged to consult with their physician if they experience these conditions.

Patients should be instructed not to use salt substitutes that contain potassium without prior consultation with their physician, as this may have implications for their treatment.

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

Female patients of childbearing age should be informed about the potential consequences of exposure to ACE inhibitors. They should be encouraged to report any pregnancies to their physician as soon as possible to ensure appropriate management.

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 to protect the contents from moisture. If the product package is subdivided, it must be dispensed in a tight container as specified by USP to maintain its quality and efficacy.

Additional Clinical Information

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

Additionally, patients are advised against using salt substitutes containing potassium without prior consultation with their physician. Any signs of infection, such as sore throat or fever, should be promptly reported, as these may indicate neutropenia. Female patients of childbearing age should be made aware of the risks associated with ACE inhibitors and are encouraged to inform their physicians immediately upon becoming pregnant.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Enalapril Maleate and Hydrochlorothiazide as submitted by Dr. Reddy's Laboratories Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)