Lisinopril/Hydrochlorothiazide

Uses and Indications

Lisinopril and hydrochlorothiazide tablets are indicated for the treatment of hypertension, aimed at lowering blood pressure. This reduction in blood pressure is associated with a decreased risk of both fatal and non-fatal cardiovascular events, particularly strokes and myocardial infarctions.

Control 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 limited sodium intake. Many patients may require more than one medication to achieve their blood pressure goals.

Numerous antihypertensive drugs, including lisinopril and hydrochlorothiazide, have demonstrated efficacy in randomized controlled trials, showing a reduction in 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, along with reductions in myocardial infarction and cardiovascular mortality.

Elevated systolic or diastolic blood pressure increases cardiovascular risk, and even modest reductions in severe hypertension can yield significant benefits. The relative risk reduction from lowering blood pressure is consistent across various populations with differing absolute risks, with greater absolute benefits seen in patients at higher risk, such as those with diabetes or hyperlipidemia.

It is important to note that some antihypertensive medications may have smaller blood pressure-lowering effects when used as monotherapy in black patients. Additionally, many antihypertensive drugs have other approved indications and effects, including those related to angina, heart failure, or diabetic kidney disease.

Limitations of Use These fixed-dose combinations are not indicated for initial therapy.

Dosage and Administration

Lisinopril monotherapy is effective in once-daily doses ranging from 10 mg to 80 mg. Hydrochlorothiazide monotherapy is effective in daily doses of 12.5 mg to 50 mg. For combination therapy with lisinopril and hydrochlorothiazide, the recommended doses are 10 mg to 80 mg of lisinopril and 6.25 mg to 50 mg of hydrochlorothiazide.

For patients whose blood pressure is not adequately controlled with either monotherapy, a switch to combination therapy may be considered, utilizing either Lisinopril and Hydrochlorothiazide tablets 10 mg/12.5 mg or 20 mg/12.5 mg, depending on the current monotherapy dose. Further increases of either or both components should be based on clinical response, with blood pressure monitored at the interdosing interval. The hydrochlorothiazide dose should generally not be increased until 2 to 3 weeks have elapsed.

If a patient is unable to discontinue the diuretic, an initial dose of 5 mg of lisinopril should be administered under medical supervision for at least two hours, ensuring that blood pressure has stabilized for an additional hour before further adjustments are made. Dosages higher than 80 mg of lisinopril and 50 mg of hydrochlorothiazide should not be used.

Regimens of therapy with Lisinopril and Hydrochlorothiazide tablets need not be adjusted based on renal function as long as the patient's creatinine clearance is greater than 30 mL/min/1.73 m² (approximately ≤3 mg/dL or 265 μmol/L).

Contraindications

Lisinopril and hydrochlorothiazide is contraindicated in patients who are hypersensitive to any component of this product. It is also contraindicated in individuals with a history of angioedema related to previous treatment with an angiotensin-converting enzyme inhibitor, as well as in patients with hereditary or idiopathic angioedema.

Due to the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Additionally, the use of lisinopril and hydrochlorothiazide in combination with a neprilysin inhibitor (e.g., sacubitril) is contraindicated; administration should not occur within 36 hours of switching to or from sacubitril/valsartan.

Furthermore, co-administration of aliskiren with lisinopril and hydrochlorothiazide is contraindicated in patients with diabetes.

Warnings and Precautions

Patients receiving ACE inhibitors, including Lisinopril and Hydrochlorothiazide, may experience serious adverse reactions, including anaphylactoid reactions and angioedema. Angioedema can affect the face, extremities, lips, tongue, glottis, and/or larynx, and may occur at any time during treatment. If angioedema occurs, Lisinopril and Hydrochlorothiazide should be promptly discontinued, and appropriate therapy and monitoring should be provided until complete resolution of signs and symptoms. Fatalities have been reported due to angioedema associated with laryngeal or tongue edema.

Serious Warnings

• Anaphylactoid Reactions: Life-threatening reactions have occurred in patients undergoing desensitization treatment while receiving ACE inhibitors. Sudden and potentially life-threatening reactions have also been reported in patients dialyzed with high-flux membranes while treated with an ACE inhibitor.

