DESCRIPTION

Lisinopril and Hydrochlorothiazide Tablets, USP combine an angiotensin converting enzyme inhibitor, lisinopril, USP and a diuretic, hydrochlorothiazide, USP.

Lisinopril, USP a synthetic peptide derivative, is an oral long-acting angiotensin converting enzyme inhibitor. It is chemically described as ( S)-1-[ N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline dihydrate. Its empirical formula is C 21H 31N 3O 5•2H 2O and its structural formula is:

Lisinopril, USP is a white to off-white, crystalline powder, with a molecular weight of 441.52. It is soluble in water, sparingly soluble in methanol, and practically insoluble in ethanol.

Hydrochlorothiazide, USP is 6-chloro-3,4-dihydro-2 H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C 7H 8ClN 3O 4S 2 and its structural formula is:

Hydrochlorothiazide, USP is a white, or practically white, crystalline powder with a molecular weight of 297.74, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.

Lisinopril and Hydrochlorothiazide Tablets, USP are available for oral use in three tablet combinations of lisinopril with hydrochlorothiazide: Lisinopril and Hydrochlorothiazide Tablets USP, 10/12.5, which contains 10 mg lisinopril and 12.5 mg hydrochlorothiazide, USP; Lisinopril and Hydrochlorothiazide Tablets USP, 20/12.5, which contains 20 mg lisinopril, USP and 12.5 mg hydrochlorothiazide, USP; and Lisinopril and Hydrochlorothiazide Tablets USP, 20/25, which contains 20 mg lisinopril, USP and 25 mg hydrochlorothiazide, USP. Inactive ingredients are colloidal silicon dioxide, dibasic calcium phosphate, magnesium stearate, mannitol, and pregelatinized corn starch. The 10 mg/12.5 mg and 20 mg/25 mg tablets also contain FD&C Red #40 Aluminum Lake. The 20 mg/12.5 mg tablet also contains FD&C Blue #2 Aluminum Lake.

CLINICAL PHARMACOLOGY

Lisinopril-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 Lisinopril and Hydrochlorothiazide Tablets 10/12.5 combination worked equally well in Black and Caucasian patients. The Lisinopril and Hydrochlorothiazide Tablets 20/12.5 and Lisinopril and Hydrochlorothiazide Tablets 20/25 (a previously - marketed strength) combinations appeared somewhat less effective in Black patients, but relatively few Black patients were studied. In most patients, the antihypertensive effect of Lisinopril and Hydrochlorothiazide Tablets was sustained for at least 24 hours.

In a randomized, controlled comparison, the mean antihypertensive effects of Lisinopril and Hydrochlorothiazide Tablets 20/12.5 and Lisinopril and Hydrochlorothiazide Tablets 20/25 were similar, suggesting that many patients who respond adequately to the latter combination may be controlled with Lisinopril and Hydrochlorothiazide Tablets 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 than0.5 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 non-Black 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 percent) at all doses tested (5 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). 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.

INDICATIONS AND USAGE

Lisinopril and Hydrochlorothiazide Tablets is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including lisinopril and hydrochlorothiazide.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous  antihypertensive  drugs,  from  a  variety  of  pharmacologic  classes  and  with  different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

These fixed-dose combinations are not indicated for initial therapy (see DOSAGE AND ADMINISTRATION).

In using Lisinopril and Hydrochlorothiazide Tablets, consideration should be given to the fact that an angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that lisinopril does not have a similar risk (see WARNINGS).

In considering use of Lisinopril and Hydrochlorothiazide Tablets, it should be noted that Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non- Blacks (see WARNINGS, Head and Neck Angioedema).

CONTRAINDICATIONS

Lisinopril and Hydrochlorothiazide Tablets is 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.

Lisinopril and Hydrochlorothiazide Tablets is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer Lisinopril and Hydrochlorothiazide Tablets within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor (see WARNINGS).

Do not coadminister aliskiren with Lisinopril and Hydrochlorothiazide Tablets in patients with diabetes.

WARNINGS

General

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 Tablets) 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 rarely 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 non-Black patients. In such cases Lisinopril and Hydrochlorothiazide Tablets should be promptly discontinued and 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 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).

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.

