Lisinopril/Hydrochlorothiazide

Description

Lisinopril and hydrochlorothiazide tablets USP combine an angiotensin converting enzyme inhibitor, lisinopril, and a diuretic, hydrochlorothiazide. Lisinopril is a synthetic peptide derivative, chemically described as (S)-1-N2-(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline dihydrate, with an empirical formula of C21H31N3O5•2H2O and a molecular weight of 441.53. It appears as a white to off-white crystalline powder, soluble in water, sparingly soluble in methanol, and practically insoluble in ethanol.

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 297.72. This compound is a white or practically white crystalline powder, slightly soluble in water, and freely soluble in sodium hydroxide solution.

The tablets are available for oral administration in three combinations: 10 mg lisinopril and 12.5 mg hydrochlorothiazide; 20 mg lisinopril and 12.5 mg hydrochlorothiazide; and 20 mg lisinopril and 25 mg hydrochlorothiazide. Inactive ingredients include dibasic calcium phosphate, magnesium stearate, mannitol, pregelatinized starch, and corn starch. The 10 mg/12.5 mg formulation contains FD&C Blue No. 2 Aluminum Lake, the 20 mg/12.5 mg formulation includes yellow iron oxide, and the 20 mg/25 mg formulation contains red iron oxide.

Uses and Indications

Lisinopril and hydrochlorothiazide tablets USP are indicated for the treatment of hypertension to effectively lower blood pressure. The reduction of blood pressure is associated with a decreased risk of both fatal and non-fatal cardiovascular events, particularly strokes and myocardial infarctions.

Management of high blood pressure should be integrated into a comprehensive cardiovascular risk management strategy, which includes lipid control, diabetes management, antithrombotic therapy, smoking cessation, regular exercise, and limited sodium intake. It is important to note that many patients may require a combination of antihypertensive medications to achieve their blood pressure targets.

Clinical evidence from randomized controlled trials has demonstrated that various antihypertensive agents can significantly reduce cardiovascular morbidity and mortality. The most substantial cardiovascular outcome benefit observed is a reduction in the risk of stroke, alongside reductions in myocardial infarction and overall cardiovascular mortality. Elevated systolic or diastolic blood pressure is linked to increased cardiovascular risk, with a greater absolute risk increase per mmHg at higher blood pressure levels. Even modest reductions in severe hypertension can yield considerable health benefits.

The relative risk reduction associated with blood pressure lowering is consistent across different populations, regardless of their baseline absolute risk. Patients identified as being at higher risk, such as those with diabetes or hyperlipidemia, may benefit from more aggressive treatment strategies aimed at achieving lower blood pressure goals. It is also noted that certain antihypertensive medications may exhibit diminished blood pressure-lowering effects in black patients, and many of these agents have additional approved indications and therapeutic effects, including those related to angina, heart failure, or diabetic kidney disease.

Dosage and Administration

Lisinopril may be administered as monotherapy at a dosage range of 10 to 80 mg once daily. Hydrochlorothiazide can be prescribed as monotherapy at a daily dosage of 12.5 to 50 mg. For patients requiring combination therapy, the dosing for lisinopril ranges from 10 to 80 mg, while hydrochlorothiazide should be administered at doses between 6.25 to 50 mg.

In cases where blood pressure is not adequately controlled with monotherapy, healthcare professionals may consider switching to lisinopril and hydrochlorothiazide combination tablets, available in strengths of 10 mg/12.5 mg or 20 mg/12.5 mg, based on the patient's current monotherapy dosage. Adjustments to the dosage of either component should be guided by the clinical response, with blood pressure measurements taken at the interdosing interval.

It is recommended that the hydrochlorothiazide dosage not be increased until a period of 2 to 3 weeks has elapsed to allow for adequate assessment of the patient's response. If discontinuation of the diuretic is not feasible, an initial dose of 5 mg of lisinopril should be administered under medical supervision, with monitoring for at least two hours until blood pressure stabilizes for an additional hour.

Contraindications

Lisinopril and hydrochlorothiazide is contraindicated in patients with a known hypersensitivity to this product. 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 patients with hereditary or idiopathic angioedema.

The hydrochlorothiazide component renders this product contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Additionally, co-administration of aliskiren with lisinopril and hydrochlorothiazide is contraindicated in patients with diabetes.

Warnings and Precautions

Patients receiving ACE inhibitors, including lisinopril, may experience serious adverse reactions, including anaphylactoid and possibly related reactions. It is crucial for healthcare professionals to monitor patients closely for signs of these reactions.

