Lisinopril/Hydrochlorothiazide

Description

Lisinopril and hydrochlorothiazide tablets, USP, are a combination of an angiotensin converting enzyme inhibitor, lisinopril, USP, and a diuretic, hydrochlorothiazide, USP. Lisinopril, USP, is a synthetic peptide derivative, chemically described as (S)-1-N2-(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline dihydrate, with a molecular formula of C21H31N3O5 • 2H2O and a molecular weight of 441.52. It appears as a white crystalline powder, soluble in water, sparingly soluble in methanol, and practically insoluble in alcohol, acetone, acetonitrile, and chloroform.

Hydrochlorothiazide, USP, is identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular formula of C7H8ClN3O4S2 and a molecular weight of 297.74. This compound is a white or practically white, practically odorless crystalline powder, slightly soluble in water, freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide, sparingly soluble in methanol, and insoluble in ether, chloroform, and dilute mineral acids.

Lisinopril and hydrochlorothiazide tablets, USP, are available in three oral tablet combinations: 10 mg lisinopril and 12.5 mg hydrochlorothiazide (10-12.5), 20 mg lisinopril and 12.5 mg hydrochlorothiazide (20-12.5), and 20 mg lisinopril and 25 mg hydrochlorothiazide (20-25). Inactive ingredients include dibasic calcium phosphate, magnesium stearate, mannitol, pregelatinized starch, and corn starch. The 10-12.5 mg formulation contains FD&C blue #2 aluminum lake, the 20-12.5 mg formulation contains yellow iron oxide, and the 20-25 mg formulation contains both yellow 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 overall cardiovascular mortality.

Elevated systolic or diastolic blood pressure is linked to increased cardiovascular risk, and even modest reductions in severe hypertension can yield considerable health 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, regardless of their hypertension status.

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

In cases where blood pressure is not adequately controlled with monotherapy, healthcare professionals may consider switching to a combination of lisinopril and hydrochlorothiazide at dosages of either 10/12.5 mg or 20/12.5 mg, depending on the current monotherapy dosage. Any further increases in 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.

For patients who are unable to discontinue diuretic therapy, 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 are made.

Both lisinopril and hydrochlorothiazide should be administered orally, with a frequency of once daily as per the specified dosages.

Contraindications

Lisinopril and hydrochlorothiazide tablets are contraindicated in patients with a known hypersensitivity to this product. The use of this medication is also contraindicated in individuals with a history of angioedema associated with prior treatment using an angiotensin-converting enzyme inhibitor, as well as in patients with hereditary or idiopathic angioedema.

Additionally, due to the hydrochlorothiazide component, this product should not be used in patients with anuria or those who have a hypersensitivity to other sulfonamide-derived drugs. Co-administration of aliskiren with Lisinopril and hydrochlorothiazide is contraindicated in patients with diabetes.

Warnings and Precautions

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

Angioedema has been reported in patients, manifesting as swelling of the face, extremities, lips, tongue, glottis, and/or larynx. This condition can occur at any time during treatment with lisinopril. In the event of angioedema, the medication should be discontinued immediately, and appropriate therapy, including monitoring, should be initiated until complete resolution of symptoms. It is important to note that fatalities have been reported due to angioedema associated with laryngeal or tongue edema.

In cases where there is involvement of the tongue, glottis, or larynx that may lead to airway obstruction, emergency medical help should be sought. Subcutaneous epinephrine solution (1:1000, 0.3 mL to 0.5 mL) and/or other measures to ensure a patent airway should be administered promptly.

Healthcare professionals should also consider intestinal angioedema in the differential diagnosis for patients on ACE inhibitors who present with abdominal pain.

Excessive hypotension may occur in patients who are salt or volume-depleted, or those undergoing dialysis. Therefore, therapy with lisinopril should be initiated under close medical supervision. If hypotension occurs, the patient should be placed in a supine position and may require an intravenous infusion of normal saline.

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

Patients developing jaundice or marked elevations in hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up to assess for potential hepatic failure.

It is critical to inform patients about the risks of fetal toxicity associated with the use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy. Such medications can reduce fetal renal function and increase morbidity and mortality. If pregnancy is detected, lisinopril and hydrochlorothiazide should be discontinued as soon as possible.

