Lisinopril and Hydrochlorothiazide

As a result of its diuretic effects, hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, and decreases serum potassium.  Administration of lisinopril blocks the renin-angiotensin aldosterone axis and tends to reverse the potassium loss associated with the diuretic.

In clinical studies, the extent of blood pressure reduction seen with the combination of lisinopril and hydrochlorothiazide was approximately additive.  The ZESTORETIC 10-12.5 combination worked equally well in black and white patients.  The ZESTORETIC 20-12.5 and ZESTORETIC 20-25 combinations appeared somewhat less effective in black patients, but relatively few black patients were studied.  In most patients, the antihypertensive effect of ZESTORETIC was sustained for at least 24 hours.

In a randomized, controlled comparison, the mean antihypertensive effects of ZESTORETIC 20-12.5 and ZESTORETIC 20-25 were similar, suggesting that many patients who respond adequately to the latter combination may be controlled with ZESTORETIC 20-12.5  (see DOSAGE AND ADMINISTRATION).

Concomitant administration of lisinopril and hydrochlorothiazide has little or no effect on the bioavailability of either drug.  The combination tablet is bioequivalent to concomitant administration of the separate entities.

Lisinopril

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.  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.  Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.  In hypertensive patients with normal renal function treated with lisinopril alone for up to 24 weeks, the mean increase in serum potassium was less than 0.1 mEq/L; however, approximately 15 percent of patients had increases greater than 0.5 mEq/L and approximately six percent had a decrease greater than 0.5 mEq/L.  In the same study, patients treated with lisinopril plus a thiazide diuretic showed essentially no change in serum potassium  (see PRECAUTIONS).

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 lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril is antihypertensive even in patients with low-renin hypertension.  Although lisinopril was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to lisinopril monotherapy than nonblack patients.

Pharmacokinetics and Metabolism

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% to 60%) at all doses tested (5 mg to 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 (see DOSAGE AND ADMINISTRATION).  In a multiple dose pharmacokinetic study in elderly versus young hypertensive patients using the lisinopril/hydrochlorothiazide combination, the AUC increased approximately 120% for lisinopril and approximately 80% for hydrochlorothiazide in older patients. Lisinopril can be removed by hemodialysis.

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.

Pharmacodynamics

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  (see WARNINGS).

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 (see PRECAUTIONS).

Hydrochlorothiazide

The mechanism of the antihypertensive effect of thiazides is unknown.  Thiazides do not usually affect normal blood pressure.

Hydrochlorothiazide is a diuretic and antihypertensive.  It affects the distal renal tubular mechanism of electrolyte reabsorption.  Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts.  Natriuresis may be accompanied by some loss of potassium and bicarbonate.

After oral use diuresis begins within two hours, peaks in about four hours and lasts about 6 to 12 hours.

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.

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 ZESTORETIC) 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.  ZESTORETIC 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  (see ADVERSE REACTIONS).

Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema (see PRECAUTIONS).

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 (see also INDICATIONS AND USAGE and CONTRAINDICATIONS).

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 (e.g., 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 (see PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS).

Syncope has been reported in 0.8 percent of patients receiving ZESTORETIC. In patients with hypertension receiving lisinopril alone, the incidence of syncope was 0.1 percent.  The overall incidence of syncope may be reduced by proper titration of the individual components (see PRECAUTIONS, Drug Interactions, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

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 two 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.

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 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 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 Interactions, Lisinopril and Hydrochlorothiazide).

General

Information for Patients

Angioedema: Angioedema, including laryngeal edema may occur at any time during treatment with angiotensin-converting enzyme inhibitors, including ZESTORETIC. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician.

Symptomatic Hypotension: Patients should be cautioned to report lightheadedness especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician.

All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with their physician.

Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician.

Leukopenia/Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of leukopenia/neutropenia.

Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to ZESTORETIC during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.

Non-melanoma Skin Cancer: Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening.

NOTE: As with many other drugs, certain advice to patients being treated with ZESTORETIC is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Drug Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility

Nursing Mothers

It is not known whether lisinopril is excreted 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 adverse reactions in nursing infants from ACE inhibitors and hydrochlorothiazide, a decision should be made whether to discontinue nursing and/or discontinue ZESTORETIC, taking into account the importance of the drug to the mother.

Pediatric Use

Neonates with a history of in utero exposure to ZESTORETIC:

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.  Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.  Lisinopril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of ZESTORETIC 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.

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.

Clinical Laboratory Test Findings

Serum Electrolytes:  (See PRECAUTIONS).

Creatinine, Blood Urea Nitrogen:  Minor reversible increases in blood urea nitrogen and serum creatinine were observed in patients with essential hypertension treated with ZESTORETIC.  More marked increases have also been reported and were more likely to occur in patients with renal artery stenosis (see PRECAUTIONS).

