Lisinopril/Hydrochlorothiazide

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# Black Box Warning

# Overview
Lisinopril/Hydrochlorothiazide is an Angiontensin converting enzyme inhibitor, Thiazide diuretic that is FDA approved for the treatment of hypotension. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include hypotension, syncope, hyperkalemia, dizziness, headache, abnormal renal function tests  and cough.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Initial dose (not initial therapy): lisinopril 10 mg/hydrochlorothiazide 12.5 mg PO gd or  lisinopril 20 mg/hydrochlorothiazide 12.5 mg  PO gd.
- Hydrochlorothiazide dosage should not be adjusted for 2-3 weeks, allow time for titration before increasing hydrochlorothiazide dose. lisinopril is effective at doses of 10 - 80 mg, and hydrochlorothiazide is effective at doses of 12.5 - 50 mg.
- Maintenance: MAX dose lisinopril 80 mg/hydrochlorothiazide 50 mg PO qd.

## Off-Label Use and Dosage (Adult)

### NonGuideline-Supported Use

### Heart Failure

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness have not been established in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
- There is limited information about Off-Label Guideline-Supported Use of Lisinopril/Hydrochlorothiazide in pediatric patients.
- Dosing Information/Recommendation
- (Dosage)

### NonGuideline-Supported Use
- There is limited information about Off-Label NonGuideline-Supported Use of Lisinopril/Hydrochlorothiazide in pediatric patients.

# Contraindications
Lisinopril and hydrochlorothiazide tablets are contraindicated in patients who are hypersensitive to any component of this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

# Warnings

## Lisinopril
- Anaphylactoid and Possibly Related Reactions
- Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including lisinopril and hydrochlorothiazide) may be subject to a variety of  Adverse Reactions, some of them serious.
- Head and Neck Angioedema
- Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors, including lisinopril. This may occur at any time during treatment.  ACE inhibitors have been associated with a higher rate of angioedema in Black than in nonblack patients. Lisinopril and hydrochlorothiazide should be promptly discontinued and the appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. Where there is 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.
- Intestinal Angioedema
- Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor.
- Anaphylactoid Reactions During Desensitization
- Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
- Anaphylactoid Reactions During Membrane Exposure
- Thiazide-containing combination products are not recommended in patients with severe renal dysfunction. Sudden and potentially life-threatening anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes (eg, AN69*) and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped immediately, and aggressive therapy for anaphylactoid reactions must be initiated. Symptoms have not been relieved by antihistamines in these situations. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
- Hypotension and Related Effects
- Excessive hypotension was rarely seen in uncomplicated hypertensive patients but is a possible consequence of lisinopril use in salt/volume-depleted persons such as those treated vigorously with diuretics or patients on dialysis.
Syncope has been reported in 0.8% of patients receiving lisinopril and hydrochlorothiazide. In patients with hypertension receiving lisinopril alone, the incidence of syncope was 0.1%. The overall incidence of syncope may be reduced by proper titration of the individual components.
In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. Such patients should be followed closely for the first 2 weeks of treatment and whenever the dose of lisinopril and/or diuretic is increased. Similar considerations apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion.
- Leukopenia/Neutropenia/Agranulocytosis
- Another angiotensin-converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment, especially if they also have a collagen vascular disease. Available data from clinical trials of lisinopril are insufficient to show that lisinopril does not cause agranulocytosis at similar rates. Marketing experience has revealed rare cases of leukopenia/neutropenia and bone marrow depression in which a causal relationship to lisinopril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered.
- Hepatic Failure
- Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

## Fetal Toxicity
'Pregnancy Category D
- Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue lisinopril and hydrochlorothiazide as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
- In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue lisinopril and hydrochlorothiazide, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to lisinopril and hydrochlorothiazide for hypotension, oliguria, and hyperkalemia.
- No teratogenic effects of lisinopril were seen in studies of pregnant rats, mice, and rabbits. On a mg/kg basis, the doses used were up to 625 times (in mice), 188 times (in rats), and 0.6 times (in rabbits) the maximum recommended human dose.

