Lisinopril by ReadyMeds LISINOPRIL tablet

Lisinopril by

Drug Labeling and Warnings

Lisinopril by is a Prescription medication manufactured, distributed, or labeled by ReadyMeds. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

Hypotension

Excessive hypotension is rare in patients with uncomplicated hypertension treated with lisinopril alone.

Patients with heart failure given lisinopril commonly have some reduction in blood pressure, with peak blood pressure reduction occurring 6 to 8 hours post dose. Evidence from the two-dose ATLAS trial suggested that incidence of hypotension may increase with dose of lisinopril in heart failure patients. Discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy (see DOSAGE AND ADMINISTRATION).

Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or characteristics: heart failure with systolic blood pressure below 100 mmHg, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with lisinopril in patients at risk for excessive hypotension who are able to tolerate such adjustments (see PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS).

Patients with acute myocardial infarction in the GISSI-3 trial had a higher (9.0% versus 3.7%) incidence of persistent hypotension (systolic blood pressure < 90 mmHg for more than 1 hour) when treated with lisinopril. Treatment with lisinopril must not be initiated in acute myocardial infarction patients at risk of further serious hemodynamic deterioration after treatment with a vasodilator (e.g., systolic blood pressure of 100 mmHg or lower) or cardiogenic shock.

In patients at risk of excessive hypotension, therapy should be started under very close medical supervision and 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 may apply to patients with ischemic heart or cerebrovascular disease, or in patients with acute myocardial infarction, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

If excessive 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 of lisinopril which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of lisinopril or concomitant diuretic may be necessary.

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 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, 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 for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use).

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.

  • PRECAUTIONS

    General

    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 patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen 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 and/or discontinuation of the diuretic and/or lisinopril may be required.

    Patients with acute myocardial infarction in the GISSI-3 trial treated with lisinopril had a higher (2.4% versus 1.1%) incidence of renal dysfunction in-hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration). In acute myocardial infarction, treatment with lisinopril should be initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. If renal dysfunction develops during treatment with lisinopril (serum creatinine concentration exceeding 3 mg/dL or a doubling from the pre-treatment value) then the physician should consider withdrawal of lisinopril.

    Evaluation of patients with hypertension, heart failure, or myocardial infarction should always include assessment of renal function (see DOSAGE AND ADMINISTRATION).

    Hyperkalemia:

    In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in approximately 2.2% of hypertensive patients and 4.8% of patients with heart failure. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in approximately 0.1% of hypertensive patients; 0.6% of patients with heart failure and 0.1% of patients with myocardial infarction. 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 should be used cautiously, if at all, with these agents and with frequent monitoring of serum potassium (see PRECAUTIONS, Drug Interactions).

    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.

    Information for Patients

    Angioedema:

    Angioedema, including laryngeal edema, may occur at any time during treatment with angiotensin-converting enzyme inhibitors, including lisinopril. 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 patient 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.

    Hypoglycemia:

    Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor should be told to closely monitor for hypoglycemia, especially during the first month of combined use (see PRECAUTIONS, Drug Interactions).

    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 lisinopril 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.

    NOTE:

    As with many other drugs, certain advice to patients being treated with lisinopril 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

    Hypotension - Patients on Diuretic Therapy:

    Patients on diuretics and especially those in whom diuretic therapy was 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 (see WARNINGS, and DOSAGE AND ADMINISTRATION). 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 (see DOSAGE AND ADMINISTRATION).

    Antidiabetics:

    Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycemic agents) may cause an increased blood-glucose-lowering effect with risk of hypoglycemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment. In diabetic patients treated with oral antidiabetic agents or insulin, glycemic control should be closely monitored for hypoglycemia, especially during the first month of treatment with an ACE inhibitor.

    Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors):

    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 lisinopril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving lisinopril and NSAID therapy.

    The antihypertensive effect of ACE inhibitors, including lisinopril, may be attenuated by NSAIDs.

    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 other agents that affect the RAS.

    Do not co-administer aliskiren with lisinopril in patients with diabetes. Avoid use of aliskiren with lisinopril in patients with renal impairment (GFR < 60 mL/min).

