Hydrochlorothiazide/Lisinopril

Description

Lisinopril, a synthetic peptide derivative, is chemically described as (S)-1-N2-(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline dihydrate. Its empirical formula is C21H31N3O5•2H2O, and it has a molecular weight of 441.53. Lisinopril appears as a white, crystalline powder that is 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. It is a white, or practically white, crystalline powder that is slightly soluble in water and freely soluble in sodium hydroxide solution.

Lisinopril and hydrochlorothiazide tablets USP are available for oral use in three tablet combinations: 10 mg/12.5 mg, 20 mg/12.5 mg, and 20 mg/25 mg. Inactive ingredients include dibasic calcium phosphate, magnesium stearate, mannitol, pregelatinized starch, and starch (corn). The 10 mg/12.5 mg tablet also contains FD&C Blue No. 2 Aluminum Lake, the 20 mg/12.5 mg tablet contains yellow iron oxide, and the 20 mg/25 mg tablet contains red iron oxide.

Uses and Indications

Lisinopril and hydrochlorothiazide tablets USP are indicated for the treatment of hypertension to lower blood pressure. Effective management of high blood pressure is essential for reducing the risk of both fatal and non-fatal cardiovascular events, particularly strokes and myocardial infarctions.

Control of hypertension should be integrated into a comprehensive cardiovascular risk management strategy, which includes lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. It is important to note that many patients may require more than one antihypertensive agent to achieve their blood pressure goals.

Clinical evidence from randomized controlled trials has demonstrated that various antihypertensive medications 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 associated with increased cardiovascular risk, with the absolute risk increase per mmHg being more pronounced at higher blood pressures. 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 risk, such as those with diabetes or hyperlipidemia.

It is also noted that some antihypertensive agents may exhibit diminished efficacy as monotherapy in black patients, and many of these medications have additional approved indications and therapeutic effects, including those related to angina, heart failure, or diabetic kidney disease.

Dosage and Administration

Lisinopril monotherapy is indicated at once-daily doses ranging from 10 mg to 80 mg. Hydrochlorothiazide monotherapy is effective at daily doses between 12.5 mg and 50 mg.

For patients requiring combination therapy with lisinopril and hydrochlorothiazide, the recommended dosing ranges for lisinopril are 10 mg to 80 mg, while hydrochlorothiazide should be administered at doses of 6.25 mg to 50 mg.

In cases where a patient's blood pressure remains inadequately controlled with either monotherapy, a transition to combination therapy with Lisinopril/HCTZ may be considered. The initial combination doses can be Lisinopril/HCTZ 10/12.5 mg or Lisinopril/HCTZ 20/12.5 mg, depending on the current monotherapy dosage.

Further adjustments to the doses 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 dose not be increased until a period of 2 to 3 weeks has elapsed to assess the patient's response adequately.

After the addition of hydrochlorothiazide, it may be appropriate to consider a reduction in the lisinopril dose. 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 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 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 used in combination with a neprilysin inhibitor, such as sacubitril; administration of Lisinopril and Hydrochlorothiazide tablets USP should be avoided within 36 hours of switching to or from sacubitril/valsartan.

Co-administration of aliskiren with lisinopril and hydrochlorothiazide is contraindicated in patients with diabetes.

Warnings and Precautions

Patients receiving angiotensin-converting enzyme (ACE) inhibitors, including lisinopril and hydrochlorothiazide, may experience a range of adverse reactions, some of which can be serious. Notably, angioedema affecting the face, extremities, lips, tongue, glottis, and/or larynx has been reported. This reaction can occur at any time during treatment and is more prevalent in black patients compared to nonblack patients. In the event of angioedema, lisinopril and hydrochlorothiazide should be discontinued immediately, and appropriate therapy and monitoring should be initiated until complete resolution of symptoms occurs. Even in cases where only the tongue is involved, patients may require prolonged observation, as treatment with antihistamines and corticosteroids may not suffice. Fatalities have been reported due to angioedema associated with laryngeal or tongue edema, which can lead to airway obstruction, particularly in patients with a history of airway surgery. In such cases, prompt administration of subcutaneous epinephrine solution (1:1000, 0.3 mL to 0.5 mL) and measures to ensure a patent airway are critical.

Intestinal angioedema has also been documented in patients treated with ACE inhibitors, presenting as abdominal pain, which may occur without prior facial angioedema and with normal C-1 esterase levels. Diagnosis may require imaging studies or surgical intervention, and symptoms typically resolve upon discontinuation of the ACE inhibitor. Therefore, intestinal angioedema should be considered in the differential diagnosis for patients on ACE inhibitors who present with abdominal pain.