• Hypotension: Excessive hypotension may occur in salt/volume-depleted persons, particularly in patients with severe congestive heart failure or ischemic heart disease. Therapy should be initiated under close medical supervision.

• Leukopenia/Neutropenia/Agranulocytosis: Rare cases of leukopenia, neutropenia, and bone marrow depression have been reported. Periodic monitoring of white blood cell counts should be considered in patients with collagen vascular disease and renal disease.

• Hepatic Failure: ACE inhibitors have been associated with a syndrome that can progress to fulminant hepatic necrosis. Discontinue the ACE inhibitor if jaundice or marked elevations of hepatic enzymes occur.

• Fetal Toxicity: Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy can reduce fetal renal function and increase morbidity and death. Discontinue Lisinopril and Hydrochlorothiazide as soon as pregnancy is detected.

General Precautions

• Aortic Stenosis/Hypertrophic Cardiomyopathy: Use with caution in patients with obstruction in the outflow tract of the left ventricle.

• Impaired Renal Function: Changes in renal function may occur; renal function should be monitored during the first few weeks of therapy.

• Hyperkalemia: Monitor serum potassium levels, especially in patients with renal insufficiency or those taking potassium-sparing diuretics.

• Cough: Persistent nonproductive cough may occur and usually resolves after discontinuation of therapy.

• Surgery/Anesthesia: Lisinopril may block angiotensin II formation during major surgery or anesthesia, potentially causing hypotension.

Laboratory Tests

• Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

• Evaluation of renal function should always be included in the assessment of hypertensive patients.

• Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered.

Emergency Medical Help Instructions

In cases of angioedema, especially with involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway should be promptly provided.

Stop Taking and Call Your Doctor Instructions

• If hypotension occurs, the patient should be placed in the supine position and may require an intravenous infusion of normal saline.

• Patients should discontinue Lisinopril and Hydrochlorothiazide if jaundice or marked elevations of hepatic enzymes occur.

Side Effects

Common adverse reactions observed in clinical trials include:

• Dizziness: 7.5% (0.8% discontinuation)

• Headache: 5.2% (0.3% discontinuation)

• Cough: 3.9% (0.6% discontinuation)

• Fatigue: 3.7% (0.4% discontinuation)

• Orthostatic Effects: 3.2% (0.1% discontinuation)

• Diarrhea: 2.5% (0.2% discontinuation)

• Nausea: 2.2% (0.1% discontinuation)

• Upper Respiratory Infection: 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)

• Impotence: 1.2% (0.3% discontinuation)

Additional adverse reactions reported include:

• Body as a Whole: Chest pain, abdominal pain, syncope, chest discomfort, fever, trauma, virus infection.

• Cardiovascular: Palpitation, orthostatic hypotension.

• Digestive: Gastrointestinal cramps, dry mouth, constipation, heartburn.

• Musculoskeletal: Back pain, shoulder pain, knee pain, back strain, myalgia, foot pain.

• Nervous/Psychiatric: Decreased libido, vertigo, depression, somnolence.

• Respiratory: Common cold, nasal congestion, influenza, bronchitis, pharyngeal pain, dyspnea, pulmonary congestion, chronic sinusitis, allergic rhinitis, pharyngeal discomfort.

• Skin: Flushing, pruritus, skin inflammation, diaphoresis, cutaneous pseudolymphoma.

• Special Senses: Blurred vision, tinnitus, otalgia.

• Urogenital: Urinary tract infection.

Warnings associated with the use of this medication include:

• Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported. In rare cases, intestinal angioedema has been reported in post-marketing experience. Angioedema associated with laryngeal edema may be fatal.

• Hypotension: In clinical trials, hypotension occurred in 1.4%, orthostatic hypotension in 0.5%, and other orthostatic effects in 3.2%. Syncope occurred in 0.8% of patients.

• Cough: Persistent nonproductive cough has been reported with all ACE inhibitors, almost always resolving after discontinuation of therapy.

Rare adverse reactions include:

• Leukopenia/Neutropenia/Agranulocytosis: Rare cases reported, particularly in patients with renal impairment.

• Hepatic Failure: Rarely associated with cholestatic jaundice or hepatitis progressing to fulminant hepatic necrosis.

