Lisinopril and 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.

Lisinopril and hydrochlorothiazide tablets, USP, are available for oral administration in three combinations: 10 mg lisinopril with 12.5 mg hydrochlorothiazide, 20 mg lisinopril with 12.5 mg hydrochlorothiazide, and 20 mg lisinopril with 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, exercise, and dietary sodium restriction. 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 and consistent benefit observed is a reduction in the risk of stroke, although reductions in myocardial infarction and overall cardiovascular mortality have also been frequently reported.

Elevated systolic or diastolic blood pressure is linked to increased cardiovascular risk, with the absolute risk increase per mmHg being more pronounced 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, with greater absolute benefits observed in individuals at higher baseline risk, such as those with diabetes or hyperlipidemia.

It is important to recognize that some antihypertensive medications may exhibit diminished efficacy as monotherapy in black patients. Additionally, many antihypertensive drugs possess other approved indications and therapeutic effects, including those related to angina, heart failure, or diabetic kidney disease. This fixed-dose combination is not indicated for initial therapy.

Dosage and Administration

Lisinopril may be administered as monotherapy at a once-daily dose ranging from 10 mg to 80 mg. Hydrochlorothiazide can be prescribed as monotherapy at daily doses between 12.5 mg and 50 mg.

For patients requiring combination therapy, Lisinopril can be dosed from 10 mg to 80 mg, while Hydrochlorothiazide should be dosed between 6.25 mg and 50 mg. Initial combination options include the Lisinopril and Hydrochlorothiazide tablet formulations of 10 mg/12.5 mg and 20 mg/12.5 mg.

Dose titration should be guided by the clinical response of the patient. Blood pressure measurements are recommended at the interdosing interval to assess efficacy. It is advised that the Hydrochlorothiazide dose not be increased until a period of 2 to 3 weeks has elapsed.

For patients currently on diuretics who cannot discontinue their use, an initial dose of 5 mg of Lisinopril should be administered under medical supervision for a minimum of two hours, ensuring that blood pressure has stabilized for at least an additional hour before further adjustments.

In cases of replacement therapy, the combination of Lisinopril and Hydrochlorothiazide may be substituted for the titrated individual components.

For patients with renal impairment, dosing regimens do not need to be adjusted if the creatinine clearance is greater than 30 mL/min/1.7m².

Contraindications

Lisinopril and hydrochlorothiazide tablets are contraindicated in patients with hypersensitivity to this product. Use is 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 medication should not be used in combination with neprilysin inhibitors, such as sacubitril, and administration should not occur 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 occur at any time during treatment.

Angioedema Risks Angioedema, particularly of the head and neck, has been reported in patients treated with ACE inhibitors. This condition can manifest as swelling of the tongue, glottis, or larynx, potentially leading to airway obstruction. In such cases, immediate discontinuation of lisinopril and appropriate therapeutic measures are essential. Fatalities have been documented due to laryngeal or tongue edema. Additionally, intestinal angioedema has been observed, presenting with abdominal pain, which resolved upon cessation of the ACE inhibitor.

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

Hypotension and Monitoring Excessive hypotension may occur, particularly in patients who are salt or volume-depleted. Close medical supervision is warranted for patients with severe congestive heart failure or ischemic heart disease. If hypotension occurs, the patient should be placed in a supine position and may require intravenous infusion of normal saline.

Hematological Monitoring Rare cases of leukopenia, neutropenia, and agranulocytosis have been reported. Therefore, periodic monitoring of white blood cell counts is advisable, especially in patients with collagen vascular disease and renal disease.

General Precautions Caution is advised when prescribing lisinopril to patients with aortic stenosis or hypertrophic cardiomyopathy due to potential obstruction in the outflow tract of the left ventricle. Changes in renal function may occur; thus, renal function should be monitored during the initial weeks of therapy. Patients with risk factors for hyperkalemia, such as renal insufficiency or concomitant use of potassium-sparing diuretics, should have their serum potassium levels frequently monitored. A persistent nonproductive cough may develop but typically resolves after discontinuation of the medication. Additionally, during major surgery or anesthesia, lisinopril may inhibit angiotensin II formation, which could lead to hypotension.