In summary, healthcare professionals must remain vigilant in monitoring for these serious adverse effects and take appropriate action when necessary to ensure patient safety.

Side Effects

Adverse reactions associated with the use of this medication have been observed in clinical trials and postmarketing experiences.

Common adverse reactions occurring in 1% or more of patients include dizziness (7.5%), headache (5.2%), cough (3.9%), fatigue (3.7%), orthostatic effects (3.2%), diarrhea (2.5%), nausea (2.2%), upper respiratory infection (2.2%), muscle cramps (2%), 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 reported include chest pain, abdominal pain, syncope, chest discomfort, fever, trauma, and viral infections. Cardiovascular effects such as palpitations and orthostatic hypotension have also been noted. Gastrointestinal disturbances may include gastrointestinal cramps, dry mouth, constipation, and heartburn. Musculoskeletal complaints such as back pain, shoulder pain, knee pain, back strain, myalgia, and foot pain have been reported.

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

Serious adverse reactions warranting attention include angioedema, which can affect the face, extremities, lips, tongue, glottis, and/or larynx, and may occur at any time during treatment. Very rarely, fatalities have been reported due to angioedema associated with laryngeal or tongue edema. Hypotension was noted in 1.4% of patients, with orthostatic hypotension occurring in 0.5% and syncope in 0.8%. Persistent nonproductive cough has been reported, particularly with ACE inhibitors, typically resolving after discontinuation. Rare cases of bone marrow depression, including leukopenia, neutropenia, agranulocytosis, and thrombocytopenia, have been documented. Additionally, ACE inhibitors have been associated with a syndrome that may begin with cholestatic jaundice or hepatitis and can progress to fulminant hepatic necrosis and, in some cases, death.

Postmarketing experiences have revealed cases of intestinal angioedema presenting with abdominal pain, with or without nausea or vomiting, and anaphylactoid reactions occurring during desensitization and membrane exposure in patients receiving ACE inhibitors.

A boxed warning highlights the risk of fetal toxicity, indicating that the use of drugs acting on the renin-angiotensin system during the second and third trimesters of pregnancy can result in injury or death to the developing fetus. It is advised to discontinue the use of lisinopril and hydrochlorothiazide as soon as pregnancy is detected.

Drug Interactions

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

Pharmacodynamic Interactions:

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

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

• Dual Blockade of the Renin-Angiotensin System (RAS): The use of lisinopril in conjunction with angiotensin receptor blockers or aliskiren can increase the risk of hypotension, hyperkalemia, and renal function changes. Close monitoring of blood pressure, renal function, and electrolytes is essential. It is contraindicated to co-administer aliskiren with lisinopril in patients with diabetes or renal impairment (GFR < 60 ml/min).

• Agents Increasing Serum Potassium: Caution is advised when using lisinopril with potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes, as significant increases in serum potassium may occur. Serum potassium levels should be monitored regularly.

• Lithium: The concomitant use of lisinopril and lithium has been associated with lithium toxicity. Frequent monitoring of serum lithium levels is recommended.

Pharmacokinetic Interactions:

• Hydrochlorothiazide: The absorption of hydrochlorothiazide can be significantly impaired by cholestyramine and colestipol resins, reducing its absorption by up to 85% and 43%, respectively.

• Alcohol, Barbiturates, or Narcotics: These substances may potentiate orthostatic hypotension when used with hydrochlorothiazide.

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

• Other Antihypertensive Drugs: There may be an additive effect or potentiation when hydrochlorothiazide is used with other antihypertensive agents.

• Corticosteroids and ACTH: The combination may lead to intensified electrolyte depletion, particularly hypokalemia.

• Pressor Amines (e.g., Norepinephrine): There is a potential for decreased response to pressor amines when used with hydrochlorothiazide.

• Skeletal Muscle Relaxants (e.g., Tubocurarine): Increased responsiveness to non-depolarizing muscle relaxants may occur.

• Lithium: The use of diuretics, including hydrochlorothiazide, can reduce renal clearance of lithium, increasing the risk of toxicity.

• Non-Steroidal Anti-Inflammatory Drugs: These agents may diminish the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide. Close monitoring for therapeutic efficacy is advised.

• Gold: Nitritoid reactions have been reported when injectable gold is used in conjunction with ACE inhibitors, including lisinopril.