    Other Agents:

    Lisinopril has 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 was 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 attenuates potassium loss caused by thiazide-type diuretics. Use of lisinopril with potassium-sparing diuretics (e.g., spironolactone, eplerenone, 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 is administered concomitantly with lithium.

    Gold:

    Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including lisinopril.

    Carcinogenesis, Mutagenesis, Impairment of Fertility

    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 times2  the maximum recommended daily human dose, based on body weight and body surface area, respectively). There was no evidence of carcinogenicity when lisinopril was administered for 92 weeks to (male and female) mice at doses up to 135 mg/kg/day (about 84 times2 the maximum recommended daily human dose). This dose was 6.8 times the maximum human dose based on body surface area in mice.

    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. This dose is 188 times and 30 times the maximum human dose when based on mg/kg and mg/m2, respectively.

  • 2 Calculations assume a human weight of 50 kg and human body surface area of 1.62 m2.

    • Nursing Mothers

    Milk of lactating rats contains radioactivity following administration of 14C lisinopril. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ACE inhibitors, a decision should be made whether to discontinue nursing or discontinue lisinopril, taking into account the importance of the drug to the mother.

    Pediatric Use

    Neonates with a history of in utero exposure to lisinopril:

    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.

    Antihypertensive effects of lisinopril have been established in hypertensive pediatric patients aged 6 to 16 years.

    There are no data on the effect of lisinopril on blood pressure in pediatric patients under age 6 or in pediatric patients with glomerular filtration rate < 30 mL/min/1.73 m2 (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism and Pharmacodynamics and Clinical Effects, and DOSAGE AND ADMINISTRATION).

    Geriatric Use

    Clinical studies of lisinopril in patients with hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience in this population 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 the ATLAS trial of lisinopril in patients with congestive heart failure, 1,596 (50%) were 65 and over, while 437 (14%) were 75 and over. In a clinical study of lisinopril in patients with myocardial infarctions 4,413 (47%) were 65 and over, while 1,656 (18%) were 75 and over. In these studies, no overall differences in safety or effectiveness were observed between elderly and younger patients, and other reported clinical experiences has not identified differences in responses between the elderly and younger patients (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Heart Failure and CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Acute Myocardial Infarction).

    Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

    Pharmacokinetic studies indicate that maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism).

    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 patients with hypertension, congestive heart failure, or myocardial infarction should always include assessment of renal function (see DOSAGE AND ADMINISTRATION).

  • ADVERSE REACTIONS

    Lisinopril has 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:

    PERCENT OF PATIENTS IN CONTROLLED STUDIES
    Lisinopril
    (n=1349)
    Incidence
    (discontinuation)     		 Lisinopril/
    Hydrochlorothiazide
    (n=629)
    Incidence
    (discontinuation)    		 Placebo
    (n=207)
    Incidence
    (discontinuation)
     Body as a Whole
     Fatigue2.5 (0.3)4.0 (0.5)

    1.0 (0.0)
     Asthenia1.3 (0.5)2.1 (0.2)

    1.0 (0.0)
     Orthostatic Effects1.2 (0.0)3.5 (0.2)1.0 (0.0)
    Cardiovascular
     Hypotension1.2 (0.5)1.6 (0.5)0.5 (0.5)
    Digestive
     Diarrhea2.7 (0.2)2.7 (0.3)2.4 (0.0)
     Nausea2.0 (0.4)2.5 (0.2)2.4 (0.0)
     Vomiting1.1 (0.2)1.4 (0.1)0.5 (0.0)
     Dyspepsia0.9 (0.0)1.9 (0.0)0.0 (0.0)
    Musculoskeletal
     Muscle Cramps0.5 (0.0)2.9 (0.8)0.5 (0.0)
    Nervous/Psychiatric
     Headache5.7 (0.2)4.5 (0.5)1.9 (0.0)
     Dizziness5.4 (0.4)9.2 (1.0)1.9 (0.0)
     Paresthesia0.8 (0.1)2.1 (0.2)0.0 (0.0)
     Decreased Libido0.4 (0.1)1.3 (0.1)0.0 (0.0)
     Vertigo0.2 (0.1)1.1 (0.2)0.0 (0.0)
    Respiratory
     Cough3.5 (0.7)4.6 (0.8)1.0 (0.0)
     Upper Respiratory Infection2.1 (0.1)2.7 (0.1)