Serum Uric Acid, Glucose, Magnesium, Cholesterol, Triglycerides and Calcium: (See PRECAUTIONS).

Hemoglobin and Hematocrit:  Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.5 g% and 1.5 vol%, respectively) occurred frequently in hypertensive patients treated with ZESTORETIC but were rarely of clinical importance unless another cause of anemia coexisted.  In clinical trials, 0.4% of patients discontinued therapy due to anemia.

Liver Function Tests:  Rarely, elevations of liver enzymes and/or serum bilirubin have occurred.  (See WARNINGS, Hepatic Failure).

Other adverse reactions that have been reported with the individual components are listed below:

Lisinopril - In clinical trials adverse reactions which occurred with lisinopril were also seen with ZESTORETIC.  In addition, and since lisinopril has been marketed, the following adverse reactions have been reported with lisinopril and should be considered potential adverse reactions for ZESTORETIC:  Body as a Whole:  Anaphylactoid reactions (see WARNINGS, Anaphylactoid Reactions During Membrane Exposure), malaise, edema, facial edema, pain, pelvic pain, flank pain, chills; Cardiovascular:  Cardiac arrest, myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see WARNINGS, Hypotension), pulmonary embolism and infarction, worsening of heart failure, arrhythmias (including tachycardia, ventricular tachycardia, atrial tachycardia, atrial fibrillation, bradycardia, and premature ventricular contractions), angina pectoris, transient ischemic attacks, paroxysmal nocturnal dyspnea, decreased blood pressure, peripheral edema, vasculitis; Digestive:  Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (see WARNINGS, Hepatic Failure), gastritis, anorexia, flatulence, increased salivation; Endocrine:  Diabetes mellitus, inappropriate antidiuretic hormone secretion; Hematologic:  Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia, and thrombocytopenia have been reported in which a causal relationship to lisinopril can not be excluded; Metabolic:  Gout, weight loss, dehydration, fluid overload, weight gain; Musculoskeletal:  Arthritis, arthralgia, neck pain, hip pain, joint pain, leg pain, arm pain, lumbago; Nervous System/Psychiatric:  Ataxia, memory impairment, tremor, insomnia, stroke, nervousness, confusion, peripheral neuropathy (e.g., paresthesia, dysesthesia), spasm, hypersomnia, irritability; mood alterations (including depressive symptoms); hallucinations; Respiratory:  Malignant lung neoplasms, hemoptysis, pulmonary edema, pulmonary infiltrates, bronchospasm, asthma, pleural effusion, pneumonia, eosinophilic pneumonitis, wheezing, orthopnea, painful respiration, epistaxis, laryngitis, sinusitis, pharyngitis, rhinitis, rhinorrhea, chest sound abnormalities; Skin: Urticaria, alopecia, herpes zoster, photosensitivity, skin lesions, skin infections, pemphigus, erythema, psoriasis, rare cases of other severe skin reactions, including toxic epidermal necrolysis and Stevens-Johnson Syndrome (causal relationship has not been established); Special Senses:  Visual loss, diplopia, photophobia, taste alteration, olfactory disturbance; Urogenital:  Acute renal failure, oliguria, anuria, uremia, progressive azotemia, renal dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), pyelonephritis, dysuria, breast pain.

Miscellaneous:  A symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia and leukocytosis.  Rash, photosensitivity or other dermatological manifestations may occur alone or in combination with these symptoms.

Hydrochlorothiazide - Body as a Whole:  Weakness; Digestive:  Anorexia, gastric irritation, cramping, jaundice (intrahepatic cholestatic jaundice) (see WARNINGS, Hepatic Failure), pancreatitis, sialoadenitis, constipation; Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia; Musculoskeletal:  Muscle spasm; Nervous System/Psychiatric: Restlessness; Renal:  Renal failure, renal dysfunction, interstitial nephritis (see WARNINGS); Skin: Erythema multiforme including Stevens-Johnson Syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia; Special Senses:  Xanthopsia; Hypersensitivity:  Purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions.

Postmarketing Experience

Non-melanoma Skin Cancer

Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

To report SUSPECTED ADVERSE REACTIONS, contact Almatica Pharma LLC at 1-877-447-7979 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch for voluntary reporting of adverse reactions.

Lisinopril

Following a single oral dose of 20 g/kg no lethality occurred in rats and death occurred in one of 20 mice receiving the same dose.  The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution.

Lisinopril can be removed by hemodialysis (see WARNINGS, Anaphylactoid Reaction During Membrane Exposure).

Hydrochlorothiazide

Oral administration of a single oral dose of 10 g/kg to mice and rats was not lethal.  The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis.  If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.