## Lisinopril and Hydrochlorothiazide
- Teratogenicity studies were conducted in mice and rats with up to 90 mg/kg/day of lisinopril (56 times the maximum recommended human dose) in combination with 10 mg/kg/day of hydrochlorothiazide (2.5 times the maximum recommended human dose). Maternal or fetotoxic effects were not seen in mice with the combination. In rats decreased maternal weight gain and decreased fetal weight occurred down to 3/10 mg/kg/day (the lowest dose tested). Associated with the decreased fetal weight was a delay in fetal ossification. The decreased fetal weight and delay in fetal ossification were not seen in saline-supplemented animals given 90/10 mg/kg/day.
- When used in pregnancy, during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, discontinue Lisinopril and Hydrochlorothiazide as soon as possible (see Lisinopril, Fetal Toxicity).

### Hydrochlorothiazide
- Acute Myopia and Secondary Angle-Closure Glaucoma
- Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and Acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated Acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
- Teratogenic Effects
- Reproduction studies in the rabbit, the mouse and the rat at doses up to 100 mg/kg/day (50 times the human dose) showed no evidence of external abnormalities of the fetus due to hydrochlorothiazide. Hydrochlorothiazide given in a two-litter study in rats at doses of 4 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 the offspring. Thiazides cross the placental barrier and appear in cord blood.
- Nonteratogenic Effects
- These may include fetal or neonatal jaundice, thrombocytopenia, and possibly other  Adverse Reactions have occurred in the adult.

### Hydrochlorothiazide
- Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.
- Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
- Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.
- The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
- Lithium generally should not be given with thiazides (see Precautions, Drug Interaction, Lisinopril and Hydrochlorothiazide).

# Precautions

## General
- Lisinopril
- Aortic Stenosis/Hypertrophic Cardiomyopathy
- As with all vasodilators, lisinopril should be given with caution to patients with obstruction in the outflow tract of the left ventricle.
- Impaired Renal Function
- As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors, including lisinopril, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
- In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another angiotensin-converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of lisinopril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy.
- Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when lisinopril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of lisinopril and/or discontinuation of the diuretic may be required.
- Evaluation of the hypertensive patient should always include assessment of renal function.
- Hyperkalemia
- In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in approximately 1.4% of hypertensive patients treated with lisinopril plus hydrochlorothiazide. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was not a cause of discontinuation of therapy. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes. Hyperkalemia can cause serious, sometimes fatal, arrhythmias. Lisinopril and hydrochlorothiazide should be used cautiously, if at all, with these agents and with frequent monitoring of serum potassium.
- Cough
- Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, almost always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
- Surgery/Anesthesia
- In patients undergoing major surgery or during anesthesia with agents that produce hypotension, lisinopril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

## Hydrochlorothiazide
- Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.
- All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
- Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy.
- Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (eg, increased ventricular irritability). Because lisinopril reduces the production of aldosterone, concomitant therapy with lisinopril attenuates the diuretic-induced potassium loss (see Precautions, Drug Interaction, Agents Increasing Serum Potassium).
- Although any chloride deficit is generally mild and usually does not require specific treatment, except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.
- Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
- Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
- In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.
- The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
- If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy.
- Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
- Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism.
- Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
- Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

# Adverse Reactions

## Clinical Trials Experience

## lisinopril
- lisinopril have been found to be generally well tolerated in controlled clinical trials involving 1969 patients with hypertension or heart failure. For the most part, adverse experiences were mild and transient.

### Hypertension
- In clinical trials in patients with hypertension treated with lisinopril, discontinuation of therapy due to clinical adverse experiences occurred in 5.7% of patients. The overall frequency of adverse experiences could not be related to total daily dosage within the recommended therapeutic dosage range.
- For adverse experiences occurring in greater than 1% of patients with hypertension treated with lisinopril or lisinopril plus hydrochlorothiazide in controlled clinical trials, and more frequently with lisinopril and/or lisinopril plus hydrochlorothiazide than placebo, comparative incidence data are listed in the table below.