    0.0 (0.0)
     Common Cold1.1 (0.1)1.3 (0.1)

    0.0 (0.0)
     Nasal Congestion0.4 (0.1)1.3 (0.1)

    0.0 (0.0)
     Influenza0.3 (0.1)1.1 (0.1)

    0.0 (0.0)
    Skin
     Rash1.3 (0.4)1.6 (0.2)0.5 (0.5)
    Urogenital
     Impotence1.0 (0.4)1.6 (0.5)0.0 (0.0)

    Chest pain and back pain were also seen, but were more common on placebo than lisinopril. 

    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.

    CONTROLLED TRIALS
    Lisinopril
    (n=407)
    Incidence
    (discontinuation)
    12 weeks    		Placebo
    (n=155)
    Incidence
    (discontinuation)
    12 weeks
    Body as a Whole
     Chest Pain 3.4 (0.2) 1.3 (0.0)
     Abdominal Pain 2.2 (0.7) 1.9 (0.0)
    Cardiovascular
     Hypotension 4.4 (1.7) 0.6 (0.6)
    Digestive
     Diarrhea 3.7 (0.5) 1.9 (0.0)
    Nervous/Psychiatric
     Dizziness 11.8 (1.2) 4.5 (1.3)
     Headache 4.4 (0.2) 3.9 (0.0)
    Respiratory
     Upper Respiratory Infection 1.5 (0.0) 1.3 (0.0)
    Skin
     Rash 1.7 (0.5) 0.6 (0.6)

    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.

    In the two-dose ATLAS trial in heart failure patients, withdrawals due to adverse events were not different between the low and high groups, either in total number of discontinuation (17 to 18%) or in rare specific events (< 1%). The following adverse events, mostly related to ACE inhibition, were reported more commonly in the high dose group:

  • * NPN = non-protein nitrogen
    		•
    % of Patients
    Events    		 High Dose
    (N=1568)    		 Low Dose
    (N=1596)
     Dizziness 18.912.1
     Hypotension 10.86.7
     Creatinine increased    9.97.0
     Hyperkalemia 6.43.5
     NPN* increased9.26.5
     Syncope 7.05.1

    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 (see WARNINGS, Anaphylactoid and Possibly Related 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 (see WARNINGS, Hypotension); 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 jaundice) (see WARNINGS, Hepatic Failure), 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, inappropriate antidiuretic hormone secretion.

    Metabolic: Weight loss, dehydration, fluid overload, gout, weight gain.

    Cases of hypoglycemia in diabetic patients on oral antidiabetic agents or insulin have been reported in post-marketing experience (see PRECAUTIONS, Drug Interactions).

    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, nervousness, mood alterations (including depressive symptoms) and hallucinations.

    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: Urticaria, alopecia, herpes zoster, photosensitivity, skin lesions, skin infections, pemphigus, erythema, flushing, diaphoresis, cutaneous pseudolymphoma, psoriasis. Other severe skin reactions have been reported rarely, including toxic epidermal necrolysis and Stevens-Johnson Syndrome; causal relationship has not been established.

    Special Senses: Visual loss, diplopia, blurred vision, tinnitus, photophobia, taste disturbances, olfactory disturbance.

    Urogenital System: Acute renal failure, oliguria, anuria, uremia, progressive azotemia, renal dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), pyelonephritis, dysuria, urinary tract infection, 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.

    Angioedema: Angioedema has been reported in patients receiving lisinopril 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 lisinopril should be discontinued and appropriate therapy instituted immediately (see WARNINGS).

    In rare cases, intestinal angioedema has been reported in post marketing experience.