Angioedema Risks Angioedema, including head and neck involvement, has been reported in patients treated with ACE inhibitors. This condition can occur at any time during treatment. If angioedema occurs, lisinopril and hydrochlorothiazide should be discontinued immediately, and appropriate therapy and monitoring should be initiated until resolution. Fatalities have been documented due to angioedema associated with laryngeal or tongue edema. Additionally, intestinal angioedema has been observed, presenting with abdominal pain, which resolved upon discontinuation of the ACE inhibitor.

Desensitization Considerations Life-threatening anaphylactoid reactions may occur in patients undergoing desensitization while on ACE inhibitors. Therefore, caution is advised in these situations.

Hypotension Management Excessive hypotension may occur in patients who are salt or volume-depleted. Therapy should be initiated under close medical supervision, particularly in patients with severe congestive heart failure. In cases of hypotension, patients should be placed in a supine position, and intravenous infusion of normal saline may be necessary.

Hematological Monitoring Periodic monitoring of white blood cell counts is recommended for patients with collagen vascular disease and renal disease due to the risk of leukopenia, neutropenia, or agranulocytosis.

Hepatic Function Monitoring In the event of jaundice or marked elevations in hepatic enzymes, the ACE inhibitor should be discontinued, and appropriate medical follow-up should be arranged to assess hepatic function.

Fetal Toxicity Warning The use of drugs that affect the renin-angiotensin system during the second and third trimesters of pregnancy can lead to reduced fetal renal function, increasing the risk of morbidity and mortality.

General Precautions Patients with a history of angioedema unrelated to ACE-inhibitor therapy may be at an increased risk of developing angioedema while receiving an ACE inhibitor. Caution is also warranted in patients with renal disease, hepatic function impairment, or progressive liver disease. Thiazide-containing combination products are not recommended for patients with severe renal dysfunction.

Emergency Medical Assistance In cases where angioedema involves the tongue, glottis, or larynx, which may lead to airway obstruction, immediate administration of subcutaneous epinephrine solution (1:1000, 0.3 mL to 0.5 mL) and measures to ensure a patent airway should be provided promptly.

Healthcare professionals are advised to remain vigilant and proactive in monitoring and managing these potential risks associated with ACE inhibitor therapy.

Side Effects

Patients may experience a range of adverse reactions while receiving treatment. The following sections categorize these reactions based on their frequency and seriousness.

Common adverse reactions, occurring in more than 1% of participants in controlled trials, include dizziness (7.5%), headache (5.2%), cough (3.9%), fatigue (3.7%), and orthostatic effects (3.2%). Other notable reactions are diarrhea (2.5%), nausea (2.2%), upper respiratory infection (2.2%), muscle cramps (2.0%), and asthenia (1.8%). Paresthesia (1.5%), hypotension (1.4%), vomiting (1.4%), dyspepsia (1.3%), rash (1.2%), and impotence (1.2%) were also reported, with respective discontinuation rates indicating the impact of these reactions on treatment adherence.

In addition to the common adverse reactions, patients may experience other reactions categorized by body systems. Cardiovascular effects may include palpitations and orthostatic hypotension. Digestive system reactions can manifest as gastrointestinal cramps, dry mouth, constipation, and heartburn. Musculoskeletal complaints such as back pain, shoulder pain, and myalgia have also been noted.

Nervous system and psychiatric effects may include decreased libido, vertigo, depression, and somnolence. Respiratory issues such as common cold, nasal congestion, and dyspnea have been reported, alongside skin reactions like flushing, pruritus, and skin inflammation. Special senses may be affected, with reports of blurred vision and tinnitus. Urogenital reactions include urinary tract infections.

Serious adverse reactions warrant particular attention. Angioedema, affecting the face, extremities, lips, tongue, glottis, and/or larynx, has been reported, with rare cases of intestinal angioedema noted in post-marketing experience. Hypotension, including orthostatic hypotension, has been observed in 1.4% of patients, with syncope occurring in 0.8%. Persistent nonproductive cough has been associated with all ACE inhibitors, resolving upon discontinuation. Rare cases of leukopenia, neutropenia, and agranulocytosis have been documented, alongside rare instances of hepatic failure, which may progress to fulminant hepatic necrosis.

