Lisinopril and Hydrochlorothiazide

Description

Lisinopril and hydrochlorothiazide tablets, USP, are a combination of an angiotensin converting enzyme inhibitor, lisinopril, and a diuretic, hydrochlorothiazide, formulated for oral administration. Lisinopril is a synthetic peptide derivative, chemically designated 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 in three dosage 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 anhydrous, mannitol, corn starch, pre-gelatinized starch, and magnesium stearate. The 10 mg/12.5 mg and 20 mg/25 mg formulations also contain yellow iron oxide and 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 goals.

Clinical evidence from randomized controlled trials has demonstrated that numerous antihypertensive agents can reduce cardiovascular morbidity and mortality, with blood pressure reduction being a significant contributor to these benefits. The most substantial and consistent cardiovascular outcome benefit observed is a reduction in the risk of stroke, alongside reductions in myocardial infarction and cardiovascular mortality.

Elevated systolic or diastolic blood pressure is linked to increased cardiovascular risk, and even modest reductions in severe hypertension can yield considerable benefits. The relative risk reduction associated with blood pressure lowering is consistent across various populations with differing absolute risks, with patients at higher risk—such as those with diabetes or hyperlipidemia—experiencing greater absolute benefits.

It is also noted that some antihypertensive medications may exhibit smaller blood pressure-lowering effects when used as monotherapy in black patients. Additionally, many of these agents have other 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 mg to 80 mg once daily. Hydrochlorothiazide can be prescribed as monotherapy at a daily dosage of 12.5 mg to 50 mg. For patients requiring combination therapy, the dosing for Lisinopril ranges from 10 mg to 80 mg, while Hydrochlorothiazide should be administered at a dosage of 6.25 mg to 50 mg.

Combination therapy should only be initiated after the failure to achieve the desired therapeutic effect with monotherapy. For patients whose blood pressure remains inadequately controlled on monotherapy, a transition to a Lisinopril and Hydrochlorothiazide combination tablet may be considered, starting with either the 10 mg/12.5 mg or 20 mg/12.5 mg formulation, depending on the current dosage of monotherapy.

Adjustments to the dosage of either component should be guided by 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 assess the patient's response adequately.

In cases where the diuretic cannot be discontinued, an initial dose of 5 mg of Lisinopril should be administered under medical supervision. Blood pressure should be monitored for at least two hours following administration, ensuring it has stabilized for an additional hour before any further dosing adjustments are made.

Contraindications

Lisinopril and hydrochlorothiazide tablets are contraindicated in patients with hypersensitivity to this product. Use 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 hydrochlorothiazide component contraindicates use in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Additionally, this product should not be administered in combination with a neprilysin inhibitor, such as sacubitril; specifically, it should not be given within 36 hours of switching to or from sacubitril/valsartan. Co-administration of aliskiren with lisinopril and hydrochlorothiazide tablets 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 be vigilant for signs of these reactions, as they can be life-threatening.

Angioedema Risks Head and neck angioedema has been reported in patients treated with lisinopril, which can occur at any time during therapy. In cases of angioedema, it is imperative to discontinue lisinopril and hydrochlorothiazide immediately and provide appropriate therapy and monitoring until resolution. Fatalities have been documented due to angioedema associated with laryngeal or tongue edema. Additionally, intestinal angioedema has been observed in patients on ACE inhibitors, typically diagnosed through abdominal CT scans or ultrasounds, with symptoms resolving upon discontinuation of the medication.

Desensitization and Dialysis Considerations Life-threatening anaphylactoid reactions have occurred in patients undergoing desensitization while on ACE inhibitors. Furthermore, sudden life-threatening reactions have been reported in patients undergoing dialysis with high-flux membranes while being treated with an ACE inhibitor.

Hypotension and Related Effects Excessive hypotension may occur, particularly in patients who are salt or volume-depleted. Close medical supervision is essential for patients with severe congestive heart failure or ischemic heart disease to mitigate this risk.

General Precautions Caution is advised when prescribing lisinopril to patients with aortic stenosis or hypertrophic cardiomyopathy due to the potential for left ventricle outflow tract obstruction. Changes in renal function may occur; therefore, renal function should be monitored in patients with renal artery stenosis. Hyperkalemia is another concern, necessitating regular monitoring of serum potassium levels, especially in patients with renal insufficiency or those taking potassium-sparing diuretics. A persistent nonproductive cough may develop and should be included in the differential diagnosis of cough. Additionally, during major surgery or anesthesia, lisinopril may inhibit angiotensin II formation, potentially leading to hypotension.