Patients undergoing desensitization treatment for hymenoptera venom while on ACE inhibitors have experienced life-threatening anaphylactoid reactions, which were avoided when ACE inhibitors were temporarily withheld. These reactions reoccurred upon inadvertent rechallenge. Additionally, sudden anaphylactoid reactions have been reported in patients undergoing dialysis with high-flux membranes (e.g., AN69®) while receiving ACE inhibitors. In such instances, dialysis should be halted immediately, and aggressive treatment for anaphylactoid reactions should be initiated, as antihistamines may not alleviate symptoms. Consideration should be given to alternative dialysis membranes or antihypertensive agents in these patients.

Excessive hypotension, although rare in uncomplicated hypertensive patients, may occur in individuals who are salt/volume-depleted, such as those receiving diuretics or undergoing dialysis. Caution is advised when initiating therapy in patients with severe congestive heart failure, as excessive hypotension may lead to oliguria, progressive azotemia, acute renal failure, or even death. Close medical supervision is recommended during the first two weeks of treatment and whenever the dose of lisinopril or diuretic is increased. Similar precautions apply to patients with ischemic heart or cerebrovascular disease, where significant drops in blood pressure could precipitate myocardial infarction or cerebrovascular accidents. In cases of hypotension, patients should be placed in a supine position and may require intravenous normal saline infusion. A transient hypotensive response does not contraindicate further doses once blood pressure stabilizes after volume expansion.

Agranulocytosis and bone marrow depression have been associated with another ACE inhibitor, captopril, particularly in patients with renal impairment or collagen vascular disease. While clinical trial data for lisinopril are insufficient to confirm a similar risk, rare cases of leukopenia/neutropenia and bone marrow depression have been reported. Therefore, periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease is advisable.

Rarely, ACE inhibitors have been linked to a syndrome that begins with cholestatic jaundice or hepatitis and can progress to fulminant hepatic necrosis and, in some cases, death. The underlying mechanism 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.

The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy poses risks to fetal renal function, increasing morbidity and mortality. Oligohydramnios resulting from this use can lead to fetal lung hypoplasia and skeletal deformities. Adverse neonatal effects may include skull hypoplasia, anuria, hypotension, renal failure, and death. Upon detection of pregnancy, lisinopril and hydrochlorothiazide should be discontinued as soon as possible.

Patients receiving coadministration of ACE inhibitors with mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus) or neprilysin inhibitors may be at an increased risk for angioedema. Additionally, those with a history of angioedema unrelated to ACE inhibitor therapy may also be at heightened risk.

In summary, healthcare professionals should remain vigilant for signs of angioedema, monitor patients closely for hypotension, and consider the potential for serious adverse effects associated with ACE inhibitors. Regular laboratory tests, including white blood cell counts in at-risk populations, are recommended to ensure patient safety.

Side Effects

Patients receiving treatment may experience a range of adverse reactions. Common adverse reactions observed in clinical trials include dizziness (7.5%, with 0.8% leading to discontinuation), headache (5.2%, 0.3% discontinuation), cough (3.9%, 0.6% discontinuation), and fatigue (3.7%, 0.4% discontinuation). Other frequently reported reactions include orthostatic effects (3.2%, 0.1% discontinuation), diarrhea (2.5%, 0.2% discontinuation), nausea (2.2%, 0.1% discontinuation), and upper respiratory infections (2.2%, 0.0% discontinuation). Muscle cramps (2.0%, 0.4% discontinuation), asthenia (1.8%, 0.2% discontinuation), paresthesia (1.5%, 0.1% discontinuation), hypotension (1.4%, 0.3% discontinuation), vomiting (1.4%, 0.1% discontinuation), dyspepsia (1.3%, 0.0% discontinuation), rash (1.2%, 0.1% discontinuation), and impotence (1.2%, 0.3% discontinuation) were also noted.

Additional adverse reactions reported include chest pain, abdominal pain, syncope, chest discomfort, fever, and viral infections. Cardiovascular effects such as palpitations and orthostatic hypotension have been documented. Digestive system reactions include gastrointestinal cramps, dry mouth, constipation, and heartburn. Musculoskeletal complaints such as back pain, shoulder pain, knee pain, and myalgia have also been reported. Nervous system and psychiatric effects include decreased libido, vertigo, depression, and somnolence. Respiratory issues such as common cold, nasal congestion, influenza, bronchitis, and dyspnea have been observed, along with skin reactions like flushing, pruritus, and skin inflammation. Special senses may be affected, leading to blurred vision and tinnitus, while urogenital issues such as urinary tract infections have also been noted.