### heart failure
- In patients with heart failure treated with lisinopril for up to four years, discontinuation of therapy due to clinical adverse experiences occurred in 11.0% of patients. In controlled studies in patients with heart failure, therapy was discontinued in 8.1% of patients treated with lisinopril for 12 weeks, compared to 7.7% of patients treated with placebo for 12 weeks.
- The following table lists those adverse experiences which occurred in greater than 1% of patients with heart failure treated with lisinopril or placebo for up to 12 weeks in controlled clinical trials, and more frequently on lisinopril than placebo.
- Also observed at >1% with lisinopril but more frequent or as frequent on placebo than lisinopril in controlled trials were asthenia, angina pectoris, nausea, dyspnea, cough, and pruritus.
- Worsening of heart failure, anorexia, increased salivation, muscle cramps, back pain, myalgia, depression, chest sound abnormalities, and pulmonary edema were also seen in controlled clinical trials, but were more common on placebo than lisinopril.

### Acute Myocardial Infarction
- In the GISSI-3 trial, in patients treated with lisinopril for six weeks following acute myocardial infarction, discontinuation of therapy occurred in 17.6% of patients.
- Patients treated with lisinopril had a significantly higher incidence of hypotension and renal dysfunction compared with patients not taking lisinopril.
- In the GISSI-3 trial, hypotension (9.7%), renal dysfunction (2.0%), cough (0.5%), post infarction angina (0.3%), skin rash and generalized edema (0.01%), and angioedema (0.01%) resulted in withdrawal of treatment. In elderly patients treated with lisinopril, discontinuation due to renal dysfunction was 4.2%.
- Other clinical adverse experiences occurring in 0.3% to 1.0% of patients with hypertension or heart failure treated with lisinopril in controlled clinical trials and rarer, serious, possibly drug-related events reported in uncontrolled studies or marketing experience are listed below, and within each category are in order of decreasing severity.

### Body as a Whole
- Anaphylactoid reactions , syncope, orthostatic effects, chest discomfort, pain, pelvic pain, flank pain, edema, facial edema, virus infection, fever, chills, malaise.

### Cardiovascular
- Cardiac arrest; myocardial infarction or cerebrovascular accident possibly secondary to excessive hypotension in high risk patients; pulmonary embolism and infarction, arrhythmias (including ventricular tachycardia, atrial tachycardia, atrial fibrillation, bradycardia and premature ventricular contractions), palpitations, transient ischemic attacks, paroxysmal nocturnal dyspnea, orthostatic hypotension, decreased blood pressure, peripheral edema, vasculitis.

### Digestive
- Pancreatitis, hepatitis (hepatocellular or cholestatic jaundic) , vomiting, gastritis, dyspepsia, heartburn, gastrointestinal cramps, constipation, flatulence, dry mouth.

### Hematologic
- Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia, and thrombocytopenia.

### Endocrine
- Diabetes mellitus.

### Metabolic
- Weight loss, dehydration, fluid overload, gout, weight gain.

### Musculoskeletal
- Arthritis, arthralgia, neck pain, hip pain, low back pain, joint pain, leg pain, knee pain, shoulder pain, arm pain, lumbago.

### Nervous System/Psychiatric
- Stroke, ataxia, memory impairment, tremor, peripheral neuropathy (e.g., dysesthesia), spasm, paresthesia, confusion, insomnia, somnolence, hypersomnia, irritability and nervousness.

### Respiratory System
- Malignant lung neoplasms, hemoptysis, pulmonary infiltrates, bronchospasm, asthma, pleural effusion, pneumonia, eosinophilic pneumonitis, bronchitis, wheezing, orthopnea, painful respiration, epistaxis, laryngitis, sinusitis, pharyngeal pain, pharyngitis, rhinitis, rhinorrhea.

### Skin
- Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster, erythema multiforme, urticaria, pruritus, alopecia, flushing, diaphoresis, photosensitivity.

### Special Senses
- Blurred vision, taste alteration, anosmia, tinnitus, conjunctivitis, dry eyes, tearing.

### Urogenital
- Renal failure, oliguria, renal dysfunction

## Postmarketing Experience
There is limited information regarding Lisinopril/Hydrochlorothiazide Postmarketing Experience in the drug label.