Laboratory Tests Evaluation of renal function should be included in the assessment of hypertensive patients. Periodic determination of serum electrolytes is recommended to detect possible imbalances. Monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should also be considered.

Emergency Medical Help In cases where there is involvement of the tongue, glottis, or larynx, which may cause 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 promptly initiated.

Healthcare professionals are advised to remain alert to these warnings and precautions to ensure the safe use of lisinopril in their patients.

Side Effects

Adverse reactions reported in clinical trials and postmarketing experiences include a range of common and serious effects.

Common adverse reactions occurring in 1% or more of participants include dizziness (7.5%), headache (5.2%), cough (3.9%), fatigue (3.7%), and orthostatic effects (3.2%). Other notable 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%).

Additional adverse reactions have been observed across various systems. In the body as a whole, patients have reported chest pain, abdominal pain, syncope, chest discomfort, fever, trauma, and viral infections. Cardiovascular effects include palpitations and orthostatic hypotension. Digestive system reactions encompass gastrointestinal cramps, dry mouth, constipation, and heartburn. Musculoskeletal complaints include back pain, shoulder pain, knee pain, back strain, myalgia, and foot pain.

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

Warnings include the occurrence of angioedema, which may affect the face, extremities, lips, tongue, glottis, and/or larynx. Rare cases of intestinal angioedema have also been reported in postmarketing experience. Hypotension-related adverse effects were noted in clinical trials, with hypotension occurring in 1.4% of patients, orthostatic hypotension in 0.5%, and other orthostatic effects in 3.2%. Syncope was reported in 0.8% of participants. Additionally, a persistent nonproductive cough has been associated with ACE inhibitors, typically resolving after discontinuation of therapy.

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

Drug Interactions

Patients receiving lisinopril should be aware of several important drug interactions that may affect their treatment outcomes and safety.

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 recommended.

• NSAIDs: Co-administration of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, may 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 advised to avoid combined use of RAS inhibitors and to closely monitor blood pressure, renal function, and electrolytes in patients taking lisinopril with hydrochlorothiazide.

• 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.

• Neprilysin Inhibitors: Patients taking neprilysin inhibitors may have an increased risk of angioedema when used with lisinopril.

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

Pharmacokinetic Interactions:

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

• Propranolol and Digoxin: No significant pharmacokinetic interactions have been observed when lisinopril is used with propranolol, digoxin, or hydrochlorothiazide.

In the case of hydrochlorothiazide, several interactions warrant attention:

Pharmacodynamic Interactions:

• Orthostatic Hypotension: Alcohol, barbiturates, or narcotics may enhance the risk of orthostatic hypotension when used with hydrochlorothiazide.

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

• Other Antihypertensives: The use of other antihypertensive agents may have an additive effect when combined with hydrochlorothiazide.

• Electrolyte Depletion: Corticosteroids and ACTH may exacerbate electrolyte depletion, particularly hypokalemia.

• Pressor Amines: There may be a decreased response to pressor amines (e.g., norepinephrine) when used with hydrochlorothiazide.

• Skeletal Muscle Relaxants: There is a potential for increased responsiveness to non-depolarizing skeletal muscle relaxants (e.g., tubocurarine) when used with hydrochlorothiazide.

Pharmacokinetic Interactions:

• Lithium Clearance: Diuretics, including hydrochlorothiazide, can reduce the renal clearance of lithium, increasing the risk of lithium toxicity.

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

• Cholestyramine and Colestipol: The absorption of hydrochlorothiazide may be impaired in the presence of cholestyramine and colestipol resins.

• Nitritoid Reactions: Patients receiving injectable gold (sodium aurothiomalate) alongside ACE inhibitors may experience nitritoid reactions.