Serious adverse reactions include angioedema, which can affect the face, extremities, lips, tongue, glottis, and/or larynx, with rare cases of intestinal angioedema reported in post-marketing experience. Hypotension-related adverse effects were noted in clinical trials, with hypotension occurring in 1.4% of patients, orthostatic hypotension in 0.5%, and syncope in 0.8%. A persistent nonproductive cough has been reported with all ACE inhibitors, typically resolving after discontinuation of therapy.

Rare but serious adverse reactions include hepatic failure, which may begin with cholestatic jaundice or hepatitis and can progress to fulminant hepatic necrosis and potentially death. Rare cases of bone marrow depression, leukopenia, neutropenia, agranulocytosis, and thrombocytopenia have also been reported. Additionally, hydrochlorothiazide has been associated with 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 several significant drug interactions that necessitate careful monitoring and potential dosage adjustments.

Pharmacodynamic Interactions:

• Co-administration of non-steroidal anti-inflammatory drugs (NSAIDs) with lisinopril can lead to a deterioration in renal function, particularly in elderly or volume-depleted patients. Additionally, the antihypertensive effect of lisinopril may be diminished by NSAIDs. It is advisable to monitor renal function and consider alternative analgesics if necessary.

• The use of dual blockade of the renin-angiotensin system (RAS) with lisinopril and other agents increases the risk of hypotension, hyperkalemia, and alterations in renal function. Caution is advised when combining these therapies.

• In diabetic patients or those with renal impairment (GFR < 60 mL/min), the co-administration of aliskiren with lisinopril should be avoided due to the increased risk of adverse effects.

• Patients on ACE inhibitors, including lisinopril, who are also taking mTOR inhibitors or neprilysin inhibitors may face an elevated risk of angioedema. Close monitoring for signs of angioedema is recommended.

Pharmacokinetic Interactions:

• Lisinopril may increase serum potassium levels when used concurrently with potassium-sparing diuretics or potassium supplements; therefore, regular monitoring of serum potassium levels is essential.

• The risk of lithium toxicity is heightened when lithium is administered alongside lisinopril. Serum lithium levels should be closely monitored to prevent toxicity.

• The combination of hydrochlorothiazide with alcohol, barbiturates, or narcotics may enhance the risk of orthostatic hypotension. Patients should be advised to use caution when combining these substances.

• Antidiabetic medications may require dosage adjustments when used in conjunction with hydrochlorothiazide, as the diuretic can affect glycemic control.

• The use of other antihypertensive agents alongside hydrochlorothiazide may result in additive effects, necessitating careful blood pressure monitoring.

• Cholestyramine and colestipol resins can significantly impair the absorption of hydrochlorothiazide, and their co-administration should be approached with caution.

• Corticosteroids may exacerbate electrolyte depletion, particularly hypokalemia, when used with hydrochlorothiazide. Monitoring of electrolyte levels is recommended.

• Lithium should generally be avoided in patients taking diuretics due to the risk of lithium toxicity.

• Non-steroidal anti-inflammatory drugs may reduce the effectiveness of thiazide diuretics, including hydrochlorothiazide, and should be used judiciously.

• Nitritoid reactions have been reported in patients receiving injectable gold in conjunction with ACE inhibitors such as lisinopril and hydrochlorothiazide. Caution is warranted when these agents are used together.

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

Pediatric patients, particularly neonates with a history of in utero exposure to lisinopril and hydrochlorothiazide, 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 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.

It is important to note that the safety and effectiveness of this medication in pediatric patients have not been established. Therefore, caution is advised when considering treatment in this population.

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 geriatric and younger patients.

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

Therefore, careful consideration must be given to dose selection in elderly patients, particularly due to their 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

When pregnancy is detected, lisinopril and hydrochlorothiazide should be discontinued as soon as possible due to the risk of fetal toxicity. Drugs that act directly on the renin-angiotensin system, including lisinopril and hydrochlorothiazide, can cause significant injury and death to the developing fetus. The use of these medications during the second and third trimesters is particularly concerning, as they can reduce fetal renal function, leading to increased morbidity and mortality in both the fetus and neonate.