• Non-melanoma Skin Cancer: Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients taking large cumulative doses.

Specific reactions related to Hydrochlorothiazide include:

• Body as a Whole: Weakness.

• Digestive: Anorexia, gastric irritation, cramping, jaundice (intrahepatic cholestatic jaundice), pancreatitis, sialadenitis, constipation.

• Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia.

• Musculoskeletal: Muscle spasm.

• Nervous System/Psychiatric: Restlessness.

• Renal: Renal failure, renal dysfunction, interstitial nephritis.

• Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia.

• Hypersensitivity: Purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions.

Drug Interactions

Patients on diuretics may experience excessive hypotension after initiating therapy with lisinopril. To minimize this effect, it is advisable to consider discontinuing the diuretic or increasing salt intake prior to starting lisinopril.

Co-administration of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, with lisinopril may lead to deterioration of renal function, including possible acute renal failure, particularly in elderly or volume-depleted patients. Additionally, the antihypertensive effect of lisinopril may be reduced by NSAIDs.

The dual blockade of the Renin-Angiotensin System (RAS) with lisinopril and other agents, such as angiotensin receptor blockers or aliskiren, is associated with increased risks of hypotension, hyperkalemia, and changes in renal function. Therefore, combined use of RAS inhibitors should be avoided, and blood pressure, renal function, and electrolytes should be closely monitored in patients receiving lisinopril and other agents affecting the RAS. Aliskiren should not be co-administered with lisinopril in patients with diabetes or renal impairment (GFR < 60 mL/min).

Lisinopril may increase serum potassium levels when used with potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes, necessitating caution and monitoring of serum potassium levels. Lithium toxicity has been reported with the concurrent use of lisinopril; therefore, serum lithium levels should be monitored frequently.

Patients receiving co-administration of ACE inhibitors and mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus) may be at increased risk for angioedema. Similarly, those taking neprilysin inhibitors with lisinopril may also face an increased risk for angioedema.

Hydrochlorothiazide may potentiate orthostatic hypotension when used with alcohol, barbiturates, or narcotics. Dosage adjustments of antidiabetic drugs may be required when used concurrently with hydrochlorothiazide. Other antihypertensive medications may have additive effects when used with hydrochlorothiazide.

The absorption of hydrochlorothiazide can be significantly impaired by cholestyramine and colestipol resins. Corticosteroids and ACTH may intensify electrolyte depletion, particularly hypokalemia, when used with hydrochlorothiazide.

Lithium should generally not be administered with diuretics due to the risk of increased lithium toxicity from reduced renal clearance. Non-steroidal anti-inflammatory drugs may also reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics, warranting close observation of patient response.

Rare nitritoid reactions, characterized by facial flushing, nausea, vomiting, and hypotension, have been reported in patients receiving injectable gold in conjunction with ACE inhibitors like lisinopril and hydrochlorothiazide.

Pediatric Use

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. Exchange transfusions or dialysis may be necessary to reverse hypotension and/or substitute for impaired renal function. Lisinopril, which crosses the placenta, has been removed from neonatal circulation through peritoneal dialysis with some clinical benefit. Theoretically, it may also be removed by exchange transfusion; however, there is no clinical experience with this procedure.

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of lisinopril and hydrochlorothiazide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients.

In general, dose selection for elderly patients should be cautious, typically starting at the low end of the dosing range. This approach reflects the greater frequency of decreased hepatic, renal, or cardiac function, as well as concomitant diseases or other drug therapies.

In a multiple-dose pharmacokinetic study comparing elderly versus young hypertensive patients, the area under the plasma concentration time curve (AUC) increased approximately 120% for lisinopril and approximately 80% for hydrochlorothiazide in older patients. Given that this drug is substantially excreted by the kidney, the risk of toxic reactions may be greater in patients with impaired renal function.

Elderly patients are more likely to have decreased renal function; therefore, careful consideration should be given to dose selection. Evaluation of hypertensive patients should always include an assessment of renal function to ensure safe and effective treatment.