    Hypotension: In hypertensive patients, hypotension occurred in 1.2% and syncope occurred in 0.1% of patients with an incidence higher in Black than in non-Black patients. Hypotension or syncope was a cause of discontinuation of therapy in 0.5% of hypertensive patients. In patients with heart failure, hypotension occurred in 5.3% and syncope occurred in 1.8% of patients. These adverse experiences were possibly dose‑related (see above data from ATLAS Trial) and caused discontinuation of therapy in 1.8% of these patients in the symptomatic trials. In patients treated with lisinopril for six weeks after acute myocardial infarction, hypotension (systolic blood pressure ≤ 100 mmHg) resulted in discontinuation of therapy in 9.7% of the patients (see WARNINGS).

    Cough: See PRECAUTIONS, Cough.

    Pediatric Patients: No relevant differences between the adverse experience profile for pediatric patients and that previously reported for adult patients were identified.

    Clinical Laboratory Test Findings

    Serum Electrolytes: Hyperkalemia (see PRECAUTIONS), hyponatremia.

    Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 2.0% of patients with essential hypertension treated with lisinopril alone. Increases were more common in patients receiving concomitant diuretics and in patients with renal artery stenosis (see PRECAUTIONS). Reversible minor increases in blood urea nitrogen and serum creatinine were observed in approximately 11.6% of patients with heart failure on concomitant diuretic therapy. Frequently, these abnormalities resolved when the dosage of the diuretic was decreased.

    Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.4 g% and 1.3 vol%, respectively) occurred frequently in patients treated with lisinopril but were rarely of clinical importance in patients without some other cause of anemia. In clinical trials, less than 0.1% of patients discontinued therapy due to anemia. Hemolytic anemia has been reported; a causal relationship to lisinopril cannot be excluded.

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

    In hypertensive patients, 2.0% discontinued therapy due to laboratory adverse experiences, principally elevations in blood urea nitrogen (0.6%), serum creatinine (0.5%) and serum potassium (0.4%).

    In the heart failure trials, 3.4% of patients discontinued therapy due to laboratory adverse experiences; 1.8% due to elevations in blood urea nitrogen and/or creatinine and 0.6% due to elevations in serum potassium.

    In the myocardial infarction trial, 2.0% of patients receiving lisinopril discontinued therapy due to renal dysfunction (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration); less than 1.0% of patients discontinued therapy due to other laboratory adverse experiences: 0.1% with hyperkalemia and less than 0.1% with hepatic enzyme alterations.

  • OVERDOSAGE

    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).

  • DOSAGE AND ADMINISTRATION

    Hypertension

    Initial Therapy:

    In patients with uncomplicated essential hypertension not on diuretic therapy, the recommended initial dose is 10 mg once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range is 20 to 40 mg per day administered in a single daily dose. The antihypertensive effect may diminish toward the end of the dosing interval regardless of the administered dose, but most commonly with a dose of 10 mg daily. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, an increase in dose should be considered. Doses up to 80 mg have been used but do not appear to give greater effect. If blood pressure is not controlled with lisinopril tablet alone, a low dose of a diuretic may be added. Hydrochlorothiazide, 12.5 mg has been shown to provide an additive effect. After the addition of a diuretic, it may be possible to reduce the dose of lisinopril tablet.

    Diuretic Treated Patients:

    In hypertensive patients who are currently being treated with a diuretic, symptomatic hypotension may occur occasionally following the initial dose of lisinopril tablet. The diuretic should be discontinued, if possible, for two to three days before beginning therapy with lisinopril tablet to reduce the likelihood of hypotension (see WARNINGS). The dosage of lisinopril tablet should be adjusted according to blood pressure response. If the patient's blood pressure is not controlled with lisinopril tablet alone, diuretic therapy may be resumed as described above.

    If the diuretic cannot be discontinued, an initial dose of 5 mg should be used under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and PRECAUTIONS, Drug Interactions).

    Concomitant administration of lisinopril tablet with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics may lead to increases of serum potassium (see PRECAUTIONS).