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: Sudden and potentially life-threatening anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes 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 Lisinopril and  Hydrochlorothiazide Tablets. 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 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.

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 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

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).

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.

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 Tablets as soon as possible. These adverse outcomes are usually associated with the 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 therapy to 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 Tablets, 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 Tablets for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use).

Lisinopril-Hydrochlorothiazide

Teratogenicity  studies  were  conducted  in  mice  and  rats  with  up  to  90 mg/kg/day  of  lisinopril  in combination with 10 mg/kg/day of hydrochlorothiazide. This dose of lisinopril is 5 times (in mice) and 10 times (in rats) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis (mg/m2); the dose of hydrochlorothiazide is 0.9 times (in mice) and 1.8 times (in rats) the MRHDD. 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.

No teratogenic effects of lisinopril were seen in studies of pregnant mice, rats, and rabbits. On a body surface area basis, the doses used were up 55 times, 33 times, and 0.15 times, respectively, the MRHDD.

Hydrochlorothiazide

Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at  doses up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus. These doses are more than 150 times the MRHDD on a body surface area basis. Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions that have occurred in adults.

PRECAUTIONS

ADVERSE REACTIONS

Lisinopril and Hydrochlorothiazide Tablets have been evaluated for safety in 930 patients, including 100 patients treated for 50 weeks or more.

In clinical trials with Lisinopril and Hydrochlorothiazide Tablets no adverse experiences peculiar to this combination drug have been observed. Adverse experiences that have occurred have been limited to those that have been previously reported with lisinopril or hydrochlorothiazide.

The most frequent clinical adverse experiences in controlled trials (including open label extensions) with any combination of lisinopril and hydrochlorothiazide were: dizziness (7.5 percent), headache (5.2 percent), cough (3.9 percent), fatigue (3.7 percent) and orthostatic effects (3.2 percent), all of which were more common than in placebo-treated patients. Generally, adverse experiences were mild and transient in  nature;  but  see  WARNINGS  regarding  angioedema  and  excessive  hypotension  or  syncope.

Discontinuation of therapy due to adverse effects was required in 4.4 percent of patients, principally because of dizziness, cough, fatigue and muscle cramps.

Adverse  experiences  occurring  in  greater  than  one  percent  of  patients  treated  with  lisinopril  plus hydrochlorothiazide in controlled clinical trials are shown below.

Clinical adverse experiences occurring in 0.3 to 1.0 percent of patients in controlled trials included:

Body as a Whole: Chest pain, abdominal pain, syncope, chest discomfort, fever, trauma, virus infection. Cardiovascular: Palpitation, orthostatic hypotension. Digestive: Gastrointestinal cramps, dry mouth, constipation, heartburn. Musculoskeletal: Back pain, shoulder pain, knee pain, back strain, myalgia, foot pain. Nervous/Psychiatric: Decreased libido, vertigo, depression, somnolence. Respiratory: Common cold, nasal congestion, influenza, bronchitis, pharyngeal pain, dyspnea, pulmonary congestion, chronic sinusitis, allergic rhinitis, pharyngeal discomfort. Skin: Flushing, pruritus, skin inflammation, diaphoresis. Special Senses: Blurred vision, tinnitus, otalgia. Urogenital: Urinary tract infection.

Angioedema: Angioedema has been reported in patients receiving PRINZIDE, with an incidence higher in Black than in non-Black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with PRINZIDE should be discontinued and appropriate therapy instituted immediately. In rare cases, intestinal angioedema has been reported with angiotensin converting enzyme inhibitors including lisinopril (see WARNINGS).

Hypotension: In clinical trials, adverse effects relating to hypotension occurred as follows: hypotension (1.4 percent), orthostatic hypotension (0.5 percent), other orthostatic effects (3.2 percent). In addition syncope occurred in 0.8 percent of patients (see WARNINGS).

Cough: See PRECAUTIONS, Cough.