Specific reactions associated with hydrochlorothiazide include weakness, anorexia, gastric irritation, and jaundice. Hematologic reactions such as leukopenia and thrombocytopenia have been reported, as well as renal issues including renal failure and interstitial nephritis. Skin reactions may include erythema multiforme and exfoliative dermatitis. Hypersensitivity reactions can manifest as purpura, photosensitivity, and anaphylactic reactions, including respiratory distress.

Healthcare providers should monitor patients for these adverse reactions and manage them appropriately to ensure patient safety and treatment efficacy.

Drug Interactions

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

Pharmacodynamic Interactions:

• Diuretics: Patients on diuretic therapy may experience excessive hypotension upon initiation of lisinopril. To mitigate this risk, it is advisable to discontinue the diuretic or increase salt intake prior to starting lisinopril.

• Non-Steroidal Anti-Inflammatory Agents (NSAIDs): Co-administration of NSAIDs, including selective COX-2 inhibitors, may lead to renal function deterioration, particularly in elderly patients or those with pre-existing renal impairment. Additionally, the antihypertensive effect of lisinopril may be diminished. Close monitoring of renal function is recommended.

• Dual Blockade of the Renin-Angiotensin System (RAS): The combination of lisinopril with angiotensin receptor blockers or aliskiren may increase the risk of hypotension, hyperkalemia, and renal function changes, including acute renal failure. Caution is advised when considering this combination.

• Agents Increasing Serum Potassium: The concomitant use of lisinopril with potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes can lead to significant hyperkalemia. Frequent monitoring of serum potassium levels is recommended.

• Lithium: The use of lisinopril with lithium has been associated with lithium toxicity. Therefore, serum lithium levels should be monitored closely during co-administration.

• mTOR Inhibitors: There is an increased risk of angioedema when lisinopril is used in conjunction with mTOR inhibitors such as temsirolimus, sirolimus, or everolimus.

Pharmacokinetic Interactions:

• Hydrochlorothiazide: The absorption of hydrochlorothiazide can be significantly impaired by cholestyramine and colestipol resins, with reductions of up to 85% and 43%, respectively. Therefore, it is recommended to separate the administration of these agents.

• Alcohol, Barbiturates, or Narcotics: The combination of hydrochlorothiazide with these substances may potentiate orthostatic hypotension, necessitating caution in patients.

• Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be required when used concurrently with hydrochlorothiazide due to potential alterations in glycemic control.

• Other Antihypertensive Drugs: The use of hydrochlorothiazide with other antihypertensive agents may result in an additive effect, which should be monitored.

• Corticosteroids and ACTH: The combination may lead to intensified electrolyte depletion, particularly hypokalemia, requiring careful monitoring of electrolyte levels.

• Pressor Amines: There may be a decreased response to pressor amines such as norepinephrine when used with hydrochlorothiazide.

• Skeletal Muscle Relaxants: Increased responsiveness to nondepolarizing skeletal muscle relaxants, such as tubocurarine, may occur when used with hydrochlorothiazide.

• Lithium: The use of hydrochlorothiazide with lithium is generally contraindicated due to the risk of reduced renal clearance and increased lithium toxicity.

• Non-Steroidal Anti-Inflammatory Drugs: The efficacy of hydrochlorothiazide may be reduced when used with NSAIDs, necessitating close observation of the patient's response.

• Gold: Nitritoid reactions have been reported in patients receiving injectable gold in conjunction with ACE inhibitors, including lisinopril. Caution is advised in this combination.

Packaging & NDC

The table below lists all NDC Code configurations of Lisinopril 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, as there is insufficient data to support its use in these populations. Healthcare professionals are advised to consider alternative treatments or therapies that have been validated for pediatric use.

Geriatric Use

Elderly patients, defined as those aged 65 and older, were not adequately represented in clinical studies of lisinopril 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 elderly and younger patients.

In general, dose selection for geriatric 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 should be given to renal function when selecting doses for elderly patients. Regular assessment of renal function is essential in the evaluation of hypertensive patients, particularly in the geriatric population, to ensure safe and effective treatment.

Pregnancy

Lisinopril crosses the placenta, and its use during pregnancy poses a risk to the developing fetus. Due to the potential for harm, lisinopril is contraindicated in pregnant patients. Exposure to lisinopril in utero may lead to adverse fetal outcomes, including oliguria and hypotension in neonates. In cases where neonates exhibit these conditions following in utero exposure to lisinopril and hydrochlorothiazide, immediate attention should be directed toward supporting blood pressure and renal perfusion.