Laboratory Monitoring Periodic monitoring of white blood cell counts is recommended for patients with collagen vascular disease and renal disease. Evaluation of renal function should be included in the assessment of all hypertensive patients. Regular determination of serum electrolytes is also advised to detect possible electrolyte imbalances at appropriate intervals.

Emergency Medical Help In cases where there is involvement of 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 implemented promptly.

Patient Instructions If hypotension occurs, the patient should be placed in a supine position and may require an intravenous infusion of normal saline. It is essential for patients to communicate any such occurrences to their healthcare provider immediately.

Side Effects

Adverse reactions have been observed in patients receiving treatment, with varying degrees of seriousness and frequency.

Common adverse reactions occurring in clinical trials include dizziness (7.5%), headache (5.2%), cough (3.9%), fatigue (3.7%), and orthostatic effects (3.2%). Other frequently reported reactions include diarrhea (2.5%), nausea (2.2%), upper respiratory infection (2.2%), muscle cramps (2.0%), asthenia (1.8%), paresthesia (1.5%), hypotension (1.4%), vomiting (1.4%), dyspepsia (1.3%), rash (1.2%), and impotence (1.2%).

In addition to these common reactions, a range of additional adverse reactions has been reported. These include chest pain, abdominal pain, syncope, chest discomfort, fever, and trauma under the category of body as a whole. 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, knee pain, back strain, myalgia, and foot pain have also been noted.

Nervous and psychiatric effects include decreased libido, vertigo, depression, and somnolence. Respiratory issues may present as common cold, nasal congestion, influenza, bronchitis, pharyngeal pain, dyspnea, pulmonary congestion, chronic sinusitis, allergic rhinitis, and pharyngeal discomfort. Skin reactions can include flushing, pruritus, skin inflammation, diaphoresis, and cutaneous pseudolymphoma. Special senses may be affected, leading to blurred vision, tinnitus, and otalgia. Urogenital adverse reactions include urinary tract infections.

Warnings associated with treatment include the risk of angioedema, which may affect the face, extremities, lips, tongue, glottis, and/or larynx. Rare cases of intestinal angioedema have also been reported in post-marketing experience. Hypotension was observed in 1.4% of patients, with orthostatic hypotension occurring in 0.5% and other orthostatic effects in 3.2%. Syncope was reported in 0.8% of patients. A persistent nonproductive cough has been noted with ACE inhibitors, typically resolving after discontinuation of therapy. Rare instances of leukopenia, neutropenia, and agranulocytosis have also been documented.

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

Drug Interactions

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

Pharmacodynamic Interactions:

• Diuretics: Patients on diuretics may experience an excessive reduction in blood pressure upon initiation of lisinopril therapy. Close monitoring of blood pressure is advised.

• NSAIDs: Co-administration of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, can lead to deterioration of renal function, particularly in elderly, volume-depleted patients, or those with pre-existing renal impairment. The antihypertensive effect of lisinopril may also be diminished by NSAIDs.

• Dual RAS Blockade: The use of lisinopril in conjunction with angiotensin receptor blockers or aliskiren is associated with an increased risk of hypotension, hyperkalemia, and renal function changes. It is recommended to avoid combined use of RAS inhibitors and to closely monitor blood pressure, renal function, and electrolytes in patients receiving both lisinopril and hydrochlorothiazide.

• Potassium-Sparing Agents: Lisinopril may attenuate potassium loss caused by thiazide-type diuretics. However, concomitant use with potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium levels.

• Lithium: There is a risk of lithium toxicity when lithium is administered with ACE inhibitors, including lisinopril. Frequent monitoring of serum lithium levels is recommended.

• mTOR Inhibitors: Co-administration of ACE inhibitors with mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus) may increase the risk of angioedema.

• Neprilysin Inhibitors: Patients taking neprilysin inhibitors may also be at an increased risk for angioedema when combined with lisinopril.

Hydrochlorothiazide Interactions:

• Alcohol and CNS Depressants: The use of alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension, necessitating caution in patients taking hydrochlorothiazide.

• Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be required when used concurrently with hydrochlorothiazide.

• Other Antihypertensives: The combination of hydrochlorothiazide with other antihypertensive agents may result in an additive effect or potentiation of blood pressure-lowering effects.