Oligohydramnios, a potential consequence of such drug use, may result in fetal lung hypoplasia and skeletal deformations. Neonatal adverse effects associated with in utero exposure include skull hypoplasia, anuria, hypotension, renal failure, and death. While most epidemiologic studies examining fetal abnormalities after antihypertensive exposure in the first trimester have not specifically distinguished between drugs affecting the renin-angiotensin system and other antihypertensive agents, the risks remain significant.

Appropriate management of maternal hypertension during pregnancy is crucial to optimize outcomes for both the mother and fetus. In cases where there is no suitable alternative to therapy with renin-angiotensin system-affecting drugs, healthcare providers should inform the mother of the potential risks to the fetus. Serial ultrasound examinations should be performed to monitor the intra-amniotic environment, and if oligohydramnios is detected, lisinopril and hydrochlorothiazide should be discontinued unless deemed lifesaving for the mother.

Fetal testing may be warranted based on the gestational age, and it is important for patients and healthcare providers to recognize that oligohydramnios may not manifest until after the fetus has sustained irreversible injury. Infants with a history of in utero exposure to lisinopril and hydrochlorothiazide should be closely monitored for hypotension, oliguria, and hyperkalemia.

Teratogenicity studies conducted in pregnant rats, mice, and rabbits have not demonstrated teratogenic effects associated with lisinopril. However, in rats, decreased maternal weight gain and fetal weight were observed at doses as low as 3/10 mg/kg/day. It is essential to note that the use of ACE inhibitors during the second and third trimesters can lead to severe fetal injury and even death.

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 another study indicating that lisinopril was present in rat milk at levels comparable to plasma levels in the dams.

Thiazides, which are components of the combination with lisinopril, are known to 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 risks and benefits when advising lactating mothers. A decision should be made regarding the discontinuation of nursing and/or the discontinuation of lisinopril and hydrochlorothiazide, taking into account the importance of the medication to the mother.

Renal Impairment

Patients with renal impairment require careful consideration regarding the use of thiazide-containing combination products, which are not recommended in those with severe renal dysfunction. Caution is advised when prescribing hydrochlorothiazide, as it may precipitate azotemia in patients with severe renal disease. The cumulative effects of this medication can develop in individuals with impaired renal function, necessitating close monitoring.

In patients undergoing dialysis with high-flux membranes, such as AN69®, there is a risk of sudden and potentially life-threatening anaphylactoid reactions when treated concomitantly with an ACE inhibitor. In these cases, dialysis should be halted immediately, and aggressive therapy for anaphylactoid reactions must be initiated.

Additionally, the use of captopril, another angiotensin-converting enzyme inhibitor, has been associated with an increased risk of agranulocytosis and bone marrow depression, particularly in patients with renal impairment and those with collagen vascular diseases. Therefore, periodic monitoring of white blood cell counts is recommended for patients with both collagen vascular disease and renal disease to mitigate these risks.

Hepatic Impairment

Patients with hepatic impairment may experience an increased risk of adverse effects when treated with ACE inhibitors. Rarely, these medications 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 underlying mechanism of this syndrome remains unclear.

In patients receiving ACE inhibitors, if jaundice or significant elevations in hepatic enzymes are observed, it is imperative to discontinue the ACE inhibitor immediately and ensure appropriate medical follow-up is provided.

Thiazide diuretics should be administered 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 management.

Overdosage

In cases of overdosage with lisinopril and hydrochlorothiazide, specific treatment protocols are not well established. Management is primarily symptomatic and supportive, necessitating the discontinuation of the medication and close observation of the patient.

Recommended Actions

For suspected overdose, the following measures are suggested:

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

• It is essential to correct any dehydration, electrolyte imbalances, and hypotension using 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; however, hypotension was observed. This condition can be managed effectively with intravenous infusion of normal saline solution.

In the case of hydrochlorothiazide, a single oral dose of 10 g/kg administered to mice and rats was also non-lethal. Common signs and symptoms associated with hydrochlorothiazide overdosage include electrolyte depletion, specifically hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis.

Additional Management Considerations

Lisinopril can be effectively removed from the system through hemodialysis, which may be considered in severe cases of overdose. Continuous monitoring and supportive care are critical in managing the patient's condition until stabilization is achieved.