# Drug Interactions

## Lisinopril

### Hypotension - Patient on Diuretic Therapy
- Patients on diuretics and especially those in whom diuretic therapywas recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with lisinopril. The possibility of hypotensive effects with lisinopril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with lisinopril. If it is necessary to continue the diuretic, initiate therapy with lisinopril at a dose of 5 mg daily, and provide close medical supervision after the initial dose until blood pressure has stabilized. When a diuretic is added to the therapy of a patient receiving lisinopril, an additional antihypertensive effect is usually observed. Studies with ACE inhibitors in combination with diuretics indicate that the dose of the ACE inhibitor can be reduced when it is given with a diuretic.

### Indomethacin
- In a study in 36 patients with mild to moderate hypertension where the antihypertensive effects of lisinopril alone were compared to lisinopril given concomitantly with indomethacin, the use of indomethacin was associated with a reduced effect, although the difference between the two regimens was not significant.

### Other Agents
- Lisinopril have been used concomitantly with nitrates and/or digoxin without evidence of clinically significant adverse interactions. This included post myocardial infarction patients who were receiving intravenous or transdermal nitroglycerin. No clinically important pharmacokinetic interactions occurred when lisinopril were used concomitantly with propranolol or hydrochlorothiazide. The presence of food in the stomach does not alter the bioavailability of lisinopril.

### Agents Increasing Serum Potassium
- Lisinopril attenuate potassium loss caused by thiazide-type diuretics. Use of lisinopril with potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. Potassium sparing agents should generally not be used in patients with heart failure who are receiving lisinopril.

### Lithium
- Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. Lithium toxicity was usually reversible upon discontinuation of lithium and the ACE inhibitor. It is recommended that serum lithium levels be monitored frequently if lisinopril are administered concomitantly with lithium.

## Hydrochlorothiazide
- Thiazides may decrease arterial responsiveness to norepinephrine, but not enough to preclude effectiveness of the pressor agent for therapeutic use.
- Thiazides may increase the responsiveness to tubocurarine.
- The diuretic, natriuretic, and antihypertensive effects of thiazide diuretics may be reduced by concurrent administration of nonsteroidal anti-inflammatory agents; the effects (if any) of these agents on the antihypertensive effect of fosinopril sodium and hydrochlorothiazide have not been studied.
- By alkalinizing the urine,hydrochlorothiazide may decrease the effectiveness of methenamine.
- Cholestyramine and Colestipol Resins:Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.
- Hydrochlorothiazide: Under the auspices of the National Toxicology Program, rats and mice received hydrochlorothiazide for two years at doses up to 100 (rats) and 600 (mice) mg/kg/day. On a body weight basis, these highest doses were about 2400 times (mice) or 400 times (rats) the fosinopril sodium and hydrochlorothiazide dose of 12.5 mg, given to a 50 kg subject. On a body surface area basis, these doses are 226 times (mice) and 82 times (rats) the fosinopril sodium and hydrochlorothiazide dose. These studies uncovered no evidence of carcinogenicity in rats or female mice, but there was equivocal evidence of hepatocarcinogenicity in male mice.
- Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo assays using mouse germinal cell chromosomes; Chinese Hamster bone-marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Using concentrations of hydrochlorothiazide of 43 to 1300 mg/mL, positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma Cell (mutagenicity) assays. Using an unspecified concentration of hydrochlorothiazide, positive test results were also obtained in the Aspergillus nidulans nondisjunction assay.
- No adverse effects upon fertility were seen when rats and mice received dietary hydrochlorothiazide prior to mating and throughout gestation at doses up to 4 (rats) and 100 (mice) mg/kg/day. These doses are from 3.2 (body surface area basis in rats) to 400 (weight basis in mice) times greater than the dose received by a 50 kg human receiving 12.5 mg a day.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): D
Pregnancy Categories C(first trimester) and D(second and third trimesters). See Warnings, Pregnancy, Lisinopril, Fetal/Neonatal Morbidity and Mortality.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lisinopril/Hydrochlorothiazide in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Lisinopril/Hydrochlorothiazide during labor and delivery.