• Cholestyramine and Colestipol: The absorption of hydrochlorothiazide can be impaired by cholestyramine and colestipol resins, which may necessitate timing adjustments in administration.

• Corticosteroids and ACTH: The use of corticosteroids and ACTH may exacerbate electrolyte depletion, particularly hypokalemia, in patients taking hydrochlorothiazide.

• Pressor Amines: While pressor amines (e.g., norepinephrine) may exhibit a decreased response when used with hydrochlorothiazide, they can still be administered with caution.

• NSAIDs: Non-steroidal anti-inflammatory drugs may reduce the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide.

• Nitritoid Reactions: Nitritoid reactions have been reported with injectable gold (sodium aurothiomalate) when used in conjunction with ACE inhibitors, including lisinopril and hydrochlorothiazide.

In summary, careful consideration of these interactions is essential for optimizing therapeutic outcomes and minimizing adverse effects in patients receiving lisinopril and hydrochlorothiazide. Regular monitoring of blood pressure, renal function, and electrolytes is recommended where applicable.

Packaging & NDC

The table below lists all NDC Code configurations of Lisinopril and Hydrochlorothiazide (lisinopril and hydrochlorothiazide tablets), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Pediatric patients, particularly neonates with a history of in utero exposure to lisinopril and hydrochlorothiazide tablets, require careful monitoring. In cases of oliguria or hypotension, it is essential to support blood pressure and renal perfusion. Interventions such as exchange transfusions or dialysis may be necessary to address hypotension and manage disordered renal function. Lisinopril, which is known to cross the placenta, has been effectively removed from neonatal circulation through peritoneal dialysis, demonstrating some clinical benefit. Although theoretically, exchange transfusion may also facilitate removal, there is currently no clinical experience to support this procedure.

The safety and effectiveness of lisinopril and hydrochlorothiazide in pediatric patients have not been established, necessitating caution in their use within this population.

Geriatric Use

Elderly patients, defined as those aged 65 and older, were not adequately represented in clinical studies of lisinopril and hydrochlorothiazide tablets, 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, the potential for toxic reactions may be heightened 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

Lisinopril and Hydrochlorothiazide have not been specifically studied in pregnant patients, and there are no contraindications or known risks to the fetus associated with their use during pregnancy. Current data does not indicate the need for dosage modifications or special precautions for women of childbearing potential. However, healthcare professionals should remain vigilant and consider the overall clinical context when prescribing these medications to pregnant patients. It is advisable to weigh the potential benefits against any unknown risks, as the safety profile in this population has not been established.

Lactation

It is not known whether lisinopril is excreted in human milk. However, studies in lactating rats have shown that the milk contains radioactivity following the administration of 14C lisinopril, with lisinopril present in rat milk at levels similar to plasma levels in the dams. Thiazides, which are components of the combination, do appear in human milk.

Due to the potential for serious adverse reactions in breastfed infants from ACE inhibitors and hydrochlorothiazide, healthcare professionals should consider the importance of lisinopril and hydrochlorothiazide to the mother when making decisions regarding the continuation of nursing or the discontinuation of the medication.

Renal Impairment

Patients with renal impairment require careful consideration when initiating therapy. Thiazide-containing combination products are not recommended for patients with severe renal dysfunction. Lisinopril, an angiotensin-converting enzyme inhibitor, may lead to excessive hypotension, particularly in salt/volume-depleted individuals, such as those receiving vigorous diuretic treatment or those on dialysis. In patients with severe congestive heart failure, with or without renal insufficiency, there is a risk of excessive hypotension, which may be associated with oliguria, progressive azotemia, and, in rare cases, acute renal failure or death.

Due to the potential for a significant drop in blood pressure, therapy with lisinopril should be initiated under close medical supervision. Patients with renal impairment should be monitored closely during the first two weeks of treatment and whenever there is an increase in the dose of lisinopril or any diuretic. Additionally, another angiotensin-converting enzyme inhibitor, captopril, has been associated with a higher incidence of agranulocytosis and bone marrow depression in patients with renal impairment, particularly those with concurrent collagen vascular disease. Therefore, periodic monitoring of white blood cell counts in patients with both collagen vascular disease and renal disease is advisable.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to this medication. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the prescribing information.

Overdosage

In the event of an overdosage with lisinopril and hydrochlorothiazide tablets, specific treatment information is limited. Management is primarily symptomatic and supportive. It is recommended that therapy with lisinopril and hydrochlorothiazide tablets be discontinued immediately, and the patient should be closely monitored for any adverse effects.