Nonclinical Toxicology

No teratogenic effects of lisinopril were observed in studies involving pregnant rats, mice, and rabbits. The doses administered were significantly higher than the maximum recommended human dose, with up to 625 times the dose in mice, 188 times in rats, and 0.6 times in rabbits. In teratogenicity studies conducted with mice and rats, lisinopril was given in combination with hydrochlorothiazide at doses up to 90 mg/kg/day (56 times the maximum recommended human dose) and 10 mg/kg/day (2.5 times the maximum recommended human dose), respectively. Maternal or fetotoxic effects were not noted in mice; however, in rats, decreased maternal weight gain and fetal weight were observed at the lowest tested dose of 3/10 mg/kg/day, accompanied by a delay in fetal ossification. These adverse effects were not present in saline-supplemented animals receiving the same combination of doses. It is recommended to discontinue lisinopril and hydrochlorothiazide as soon as pregnancy is detected, as adverse outcomes are typically associated with the use of these medications during the second and third trimesters.

Potential non-teratogenic neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. Hydrochlorothiazide, when administered in a two-litter study in rats at doses ranging from 4 mg/kg/day to 5.6 mg/kg/day (approximately 1 to 2 times the usual daily human dose), did not impair fertility or result in birth abnormalities in the offspring. Other non-teratogenic effects may encompass fetal or neonatal jaundice, thrombocytopenia, and possibly additional adverse reactions that have been observed in adults.

Lisinopril, in combination with hydrochlorothiazide, was not found to be mutagenic in microbial mutagen tests using Salmonella typhimurium (Ames test) or Escherichia coli, both with and without metabolic activation. Additionally, it did not produce DNA single strand breaks in an in vitro alkaline elution assay using rat hepatocytes, nor did it induce increases in chromosomal aberrations in tests conducted in Chinese hamster ovary cells or in vivo in mouse bone marrow. There was no evidence of tumorigenicity when lisinopril was administered for 105 weeks to male and female rats at doses up to 90 mg/kg/day (approximately 56 or 9 times the maximum daily human dose, based on body weight and body surface area). Similarly, no evidence of carcinogenicity was observed when lisinopril was given for 92 weeks to male and female mice at doses up to 135 mg/kg/day (about 84 times the maximum recommended daily human dose).

Studies in rats indicate that lisinopril poorly crosses the blood-brain barrier, and multiple doses do not lead to tissue accumulation. However, the milk of lactating rats contained radioactivity following administration of 14C-lisinopril. Whole body autoradiography revealed radioactivity in the placenta of pregnant rats after administration of the labeled drug, but none was detected in the fetuses. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay using Salmonella typhimurium strains, nor in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive results were only obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays.

Postmarketing Experience

Postmarketing experience has identified an association between hydrochlorothiazide and an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data derived from a study conducted within the Sentinel System indicate that this increased risk is notably observed in white patients who are administered large cumulative doses of the medication. Specifically, the overall population exhibits an approximate risk increase of one additional case of SCC per 16,000 patients per year. In contrast, white patients receiving a cumulative dose of 50,000 mg or more demonstrate a heightened risk, with an estimated one additional case of SCC occurring 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 decreased 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.

Female patients of childbearing age should be informed about the potential consequences of 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 notify their physicians as soon as they become pregnant.

Patients taking hydrochlorothiazide should be instructed 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 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 those undergoing treatment with thiazides. Clinicians should assess renal function in hypertensive patients and monitor serum and urine electrolytes, especially in cases of excessive vomiting or parenteral fluid administration. Thiazides can increase urinary magnesium excretion, potentially leading to hypomagnesemia, and may decrease urinary calcium excretion, which can cause slight elevations in serum calcium levels. Marked hypercalcemia may indicate hidden hyperparathyroidism, necessitating discontinuation of thiazides prior to parathyroid function tests.

Patient counseling should emphasize the importance of reporting any signs of angioedema, such as facial or extremity swelling and difficulty breathing. Patients should be advised to monitor for lightheadedness, particularly during the initial days of therapy, and to discontinue the medication if syncope occurs until consulting their physician. Caution is warranted regarding excessive perspiration and dehydration, which can lead to significant drops in blood pressure. Patients should avoid potassium-containing salt substitutes without physician consultation and report any signs of infection that may indicate leukopenia or neutropenia. Female patients of childbearing age should be informed about the risks associated with lisinopril and hydrochlorothiazide during pregnancy and encouraged to report any pregnancies promptly. Additionally, patients taking hydrochlorothiazide should be advised to protect their skin from sun exposure and to undergo regular skin cancer screenings.

FDA Insert (PDF)

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

View full prescribing information (PDF)