    Dosage Adjustment in Renal Impairment:

    The usual dose of lisinopril tablet (10 mg) is recommended for patients with creatinine clearance > 30 mL/min (serum creatinine of up to approximately 3 mg/dL). For patients with creatinine clearance ≥ 10 mL/min ≤ 30 mL/min (serum creatinine ≥ 3 mg/dL), the first dose is 5 mg once daily. For patients with creatinine clearance < 10 mL/min (usually on hemodialysis) the recommended initial dose is 2.5 mg. The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.

  • *

    See WARNINGS, Anaphylactoid Reactions During Membrane Exposure.

  • † Dosage or dosing interval should be adjusted depending on the blood pressure response.
    		•
    Renal StatusCreatinine Clearance
    mL/min    		Initial Dose
    mg/day
    Normal Renal Function to Mild Impairment> 30

    10
    Moderate to Severe Impairment≥ 10 ≤ 305
    Dialysis Patients*< 102.5†

    Heart Failure

    Lisinopril tablet is indicated as adjunctive therapy with diuretics and (usually) digitalis. The recommended starting dose is 5 mg once a day. When initiating treatment with lisinopril in patients with heart failure, the initial dose should be administered under medical observation, especially in those patients with low blood pressure (systolic blood pressure below 100 mmHg). The mean peak blood pressure lowering occurs six to eight hours after dosing. Observation should continue until blood pressure is stable. The concomitant diuretic dose should be reduced, if possible, to help minimize hypovolemia which may contribute to hypotension (see WARNINGS and PRECAUTIONS, Drug Interactions). The appearance of hypotension after the initial dose of lisinopril tablet does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension.

    The usual effective dosage range is 5 to 40 mg per day administered as a single daily dose. The dose of lisinopril tablet can be increased by increments of no greater than 10 mg, at intervals of no less than 2 weeks to the highest tolerated dose, up to a maximum of 40 mg daily. Dose adjustment should be based on the clinical response of individual patients.

    Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia:

    In patients with heart failure who have hyponatremia (serum sodium < 130 mEq/L) or moderate to severe renal impairment (creatinine clearance ≤ 30 mL/min or serum creatinine > 3 mg/dL), therapy with lisinopril tablet should be initiated at a dose of 2.5 mg once a day under close medical supervision (see WARNINGS and PRECAUTIONS, Drug Interactions).

    Acute Myocardial Infarction

    In hemodynamically stable patients within 24 hours of the onset of symptoms of acute myocardial infarction, the first dose of lisinopril tablet is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg of lisinopril tablet once daily. Dosing should continue for six weeks. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers.

    Patients with a low systolic blood pressure (≤ 120 mmHg) when treatment is started or during the first 3 days after the infarct should be given a lower 2.5 mg oral dose of lisinopril tablet (see WARNINGS). If hypotension occurs (systolic blood pressure ≤ 100 mmHg) a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure < 90 mmHg for more than 1 hour) lisinopril tablet should be withdrawn. For patients who develop symptoms of heart failure, see DOSAGE AND ADMINISTRATION, Heart Failure.

    Dosage Adjustment in Patients With Myocardial Infarction with Renal Impairment:

    In acute myocardial infarction, treatment with lisinopril tablet should be initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. No evaluation of dosing adjustments in myocardial infarction patients with severe renal impairment has been performed.

    Use in Elderly

    In general, the clinical response was similar in younger and older patients given similar doses of lisinopril tablet. Pharmacokinetic studies, however, indicate that maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients, so that dosage adjustments should be made with particular caution.

    Pediatric Hypertensive Patients ≥ 6 years of age

    The usual recommended starting dose is 0.07 mg/kg once daily (up to 5 mg total). Dosage should be adjusted according to blood pressure response. Doses above 0.61 mg/kg (or in excess of 40 mg) have not been studied in pediatric patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism and Pharmacodynamics and Clinical Effects).

    Lisinopril is not recommended in pediatric patients < 6 years or in pediatric patients with glomerular filtration rate < 30 mL/min/1.73 m2  (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism and Pharmacodynamics and Clinical Effects and PRECAUTIONS).