In summary, careful consideration and monitoring are essential when prescribing lisinopril and hydrochlorothiazide, particularly in the context of the aforementioned drug interactions.

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 its use 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 these age groups.

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 medications. Given that this drug is primarily excreted by the kidneys, there is an elevated risk of toxic reactions in patients with impaired renal function.

Due to the higher prevalence of renal impairment among elderly patients, careful consideration must be given to dose selection. Furthermore, a thorough evaluation of hypertensive elderly patients should always include an assessment of renal function to ensure safe and effective treatment.

Pregnancy

There were no adverse effects on reproductive performance observed in male and female rats treated with lisinopril at doses up to 300 mg/kg/day. Additionally, hydrochlorothiazide did not adversely affect 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.

While these findings suggest a lack of reproductive toxicity in animal studies, the relevance of these results to human pregnancy outcomes is not established. Therefore, healthcare professionals should consider the potential risks and benefits when prescribing this medication to pregnant patients or women of childbearing potential.

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 risks and benefits when advising lactating mothers. A decision should be made whether to discontinue nursing and/or discontinue lisinopril and hydrochlorothiazide, taking into account the importance of the medication to the mother.

Renal Impairment

Patients with renal impairment should be closely monitored when considering the use of thiazide-containing combination products, as these are not recommended for individuals with severe renal dysfunction. Caution is advised when prescribing thiazides in patients with severe renal disease, as they may precipitate azotemia and lead to cumulative effects due to impaired renal function.

In patients with severe congestive heart failure, whether or not accompanied by renal insufficiency, there is a risk of excessive hypotension, which may result in oliguria, progressive azotemia, and, in rare cases, acute renal failure or death. Additionally, there have been reports of sudden and potentially life-threatening anaphylactoid reactions in patients undergoing dialysis with high-flux membranes who are concurrently treated with an ACE inhibitor.

For patients with collagen vascular disease and renal disease, periodic monitoring of white blood cell counts should be considered to ensure patient safety and effective management of their condition.

Hepatic Impairment

Patients with hepatic impairment should be closely monitored when receiving ACE inhibitors, as there is a rare association with a syndrome that may begin with cholestatic jaundice or hepatitis and can progress to fulminant hepatic necrosis, potentially resulting in death. In the event that patients develop jaundice or significant elevations in hepatic enzymes, the ACE inhibitor should be discontinued immediately, and appropriate medical follow-up should be initiated.

Thiazides should be administered with caution in patients with impaired hepatic function or progressive liver disease. Minor alterations in fluid and electrolyte balance in these patients may precipitate hepatic coma, necessitating careful monitoring and potential dosage adjustments.

Overdosage

In cases of overdosage with lisinopril and hydrochlorothiazide, specific treatment information is limited. Management is primarily symptomatic and supportive. It is recommended that therapy with lisinopril and hydrochlorothiazide be discontinued, and the patient should be closely monitored.

Recommended Actions

Suggested measures for managing overdosage include the induction of emesis and/or gastric lavage. Additionally, it is crucial to correct any dehydration, electrolyte imbalances, and hypotension using established medical procedures.

Potential Symptoms

The most likely manifestation of overdosage is hypotension, which can be addressed with intravenous infusion of normal saline solution. Following a single oral dose of 20 g/kg, no lethality was observed in rats, while one out of twenty mice receiving the same dose did not survive. Furthermore, oral administration of a single dose of 10 g/kg to mice and rats was also non-lethal.

Common signs and symptoms associated with overdosage may include those resulting from electrolyte depletion, such as hypokalemia, hypochloremia, and hyponatremia, as well as dehydration due to excessive diuresis. It is important to note that if digitalis has been administered concurrently, hypokalemia may exacerbate the risk of cardiac arrhythmias.

Additional Considerations

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

Nonclinical Toxicology

There were no adverse effects on reproductive performance observed in male and female rats treated with lisinopril at doses up to 300 mg/kg/day, which is significantly higher than the maximum daily human dose based on both body weight and body surface area. 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. These doses correspond to multiples of the maximum daily human dose, indicating a favorable reproductive safety profile.