Pregnancy

When pregnancy is detected, it is crucial to discontinue the use of lisinopril and hydrochlorothiazide as soon as possible due to the risk of fetal toxicity. Drugs that act directly on the renin-angiotensin system, such as lisinopril, can cause significant injury and even death to the developing fetus, particularly during the second and third trimesters. The use of these medications during this period is associated with reduced fetal renal function, increased fetal and neonatal morbidity, and potential death. Oligohydramnios, a condition that may arise from this medication use, can lead to serious fetal complications, including lung hypoplasia and skeletal deformations.

Potential adverse effects on neonates exposed in utero include skull hypoplasia, anuria, hypotension, renal failure, and death. It is important to note that most epidemiological studies examining fetal abnormalities following antihypertensive use in the first trimester have not specifically distinguished between drugs affecting the renin-angiotensin system and other antihypertensive agents.

For pregnant patients requiring management of hypertension, appropriate alternatives should be considered to optimize outcomes for both mother and fetus. In cases where no suitable alternative exists, healthcare providers should inform the patient of the potential risks to the fetus and conduct serial ultrasound examinations to monitor the intra-amniotic environment. If oligohydramnios is detected, discontinuation of the medication should be considered unless it is deemed lifesaving for the mother.

Close monitoring of infants with a history of in utero exposure to lisinopril and hydrochlorothiazide is essential, particularly for signs of hypotension, oliguria, and hyperkalemia. While no teratogenic effects have been observed in animal studies with lisinopril, the absence of adverse effects in these studies does not guarantee safety in human pregnancies. Therefore, both lisinopril and hydrochlorothiazide are contraindicated during pregnancy, and their use should be avoided unless the potential benefits outweigh the risks to the fetus.

Lactation

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

Due to the potential for serious adverse reactions in nursing infants from ACE inhibitors and hydrochlorothiazide, healthcare providers should carefully consider whether to discontinue breastfeeding or to discontinue the use of lisinopril and hydrochlorothiazide. This decision should take into account the importance of the medication to the lactating mother.

Renal Impairment

Patients with renal impairment should be treated with caution when using thiazide-containing combination products, such as Lisinopril and Hydrochlorothiazide. These medications are not recommended for individuals with severe renal dysfunction, as thiazides may precipitate azotemia and lead to cumulative effects in those with impaired renal function.

Close monitoring is essential for patients with renal impairment, particularly during the initial two weeks of treatment and whenever there is an increase in the dosage of Lisinopril or the diuretic component. Regular renal function tests and blood pressure assessments should be performed to ensure patient safety. Excessive hypotension has been observed in patients with severe congestive heart failure, with or without renal insufficiency, and may be associated with oliguria, progressive azotemia, and, in rare cases, acute renal failure or death. Therefore, therapy should be initiated under strict medical supervision.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at an increased risk of experiencing angioedema while receiving Lisinopril. Additionally, those on dialysis must be monitored closely for anaphylactoid reactions, which can occur, particularly in patients treated with high-flux dialysis membranes. If such reactions occur, dialysis should be stopped immediately, and aggressive treatment should be initiated.

Furthermore, there is a risk of agranulocytosis and bone marrow depression associated with ACE inhibitors, particularly in patients with renal impairment and those with collagen vascular diseases. Periodic monitoring of white blood cell counts is recommended for these patients.

In summary, careful consideration of dosing adjustments, vigilant monitoring of renal function and blood pressure, and awareness of potential adverse reactions are critical when managing patients with renal impairment on Lisinopril and Hydrochlorothiazide.

Hepatic Impairment

Patients with hepatic impairment may experience serious adverse effects when treated with ACE inhibitors, such as cholestatic jaundice or hepatitis, which can progress to fulminant hepatic necrosis and, in some cases, death. The underlying mechanism of this syndrome remains unclear.

In the event that patients receiving ACE inhibitors develop jaundice or significant elevations in hepatic enzymes, it is imperative to discontinue the ACE inhibitor and ensure appropriate medical follow-up.

Thiazide diuretics should be administered with caution in patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance may precipitate hepatic coma.

Currently, there is no specific information regarding dosage adjustments, special monitoring, or additional precautions for patients with liver problems provided in the drug insert text. Regular monitoring of liver function tests may be advisable to detect any potential hepatic complications early.