### Nursing Mothers
- It is not known whether lisinopril is secreted in human milk. However, milk of lactating rats contains radioactivity following administration of 14C lisinopril. In another study, lisinopril was present in rat milk at levels similar to plasma levels in the dams. Thiazides do appear in human milk. Because of the potential for serious reactions in nursing infants from ACE inhibitors and hydrochlorothiazide, a decision should be made whether to discontinue nursing or to discontinue lisinopril and hydrochlorothiazide, taking into account the importance of the drug to the mother.

### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.

### Geriatic 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 subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In a multiple dose pharmacokinetic study in elderly versus young hypertensive patients using the lisinopril and hydrochlorothiazide combination, area under the plasma concentration time curve (AUC) increased approximately 120% for lisinopril and approximately 80% for hydrochlorothiazide in older patients.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Evaluation of the hypertensive patient should always include assessment of renal function. (See Dosage and Administration.)

### Gender
There is no FDA guidance on the use of Lisinopril/Hydrochlorothiazide with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Lisinopril/Hydrochlorothiazide with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Lisinopril/Hydrochlorothiazide in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Lisinopril/Hydrochlorothiazide in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lisinopril/Hydrochlorothiazide in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Lisinopril/Hydrochlorothiazide in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Lisinopril monotherapy is an effective treatment of hypertension in once-daily doses of 10 to 80 mg, while hydrochlorothiazide monotherapy is effective in doses of 12.5 to 50 mg per day. In clinical trials of lisinopril / hydrochlorothiazide combination therapy using lisinopril doses of 10 to 80 mg and hydrochlorothiazide doses of 6.25 to 50 mg, the antihypertensive response rates generally increased with increasing dose of either component.
- The side effects (see Warnings) of lisinopril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (eg, pancreatitis), the former much more common than the latter. Therapy with any combination of lisinopril and hydrochlorothiazide may be associated with either or both dose-independent or dose-dependent side effects, but addition of lisinopril in clinical trials blunted the hypokalemia normally seen with diuretics.
- To minimize dose-dependent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.

## Dose Titration Guided by Clinical Effect
- A patient whose blood pressure is not adequately controlled with either lisinopril or hydrochlorothiazide monotherapy may be switched to lisinopril/HCTZ 10/12.5 or lisinopril/HCTZ 20/12.5, depending on current monotherapy dose. Further increases of either or both components should depend on clinical response with blood pressure measured at the interdosing interval to ensure that there is an adequate antihypertensive effect at that time. The hydrochlorothiazide dose should generally not be increased until 2 to 3 weeks have elapsed. After addition of the diuretic it may be possible to reduce the dose of lisinopril. Patients whose blood pressures are adequately controlled with 25 mg of daily hydrochlorothiazide, but who experience significant potassium loss with this regimen may achieve similar or greater blood-pressure control without electrolyte disturbance if they are switched to lisinopril/HCTZ 10/12.5.
- In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of lisinopril. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with lisinopril to reduce the likelihood of hypotension. If the patient's blood pressure is not controlled with lisinopril alone, diuretic therapy may be resumed.
If the diuretic cannot be discontinued, an initial dose of 5 mg of lisinopril should be used under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour.
- Concomitant administration of lisinopril and hydrochlorothiazide with potassium supplements, potassium salt substitutes or potassium-sparing diuretics may lead to increases of serum potassium .

### Replacement Therapy
- The combination may be substituted for the titrated individual components.

### Use in Renal Impairment
- Regimens of therapy with lisinopril/HCTZ need not take account of renal function as long as the patients creatinine clearance is >30 mL/min/1.7m2 (serum creatinine roughly 3 mg/dL or 265 mcmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so lisinopril/HCTZ is not recommended.

### Monitoring

### Monitor Neutropenia/Agranulocytosis
- Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in patients with uncomplicated hypertension, but more frequently in hypertensive patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Although there were no instances of severe neutropenia (absolute neutrophil count <500/mm3) among patients given Lisinopril and Hydrochlorothiazide, as with other ACE inhibitors, monitoring of white blood cell counts should be considered for patients who have collagen-vascular disease, especially if the disease is associated with impaired renal function. Available data from clinical trials of Lisinopril and Hydrochlorothiazide are insufficient to show that Lisinopril and Hydrochlorothiazide does not cause agranulocytosis at rates similar to captopril.