In certain instances, exchange transfusions or dialysis may be necessary to address hypotension and/or to manage disordered renal function in affected neonates. Clinical experience has shown that peritoneal dialysis can effectively remove lisinopril from neonatal circulation, providing some clinical benefit. Healthcare professionals should exercise caution and consider alternative therapies for women of childbearing potential to avoid the risks associated with lisinopril during pregnancy.

Lactation

There is no specific information available regarding the use of this medication in nursing mothers or its effects on lactation. Consequently, healthcare professionals should exercise caution when considering this medication for lactating mothers. The potential risks and benefits should be carefully evaluated, and alternative treatments may be considered if necessary. Breastfed infants should be monitored for any adverse effects if the mother is using this medication.

Renal Impairment

Patients with renal impairment require careful consideration when prescribing thiazide-containing combination products, as these are not recommended for individuals with severe renal dysfunction. In patients with renal disease, thiazides may precipitate azotemia, and the cumulative effects of the drug can develop in those with impaired renal function.

Periodic monitoring of white blood cell counts is advisable for patients with collagen vascular disease and renal disease. Additionally, excessive hypotension has been observed in patients with severe congestive heart failure, regardless of renal status, and may lead to oliguria, progressive azotemia, and, in rare cases, acute renal failure or death.

Close monitoring is essential during the first two weeks of treatment and whenever there is an increase in the dose of lisinopril or diuretic. Patients receiving ACE inhibitors, including lisinopril, may experience a range of adverse reactions, particularly those with renal impairment. Anaphylactoid reactions have been reported in patients undergoing dialysis with high-flux membranes who are also treated with an ACE inhibitor.

Patients with a history of angioedema unrelated to ACE-inhibitor therapy may be at an increased risk of angioedema while receiving an ACE inhibitor. For patients on dialysis, close monitoring is critical, and dialysis should be halted immediately if anaphylactoid reactions occur. Lisinopril should be used with caution in patients with renal impairment, and renal function tests should be performed periodically to ensure patient safety.

Hepatic Impairment

Patients with hepatic impairment should be monitored closely when receiving treatment with ACE inhibitors and thiazides. Rarely, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice or hepatitis and can progress to fulminant hepatic necrosis, which may result in death. The mechanism underlying this syndrome remains unclear. Therefore, patients receiving ACE inhibitors who develop jaundice or significant elevations in hepatic enzymes should discontinue the medication immediately and receive appropriate medical follow-up.

Thiazides 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 lisinopril and hydrochlorothiazide, specific treatment information is limited. Management is primarily symptomatic and supportive. It is recommended that therapy with lisinopril and hydrochlorothiazide be discontinued, and the patient should be closely monitored. Suggested interventions include the induction of emesis and/or gastric lavage, along with the correction of dehydration, electrolyte imbalances, and hypotension through established medical procedures.

The most likely manifestation of overdosage is hypotension. In such instances, the standard treatment involves the intravenous infusion of normal saline solution. Animal studies indicate that a single oral dose of 20 mg/kg did not result in lethality in rats, while one out of twenty mice administered the same dose did not survive. Furthermore, a single oral dose of 10 mg/kg was not lethal in either mice or rats. The predominant signs and symptoms associated with overdosage are typically those resulting from electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration due to excessive diuresis. It is important to note that if digitalis has also been administered, hypokalemia may exacerbate the risk of cardiac arrhythmias.

For patients experiencing severe overdosage, hemodialysis may be considered as a method to remove lisinopril from the system. Continuous monitoring and supportive care are essential to manage the patient's condition effectively.

Nonclinical Toxicology

No teratogenic effects were reported in the studies. In terms of non-teratogenic effects, there were no adverse effects on reproductive performance in male and female rats treated with up to 300 mg/kg/day of lisinopril. Hydrochlorothiazide also demonstrated no adverse effects on the fertility of mice and rats of either sex when these species were exposed, via their diet, to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to conception and throughout gestation.

Lisinopril in combination with hydrochlorothiazide was not mutagenic in a microbial mutagen test using Salmonella typhimurium (Ames test) or Escherichia coli with or without metabolic activation, nor in a forward mutation assay using Chinese hamster lung cells. Additionally, neither lisinopril nor hydrochlorothiazide produced DNA single strand breaks in an in vitro alkaline elution rat hepatocyte assay. Lisinopril did not induce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.