    Preparation of Suspension (for 200 mL of a 1.0 mg/mL suspension):

    Add 10 mL of Purified Water USP to a polyethylene terephthalate (PET) bottle containing ten 20-mg tablets of lisinopril and shake for at least one minute. Add 30 mL of Bicitra®3 diluent and 160 mL of Ora-Sweet SF™4 to the concentrate in the PET bottle and gently shake for several seconds to disperse the ingredients. The suspension should be stored at or below 25ºC (77ºF) and can be stored for up to four weeks. Shake the suspension before each use.

  • 3

    Registered trademark of Alza Corporation

  • 4 Trademark of Paddock Laboratories, Inc.
  • HOW SUPPLIED

    Lisinopril Tablets 2.5 mg are white, oval shaped, convex tablets, debossed “4209” on one side and “V” on the reverse side; and supplied as follows:

    Lisinopril Tablets 5 mg are white, capsule shaped, convex, bisected tablets, debossed “42/10” on one side and “V” on the reverse side; and supplied as follows:

    Lisinopril Tablets 10 mg are white, round, convex tablets, debossed “3972” on one side and “V” on the reverse side; and supplied as follows:

    Lisinopril Tablets 20 mg are white, round, convex tablets, debossed “3973” on one side and “V” on the reverse side; and supplied as follows:

    Lisinopril Tablets 30 mg are white, round, convex tablets, debossed “3974” on one side and “V” on the reverse side; and supplied as follows:

    Lisinopril Tablets 40 mg are white, round, convex tablets, debossed “4214” on one side and “V” on the reverse side; and supplied as follows:

    STORAGE

    Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from moisture, freezing and excessive heat. Dispense in a tight container.

  • SPL UNCLASSIFIED SECTION

    Manufactured for:
    QUALITEST PHARMACEUTICALSHuntsville, AL 35811

    Repackaged By:

    ReadyMeds

    Dothan, AL 36301

    8183032
    Rev 1/14
    R10

  • PRINCIPAL DISPLAY PANEL

    photo 1
  • PRINCIPAL DISPLAY PANEL

    photo 2
  • INGREDIENTS AND APPEARANCE
    LISINOPRIL 
    lisinopril tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 64205-211(NDC: 0603-4211)
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    LISINOPRIL (UNII: E7199S1YWR) (LISINOPRIL ANHYDROUS - UNII:7Q3P4BS2FD) LISINOPRIL10 mg
    Inactive Ingredients
    Ingredient NameStrength
    STARCH, CORN (UNII: O8232NY3SJ)  
    CALCIUM PHOSPHATE, DIBASIC, DIHYDRATE (UNII: O7TSZ97GEP)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    MANNITOL (UNII: 3OWL53L36A)  
    TALC (UNII: 7SEV7J4R1U)  
    Product Characteristics
    ColorWHITEScoreno score
    ShapeROUNDSize6mm
    FlavorImprint Code 3972;V
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 64205-211-3030 in 1 BOTTLE
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA07574307/01/2002
    LISINOPRIL 
    lisinopril tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 64205-212(NDC: 0603-4212)
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    LISINOPRIL (UNII: E7199S1YWR) (LISINOPRIL ANHYDROUS - UNII:7Q3P4BS2FD) LISINOPRIL20 mg
    Inactive Ingredients
    Ingredient NameStrength
    STARCH, CORN (UNII: O8232NY3SJ)  
    CALCIUM PHOSPHATE, DIBASIC, DIHYDRATE (UNII: O7TSZ97GEP)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    MANNITOL (UNII: 3OWL53L36A)  
    TALC (UNII: 7SEV7J4R1U)  
    Product Characteristics
    ColorWHITEScoreno score
    ShapeROUNDSize8mm
    FlavorImprint Code 3973;V
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 64205-212-3030 in 1 BOTTLE
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA07574307/01/2002
    Labeler - ReadyMeds (072115132)
    Establishment
    NameAddressID/FEIBusiness Operations
    ReadyMeds072115132repack(64205-211, 64205-212)
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