### Monitor Renal Functions in Hypertensive Patients With Renal Artery Stenosis
- In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.

### Monitor Potassium with Diuretics
- Lisinopril and Hydrochlorothiazide can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored.

### Monitor serum Lithium
- Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

### Monitor renal function in Non-Steroidal Anti-Inflammatory Agents
- In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDS, including selective COX-2 inhibitors, with ACE inhibitors, including moexipril, may result in deterioration of renal function, including possible acute renal failure.  These effects are usually reversible.  Monitor renal function periodically in patients receiving moexipril and NSAID therapy.The antihypertensive effect of ACE inhibitors, including Lisinopril and Hydrochlorothiazide, may be attenuated by NSAIDS.

### Monitor Blood Pressue with Dual Blockade of the Renin-Angiotensin System (RAS)
- Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Lisinopril and Hydrochlorothiazide and other agents that affect the RAS.

# IV Compatibility
There is limited information regarding the compatibility of Lisinopril/Hydrochlorothiazide and IV administrations.

# Overdosage
There is limited information regarding Lisinopril/Hydrochlorothiazide overdosage.  If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology
There is limited information regarding Lisinopril/Hydrochlorothiazide Pharmacology in the drug label.

## Mechanism of Action
- Lisinopril inhibits angiotensin converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.
- The beneficial effects of isinopril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with lisinopril alone for up to 24 weeks, the mean increase in serum potassium was approximately 0.1 mEq/L; however, approximately 15% of patients had increases greater than 0.5 mEq/L and approximately 6% had a decrease greater than 0.5 mEq/L. In the same study, patients treated with lisinopril and hydrochlorothiazide for up to 24 weeks had a mean decrease in serum potassium of 0.1 mEq/L; approximately 4% of patients had increases greater than 0.5 mEq/L and approximately 12% had a decrease greater than 0.5 mEq/L. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of lisinopril remains to be elucidated. While the mechanism through which lisinopril lower blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril are antihypertensive even in patients with low-renin hypertension.
- Although lisinopril were antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to monotherapy than nonblack patients.
- Concomitant administration of lisinopril and hydrochlorothiazide further reduced blood pressure in black and non-black patients and any racial differences in blood pressure response were no longer evident.
- Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin, so coadministration of an ACE inhibitor tends to reverse the potassium loss associated with these diuretics.
- The mechanism of the antihypertensive effect of thiazides is unknown.

## Structure
There is limited information regarding Lisinopril/Hydrochlorothiazide Structure in the drug label.

## Pharmacodynamics

### Lisinopril
- Administration of lisinopril to patients with hypertension results in a reduction of supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is usually not observed although it can occur and should be anticipated in volume and/or salt-depleted patients.
- In most patients studied, onset of antihypertensive activity was seen at one hour after oral administration of an individual dose of lisinopril, with peak reduction of blood pressure achieved by six hours.
- In some patients achievement of optimal blood pressure reduction may require two to four weeks of therapy.
- At recommended single daily doses, antihypertensive effects have been maintained for at least 24 hours after dosing, although the effect at 24 hours was substantially smaller than the effect six hours after dosing.
- The antihypertensive effects of lisinopril have continued during long-term therapy. Abrupt withdrawal of lisinopril has not been associated with a rapid increase in blood pressure; nor with a significant overshoot of pretreatment blood pressure.
- In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and in heart rate. In a study in nine hypertensive patients, following administration of lisinopril, there was an increase in mean renal blood flow that was not significant. Data from several small studies are inconsistent with respect to the effect of lisinopril on glomerular filtration rate in hypertensive patients with normal renal function, but suggest that changes, if any, are not large.
- In patients with renovascular hypertension lisinopril has been shown to be well tolerated and effective in controlling blood pressure.