There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks to male and female rats at doses up to 90 mg/kg/day. Similarly, no evidence of carcinogenicity was observed when lisinopril was administered for 92 weeks to male and female mice at doses up to 135 mg/kg/day. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. However, positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays.

Two-year feeding studies in mice and rats revealed no evidence of a carcinogenic potential of hydrochlorothiazide in female mice or in male and female rats. The National Toxicology Program (NTP) found equivocal evidence for hepatocarcinogenicity in male mice.

Postmarketing Experience

Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported in patients treated with angiotensin-converting enzyme (ACE) inhibitors, including lisinopril. This adverse event may occur at any time during treatment. Notably, ACE inhibitors have been associated with a higher incidence of angioedema in black patients compared to nonblack patients.

Intestinal angioedema has also been documented in patients receiving ACE inhibitors, presenting with abdominal pain, which may occur with or without nausea or vomiting. In some instances, patients had no prior history of facial angioedema, and C-1 esterase levels were found to be normal. Diagnosis of intestinal angioedema was made through abdominal CT scans, ultrasounds, or surgical procedures, with symptoms resolving upon discontinuation of the ACE inhibitor.

Rare cases of leukopenia/neutropenia and bone marrow depression have been reported, where a causal relationship to lisinopril cannot be excluded. It is advisable to consider periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease.

Marketing experience has revealed rare instances of a syndrome associated with ACE inhibitors, beginning with cholestatic jaundice or hepatitis and potentially progressing to fulminant hepatic necrosis and, in some cases, death. The mechanism underlying this syndrome remains unclear. Patients who develop jaundice or significant elevations in hepatic enzymes while on ACE inhibitors should discontinue the medication and receive appropriate medical follow-up.

Syncope has been reported in 0.8 percent of patients receiving a combination of lisinopril and hydrochlorothiazide, while the incidence of syncope in patients treated with lisinopril alone was 0.1 percent. Proper titration of the individual components may reduce the overall incidence of syncope.

Adverse experiences occurring in more than one percent of patients treated with lisinopril plus hydrochlorothiazide in controlled clinical trials include dizziness (7.5%), headache (5.2%), cough (3.9%), fatigue (3.7%), and orthostatic effects (3.2%), all of which were reported more frequently than in placebo-treated patients.

Patient Counseling

Healthcare providers should advise patients that if pregnancy is detected, lisinopril and hydrochlorothiazide should be discontinued as soon as possible. It is important for patients to be informed about the signs and symptoms of angioedema, including swelling of the face, extremities, eyes, lips, and tongue, as well as difficulty in swallowing or breathing. Patients should be instructed to report any such symptoms immediately and to refrain from taking any further medication until they have consulted with their prescribing physician.

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

It is essential for patients to report any signs of infection, such as a sore throat or fever, as these may indicate leukopenia or neutropenia. Female patients of childbearing age should be made aware of the risks associated with exposure to lisinopril and hydrochlorothiazide during pregnancy. Healthcare providers should discuss treatment options with women who are planning to become pregnant and encourage patients to report any pregnancies to their physicians as soon as possible.

Storage and Handling

The product is supplied in accordance with the following specifications: it should be stored at a temperature range of 20° to 25°C (68° to 77°F), in compliance with USP Controlled Room Temperature guidelines. It is essential to protect the product from excessive light and humidity to maintain its integrity and efficacy.

Additional Clinical Information

Periodic monitoring of serum electrolytes is recommended to identify potential imbalances in patients receiving lisinopril and hydrochlorothiazide. Clinicians should be aware of the possibility of minor reversible increases in blood urea nitrogen and serum creatinine, particularly in patients with essential hypertension and renal artery stenosis. Small decreases in hemoglobin and hematocrit may occur, though they are rarely clinically significant unless other causes of anemia are present. Additionally, rare elevations in liver enzymes and/or serum bilirubin have been noted.

Patients should be advised to report any lightheadedness, especially during the initial days of therapy, and to discontinue the medication if syncope occurs until consulting their physician. The use of potassium-containing salt substitutes should be avoided without medical consultation. Prompt reporting of signs of infection is essential due to the risk of leukopenia/neutropenia. Female patients of childbearing age should be informed about the risks associated with the use of this medication during pregnancy and should discuss treatment options with their healthcare provider. Postmarketing reports have indicated cases of angioedema affecting various body parts, including rare instances of intestinal angioedema.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Lisinopril and Hydrochlorothiazide as submitted by International Laboratories, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)