Healthcare providers should consider these interactions when prescribing lisinopril or hydrochlorothiazide and ensure appropriate monitoring and dosage adjustments as necessary.

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

Neonates with a history of in utero exposure to lisinopril and hydrochlorothiazide tablets may experience complications such as oliguria or hypotension. In such cases, 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 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 could also facilitate the removal of the drug, there is currently no clinical experience to support this procedure.

It is important to note that the safety and effectiveness of lisinopril and hydrochlorothiazide in pediatric patients have not been established.

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, 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 higher propensity for renal impairment. 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, and lisinopril was 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 nursing 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 breastfeeding. A decision should be made whether to discontinue nursing and/or discontinue the use of lisinopril and hydrochlorothiazide tablets.

Renal Impairment

Patients with renal impairment require careful consideration regarding medication management. Thiazide-containing combination products are not recommended for patients with severe renal dysfunction. Lisinopril use in individuals who are salt or volume-depleted, such as those receiving vigorous diuretic therapy or patients on dialysis, may lead to excessive hypotension. In patients with severe congestive heart failure, whether or not accompanied by 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.

Additionally, patients with a history of angioedema unrelated to ACE inhibitor therapy may have an increased risk of experiencing angioedema while on an ACE inhibitor. Captopril, another angiotensin-converting enzyme inhibitor, has been associated with agranulocytosis and bone marrow depression, particularly in patients with renal impairment, especially those with concurrent collagen vascular disease. Therefore, periodic monitoring of white blood cell counts in patients with both collagen vascular disease and renal disease should be considered to mitigate potential risks.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to this medication. Consequently, there are no established 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 available prescribing information.

Overdosage

In cases of 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.

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 lisinopril overdosage 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 adversely affect reproductive performance in male and female rats treated with doses up to 300 mg/kg/day. Similarly, hydrochlorothiazide demonstrated no adverse effects on the fertility of both male and female mice and rats when administered via diet at 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 by lisinopril in an in vitro alkaline elution assay using rat hepatocytes. Furthermore, lisinopril did not induce chromosomal aberrations in 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 to male and female rats for 105 weeks 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 shown to be non-genotoxic in vitro, as evidenced by results from the Ames mutagenicity assay and the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. In vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene also indicated a lack of genotoxicity. Positive results were only observed 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 the elevated risk is most pronounced in white patients who are administered large cumulative doses of the medication. Specifically, the overall population exhibits an approximate increase of 1 additional case of SCC per 16,000 patients per year. For white patients receiving a cumulative dose of ≥50,000 mg, the risk escalates to about 1 additional case of SCC for every 6,700 patients per year.

Healthcare professionals and patients are encouraged to report any suspected adverse reactions to Exelan Pharmaceuticals, Inc. at 1-866-604-3268, or to the FDA at 1-800-FDA-1088 or via www.fda.gov/medwatch.

Patient Counseling

Healthcare providers should advise patients that if pregnancy is detected, lisinopril and hydrochlorothiazide tablets should be discontinued as soon as possible. It is important for patients 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. Patients should be instructed to refrain from taking any further medication 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 patients experience actual syncope, they 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 signs of infection, such as a sore throat or fever, is essential, 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. 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 instruct them to protect their skin from sun exposure and to undergo regular skin cancer screenings.

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), 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. Proper storage conditions are critical to ensure the product remains within its specified parameters.

Additional Clinical Information

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). A study conducted within the Sentinel System indicated that this risk is notably higher in white patients who have received large cumulative doses of the medication. Specifically, the overall population faces an approximate risk of 1 additional case of SCC per 16,000 patients per year. For white patients with a cumulative dose of ≥50,000 mg, the risk escalates to about 1 additional SCC case for every 6,700 patients per year. Clinicians are encouraged to report any suspected adverse reactions to Exelan Pharmaceuticals, Inc. or the FDA.

FDA Insert (PDF)

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

View full prescribing information (PDF)