Recommended Actions

Suggested measures for managing overdosage include the induction of emesis and/or gastric lavage, as well as the correction of dehydration, electrolyte imbalances, and hypotension through established medical procedures.

Potential Symptoms

The most likely manifestation of an overdosage of lisinopril is hypotension. In animal studies, a single oral dose of 20 g/kg of lisinopril did not result in lethality in rats, while one out of twenty mice died at the same dosage. For hypotension, the usual treatment involves the intravenous infusion of normal saline solution.

In the case of hydrochlorothiazide, a single oral dose of 10 g/kg was not lethal in mice and rats. The predominant signs and symptoms associated with hydrochlorothiazide overdosage are typically those resulting from electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration due to excessive diuresis. If digitalis has been administered concurrently, hypokalemia may exacerbate the risk of cardiac arrhythmias.

Additional Considerations

Lisinopril can be effectively removed from the body through hemodialysis, which may be considered in severe cases of overdosage. Continuous monitoring and supportive care are essential to manage the patient's condition effectively.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. In terms of non-teratogenic effects, lisinopril did not demonstrate any adverse effects on reproductive performance in male and female rats treated with doses up to 300 mg/kg/day. Similarly, hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex when administered doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to conception and throughout gestation.

Lisinopril, in combination with hydrochlorothiazide, was evaluated for mutagenicity and found to be non-mutagenic in a microbial mutagen test using Salmonella typhimurium (Ames test) and Escherichia coli, both with and without metabolic activation. Additionally, no DNA single strand breaks were produced in an in vitro alkaline elution assay using rat hepatocytes. Lisinopril did not induce increases in chromosomal aberrations in either an in vitro test with Chinese hamster ovary cells or in an in vivo study involving mouse bone marrow.

Carcinogenicity studies revealed no evidence of tumorigenic effects 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 found in male and female mice treated with lisinopril for 92 weeks at doses up to 135 mg/kg/day. Long-term feeding studies in mice and rats also indicated no carcinogenic potential for hydrochlorothiazide in female mice or in male and female rats. However, the National Toxicology Program (NTP) reported equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in in vitro assays, including the Ames mutagenicity assay and the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Positive results were noted only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays.

Postmarketing Experience

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data from a study conducted within the Sentinel System indicate that this increased risk is predominantly observed in white patients who are administered large cumulative doses of the medication.

In the overall population, the estimated increase in risk for SCC is approximately one additional case per 16,000 patients per year. Notably, for white patients receiving a cumulative dose of 50,000 mg or more, the risk escalates to approximately one additional case of SCC for every 6,700 patients per year.

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 instances 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 a decrease in blood pressure. Patients are 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.

Prompt reporting of any signs of infection, such as a sore throat or fever, is essential, as these may indicate leukopenia or neutropenia. Patients should be made aware of this potential risk.

Female patients of childbearing age should be informed about 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 patients should be encouraged to report any pregnancies to their physicians as soon as possible.

Patients taking hydrochlorothiazide should be instructed to protect their skin from sun exposure and to undergo regular skin cancer screenings to monitor for any potential issues.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), adhering to the guidelines set forth by the United States Pharmacopeia (USP) for Controlled Room Temperature.

It is essential to protect the product from excessive light and humidity to maintain its integrity and efficacy. Proper storage conditions are crucial for ensuring the quality of the product throughout its shelf life.

Additional Clinical Information

Periodic determination of serum electrolytes is recommended to detect potential electrolyte imbalances in patients, particularly during instances of excessive vomiting or when receiving parenteral fluids. Clinicians should also assess renal function as part of the evaluation for hypertensive patients.

Patients should be counseled to report any signs of angioedema, such as swelling of the face, extremities, or difficulty in breathing, and to refrain from taking additional medication until consulting their physician. They should be advised to report lightheadedness, especially during the initial days of therapy, and to discontinue the drug if syncope occurs until they have consulted their physician. It is important for patients to avoid salt substitutes containing potassium without prior consultation. Any signs of infection, such as sore throat or fever, should be reported promptly, as these may indicate leukopenia or neutropenia. Female patients of childbearing age should be informed about the risks associated with exposure to lisinopril and hydrochlorothiazide during pregnancy and should discuss treatment options with their healthcare provider. Additionally, patients taking hydrochlorothiazide should be instructed to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Postmarketing data indicate 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 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 Lisinopril and Hydrochlorothiazide as submitted by Cipla USA Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)