Overdosage

In cases of overdosage with Zestoretic or Lisinopril and Hydrochlorothiazide, treatment is primarily symptomatic and supportive. Therapy should be discontinued, and the patient must be closely observed. 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, which can be managed with intravenous infusion of normal saline solution. Animal studies indicate that following a single oral dose of 20 g/kg of lisinopril, no lethality occurred in rats, while one of twenty mice died at the same dosage. Additionally, oral administration of a single dose of 10 g/kg of hydrochlorothiazide to mice and rats was not lethal; however, it may lead to common signs and symptoms such as electrolyte depletion (including hypokalemia, hypochloremia, and hyponatremia) and dehydration due to excessive diuresis.

If digitalis has been co-administered, hypokalemia may exacerbate the risk of cardiac arrhythmias. Lisinopril can be removed from the body through hemodialysis, which may be considered in severe cases of overdose.

Nonclinical Toxicology

Teratogenic Effects

The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with reduced fetal renal function, leading to increased fetal and neonatal morbidity and mortality. Oligohydramnios resulting from such use can be linked to fetal lung hypoplasia and skeletal deformations. Potential adverse neonatal effects include skull hypoplasia, anuria, hypotension, renal failure, and death. It is recommended to discontinue lisinopril and hydrochlorothiazide as soon as pregnancy is detected. Most epidemiologic studies examining fetal abnormalities following exposure to antihypertensive agents in the first trimester have not differentiated between drugs affecting the renin-angiotensin system and other antihypertensive medications.

In studies involving pregnant rats, mice, and rabbits, no teratogenic effects of lisinopril were observed, with doses administered being up to 625 times (in mice), 188 times (in rats), and 0.6 times (in rabbits) the maximum recommended human dose (MRHD). Teratogenicity studies conducted with doses of up to 90 mg/kg/day of lisinopril (56 times the MRHD) in combination with 10 mg/kg/day of hydrochlorothiazide (2.5 times the MRHD) showed no maternal or fetotoxic effects in mice. However, in rats, decreased maternal weight gain and fetal weight were noted at lower doses, accompanied by a delay in fetal ossification, which was not observed in saline-supplemented controls.

Non-Teratogenic Effects

Non-teratogenic effects may include fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions in adults. Hydrochlorothiazide, when administered in a two-litter study in rats at doses of 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 produce birth abnormalities in offspring.

Nonclinical Toxicology

Lisinopril, in combination with hydrochlorothiazide, was not mutagenic in microbial mutagen tests using Salmonella typhimurium (Ames test) or Escherichia coli, with or without metabolic activation, nor in a forward mutation assay using Chinese hamster lung cells. The combination did not produce DNA single strand breaks in an in vitro alkaline elution rat hepatocyte assay and did not increase chromosomal aberrations in in vitro tests using Chinese hamster ovary cells or in vivo studies in mouse bone marrow.

There was 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, or for 92 weeks to male and female mice at doses up to 135 mg/kg/day. These doses are approximately 10 times and 7 times the MRHD, respectively, when compared on a body surface area basis. Two-year feeding studies conducted under the auspices of the National Toxicology Program (NTP) found no evidence of carcinogenic potential for hydrochlorothiazide in female mice or in male and female rats at doses of up to approximately 600 mg/kg/day (53 times the MRHD) and 100 mg/kg/day (18 times the MRHD), respectively. However, the NTP did find equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, nor in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays.

Animal Pharmacology and Toxicology

Studies indicate that lisinopril crosses the blood-brain barrier poorly, and multiple doses do not result in tissue accumulation. However, radioactivity was detected in the milk of lactating rats following administration of 14C-lisinopril. Whole body autoradiography revealed radioactivity in the placenta of pregnant rats, but none was found in the fetuses. Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies where these species were exposed to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to conception and throughout gestation.

Storage and Handling

Zestoretic and Lisinopril and Hydrochlorothiazide are supplied in tablet form.

Tablets should be stored at a controlled room temperature of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) for Lisinopril and Hydrochlorothiazide. It is essential to protect the tablets from excessive light and humidity.

When dispensing, if the product package is subdivided, it should be placed in a well-closed container. Additionally, for Lisinopril and Hydrochlorothiazide, it is recommended to dispense in a tight, light-resistant container, utilizing a child-resistant closure as defined in the USP.