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   Lisinopril   and Hydrochlorothiazide Tablets. 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  percent  and  1.5 vol  percent,  respectively)  occurred  frequently  in  hypertensive patients treated with Lisinopril and Hydrochlorothiazide Tablets but were rarely of clinical importance unless another cause of anemia coexisted. In clinical trials, 0.4 percent 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 Lisinopril and Hydrochlorothiazide Tablets. 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 Lisinopril and Hydrochlorothiazide Tablets: Body as a Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly Related Reactions), 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, syndrome of inappropriate antidiuretic hormone secretion (SIADH); Hematologic: Rare cases of neutropenia, thrombocytopenia, and bone marrow depression have been reported. Hemolytic anemia has been reported; a causal relationship to lisinopril cannot 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, eosinophilic pneumonitis, bronchospasm, asthma, pleural effusion, pneumonia, 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. Other severe skin reactions (including toxic epidermal necrolysis, Stevens-Johnson syndrome and cutaneous pseudolymphoma) have been reported rarely; causal relationship has not been established; Special Senses: Visual loss, diplopia, photophobia, taste disturbances, olfactory disturbances; 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, leukocytosis, eosinophilia, photosensitivity, rash, and other dermatological manifestations.

Fetal/Neonatal  Morbidity  and  Mortality:  See   WARNINGS,   Pregnancy,   Lisinopril,   Fetal/Neonatal Morbidity and Mortality.

Hydrochlorothiazide — Body as a Whole: Weakness; Digestive: Anorexia, gastric irritation, cramping, jaundice (intrahepatic cholestatic jaundice) (see WARNINGS, Hepatic Failure), pancreatitis, sialadenitis, constipation; Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolyticanemia; 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 Actavis at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

OVERDOSAGE

No  specific  information  is  available  on  the  treatment  of  overdosage  with  Lisinopril  and Hydrochlorothiazide Tablets. Treatment is symptomatic and supportive. Therapy with Lisinopril and Hydrochlorothiazide Tablets should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage, and correction of dehydration, electrolyte imbalance and hypotension by established procedures.

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 reactions 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.

DOSAGE AND ADMINISTRATION

Lisinopril monotherapy is an effective treatment of hypertension in once-daily doses of 10 mg to 80 mg, while hydrochlorothiazide monotherapy is effective in doses of 12.5 mg to 50 mg per day. In clinical trials of  lisinopril/hydrochlorothiazide combination  therapy  using  lisinopril  doses  of  10  mg  to  80 mg  and hydrochlorothiazide doses of 6.25 mg 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  (e.g.,  pancreatitis),  the  former  much  more  common  than  the  latter. Therapy with any combination of lisinopril and hydrochlorothiazide will be associated with both sets of dose-independent side effects, but addition of lisinopril in clinical trials blunted the hypokalemia normally seen with diuretics.

To minimize dose-independent 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 and Hydrochlorothiazide Tablets 10/12.5 or Lisinopril and Hydrochlorothiazide Tablets 20/12.5. Further increases of either or both components could depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2 to 3 weeks have elapsed. 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 with less potassium loss if they are switched to Lisinopril and Hydrochlorothiazide Tablets 10/12.5. Dosage higher than lisinopril 80 mg and hydrochlorothiazide 50 mg should not be used.

Replacement Therapy

The combination may be substituted for the titrated individual components.

Use in Renal Impairment

The usual regimens of therapy with Lisinopril and Hydrochlorothiazide Tablets need not be adjusted as long  as  the  patient's  creatinine  clearance  is  greater  than  30 mL/min/1.73 m 2   (serum  creatinine approximately  less  than  or  equal  to  3 mg/dL  or  265 µmol/L).  In  patients  with  more  severe  renal impairment, loop diuretics are preferred to thiazides, so Lisinopril and Hydrochlorothiazide Tablets is not recommended (see WARNINGS, Anaphylactoid reactions during membrane exposure).

HOW SUPPLIED

Lisinopril and hydrochlorothiazide tablets USP are available as follows:

20 mg/25 mg: Pink, round, unscored, flat-faced, beveled-edge tablets, debossed “WATSON” and “862” on the periphery of one side and plain on the other side are supplied in bottles of 30 (NDC 70934-668-30).

Storage

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from excessive light and humidity.

Dispense in a tight, light-resistant container according to USP/NF.

Brands listed are trademarks of their respective owners.

Manufactured in India by:

Watson Pharma Private Limited

Verna, Salcette Goa 403 722 INDIA

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Rev. B 5/2020

Principal Display Panel

NDC: 70934-668-30