In terms of non-teratogenic effects, lisinopril did not demonstrate any tumorigenic potential when administered to male and female rats for 105 weeks at doses up to 90 mg/kg/day, nor was there evidence of carcinogenicity in male and female mice treated for 92 weeks at doses up to 135 mg/kg/day. The findings from two-year feeding studies conducted by the National Toxicology Program (NTP) also revealed no carcinogenic potential for hydrochlorothiazide in female mice or in male and female rats at doses significantly exceeding the maximum human daily dose. However, the NTP did report equivocal evidence for hepatocarcinogenicity in male mice.

Lisinopril and hydrochlorothiazide were evaluated for mutagenicity and genotoxicity. Both compounds were not mutagenic in the Ames test using Salmonella typhimurium or Escherichia coli, nor did they produce DNA single strand breaks in an in vitro alkaline elution assay using rat hepatocytes. Lisinopril did not induce chromosomal aberrations in either in vitro tests with Chinese hamster ovary cells or in vivo studies involving mouse bone marrow. Hydrochlorothiazide also showed no genotoxic effects in various in vitro and in vivo assays, although positive results were noted in specific clastogenicity and mutagenicity assays at certain concentrations.

Overall, the nonclinical toxicology data suggest that lisinopril and hydrochlorothiazide exhibit a favorable safety profile with respect to reproductive performance, carcinogenicity, and mutagenicity in animal studies.

Postmarketing Experience

Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported in patients treated with angiotensin-converting enzyme (ACE) inhibitors, including lisinopril. Intestinal angioedema has also been documented in patients receiving ACE inhibitors, presenting with abdominal pain (with or without nausea or vomiting). In some instances, these patients had no prior history of facial angioedema, and C-1 esterase levels were found to be normal. Diagnosis of intestinal angioedema was made through abdominal CT scans, ultrasounds, or surgical procedures, with symptom resolution following the discontinuation of the ACE inhibitor.

Rare cases of leukopenia/neutropenia and bone marrow depression have been reported, although a causal relationship to lisinopril cannot be excluded. Additionally, ACE inhibitors have been infrequently associated with a syndrome that begins with cholestatic jaundice or hepatitis and may progress to fulminant hepatic necrosis and, in some cases, death.

In clinical trials, adverse effects related to hypotension were observed, 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 patients. Among patients treated with lisinopril plus hydrochlorothiazide in controlled clinical trials, adverse experiences occurring in greater than 1% of patients included dizziness (7.5%), headache (5.2%), cough (3.9%), fatigue (3.7%), and orthostatic effects (3.2%). Furthermore, rare cases of intestinal angioedema have been noted in postmarketing experience.

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, as this may have implications for their treatment.

Patients must be advised to report any signs of infection, such as a sore throat or fever, promptly, 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. 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.

Storage and Handling

The product is supplied in a well-closed container to ensure integrity, particularly if the package has been subdivided. It should be stored at a temperature range of 20° to 25° C (68° to 77° F), in accordance with USP Controlled Room Temperature guidelines. Care should be taken to protect the product from excessive light and humidity to maintain its quality and efficacy.

Additional Clinical Information

Periodic monitoring of serum electrolytes is recommended to identify potential electrolyte imbalances in patients. In clinical studies, minor reversible increases in blood urea nitrogen and serum creatinine were noted in patients with essential hypertension treated with lisinopril and hydrochlorothiazide, particularly in those with renal artery stenosis. Small decreases in hemoglobin and hematocrit were also observed, though these were rarely clinically significant unless accompanied by other causes of anemia. Rare elevations in liver enzymes and/or serum bilirubin have been reported.

Clinicians should counsel patients on the risk of angioedema, advising them to report any signs such as swelling of the face or difficulty breathing immediately. Patients should be aware of the potential for symptomatic hypotension, especially during the initial days of therapy, and should discontinue the medication if syncope occurs until consulting their physician. Caution is advised regarding the use of potassium-containing salt substitutes, and patients should promptly report any signs of infection that may indicate leukopenia or neutropenia. Female patients of childbearing age should be informed about the risks associated with the use of lisinopril and hydrochlorothiazide during pregnancy and should report any pregnancies to their healthcare provider. Postmarketing reports have indicated cases of angioedema and, in rare instances, intestinal angioedema.

FDA Insert (PDF)

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

View full prescribing information (PDF)