### Hydrochlorothiazide
- Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier.

## Pharmacokinetics

### Lisinopril
- Following oral administration of lisinopril, peak serum concentrations occur within about 7 hours. Declining serum concentrations exhibit a prolonged terminal phase which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose. Lisinopril does not appear to be bound to other serum proteins.
- Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25 percent, with large intersubject variability (6-60 percent) at all doses tested (5-80 mg). Lisinopril absorption is not influenced by the presence of food in the gastrointestinal tract.
- Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.
- Impaired renal function decreases elimination of lisinopril, which is excreted principally through the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below 30 mL/min.
- Above this glomerular filtration rate, the elimination half-life is little changed. With greater impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and time to attain steady state is prolonged. Older patients, on average, have (approximately doubled) higher blood levels and area under the plasma concentration time curve (AUC) than younger patients.
- Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril in rats do not result in accumulation in any tissues. However, milk of lactating rats contains radioactivity following administration of 14C lisinopril. By whole body autoradiography, radioactivity was found in the placenta following administration of labeled drug to pregnant rats, but none was found in the fetuses.

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, Impairment of Fertility

### Lisinopril
- There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks to male and female rats at doses up to 90 mg/kg/day (about 56 or 9 times- the maximum recommended daily human dose.
- Lisinopril-Hydrochlorothiazide: Lisinopril in combination with hydrochlorothiazide was not mutagenic in a microbial mutagen test using Salmonella typhimurium (Ames test) or Escherichia coli with or without metabolic activation or in a forward mutation assay using Chinese hamster lung cells. Lisinopril and hydrochlorothiazide did not produce DNA single strand breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, it did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.
- Lisinopril:There was no evidence of a tumorigenic effect when lisinopril was administered orally 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 10 times and 7 times, respectively, the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis.
- Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. It was also negative in a forward mutation assay using Chinese hamster lung cells.
- Lisinopril did not produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, lisinopril did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.
- There were no adverse effects on reproductive performance in male and female rats treated with up to 300 mg/kg/day of lisinopril (33 times the MRHDD when compared on a body surface area basis).
- Under the auspices of the National Toxicology Program, rats and mice received hydrochlorothiazide for two years at doses up to 100 (rats) and 600 (mice) mg/kg/day. On a body weight basis, these highest doses were about 2400 times (mice) or 400 times (rats) the fosinopril sodium and hydrochlorothiazide dose of 12.5 mg, given to a 50 kg subject. On a body surface area basis, these doses are 226 times (mice) and 82 times (rats) the fosinopril sodium and hydrochlorothiazide dose. These studies uncovered no evidence of carcinogenicity in rats or female mice, but there was equivocal evidence of hepatocarcinogenicity in male mice.
- Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo assays using mouse germinal cell chromosomes; Chinese Hamster bone-marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Using concentrations of hydrochlorothiazide of 43 to 1300 mg/mL, positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma Cell (mutagenicity) assays. Using an unspecified concentration of hydrochlorothiazide, positive test results were also obtained in the Aspergillus nidulans nondisjunction assay.
- No adverse effects upon fertility were seen when rats and mice received dietary hydrochlorothiazide prior to mating and throughout gestation at doses up to 4 (rats) and 100 (mice) mg/kg/day. These doses are from 3.2 (body surface area basis in rats) to 400 (weight basis in mice) times greater than the dose received by a 50 kg human receiving 12.5 mg a day.

# Clinical Studies
There is limited information regarding Lisinopril/Hydrochlorothiazide Clinical Studies in the drug label.

# How Supplied
There is limited information regarding Lisinopril/Hydrochlorothiazide How Supplied in the drug label.

## Storage
There is limited information regarding Lisinopril/Hydrochlorothiazide Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
There is limited information regarding Lisinopril/Hydrochlorothiazide Patient Counseling Information in the drug label.

# Precautions with Alcohol
Alcohol-Lisinopril/Hydrochlorothiazide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
There is limited information regarding Lisinopril/Hydrochlorothiazide Brand Names in the drug label.

# Look-Alike Drug Names
There is limited information regarding Lisinopril/Hydrochlorothiazide Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price