Drug Label
Uses
INDICATIONS & USAGE Hypertension Lisinopril tablets USP are 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. 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 ProgramJoint 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. Lisinopril tablets USP may be administered alone or with other antihypertensive agents Heart Failure Lisinopril tablets USP are indicated as adjunctive therapy in the management of heart failure in patients who are not responding adequately to diuretics and digitalis. Acute Myocardial Infarction Lisinopril tablets USP are indicated for the treatment of hemodynamically stable patients within 24 hours of acute myocardial infarction, to improve survival. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers. In using lisinopril tablets USP, consideration should be given to the fact that another 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 tablets USP do not have a similar risk (see WARNINGS). In considering the use of lisinopril tablets USP, it should be noted that in controlled clinical trials, ACE inhibitors have an effect on blood pressure that is less in Black patients than in non-Blacks. In addition, ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients (see WARNINGS, Anaphylactoid and Possibly Related Reactions).
Dosage & Administration
DOSAGE & 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 tablets USP 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 tablets USP. 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 tablets USP. The diuretic should be discontinued, if possible, for two to three days before beginning therapy with lisinopril tablets USP to reduce the likelihood of hypotension (see WARNINGS). The dosage of lisinopril tablets USP should be adjusted according to blood pressure response. If the patientblood pressure is not controlled with lisinopril tablets USP 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 WARNINGSand PRECAUTIONS, Drug Interactions). Concomitant administration of lisinopril tablets USP 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 tablets USP (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 clearance10 mL/min30 mL/min (serum creatinine3 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 ReactionsDuring Membrane Exposure. **Dosage or dosing interval should be adjusted depending on the blood pressure response.Renal StatusCreatinine Clearance mL/minInitial Dose mg/dayNormal renal function to mild impairment> 3010Moderate to severe impairment10305Dialysis patients* * < 102.5 ** Heart Failure Lisinopril tablets USP are indicated as adjunctive therapy with diuretics and (usually) digitalis. The recommended starting dose is 5 mg once a day. When initiating treatment with lisinopril, USP 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 WARNINGSand PRECAUTIONS, Drug Interactions). The appearance of hypotension after the initial dose of lisinopril tablets USP 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 tablets USP 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 clearance30 mL/min or serum creatinine > 3 mg/dL), therapy with lisinopril tablets USP should be initiated at a dose of 2.5 mg once a day under close medical supervision (see WARNINGSand 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 tablets USP is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg of lisinopril tablets USP 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 tablets USP (see WARNINGS). If hypotension occurs (systolic blood pressure100 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 tablets USP 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 tablets USP 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 tablets USP. 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 Patients6 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, PharmacokineticsandMetabolism and Pharmacodynamics and Clinical Effects). Lisinopril tablets USP are 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 mg/mL Suspension) Add 10 mL of Purified Water USP to a polyethylene terephthalate (PET) bottle containing ten 20 mg tablets of lisinopril tablets USP and shake for at least one minute. Add 30 mL of Bicitradiluent and 160 mL of Ora-Sweet SFto the concentrate in the PET bottle and gently shake for several seconds to disperse the ingredients. The suspension should be stored at or below 25(77and can be stored for up to four weeks. Shake the suspension before each use.
Warnings
WARNINGS
Side Effects
ADVERSE REACTIONS Lisinopril has been found to be generally well tolerated in controlled clinical trials involving 1,969 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 (0.5)1 (0)Asthenia1.3 (0.5)2.1 (0.2)1 (0)Orthostatic effects1.2 (0)3.5 (0.2)1 (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)Nausea2 (0.4)2.5 (0.2)2.4 (0)Vomiting1.1 (0.2)1.4 (0.1)0.5 (0)Dyspepsia0.9 (0)1.9 (0)0 (0) Musculoskeletal Muscle cramps0.5 (0)2.9 (0.8)0.5 (0) Nervous/Psychiatric Headache5.7 (0.2)4.5 (0.5)1.9 (0)Dizziness5.4 (0.4)9.2 (1)1.9 (0)Paresthesia0.8 (0.1)2.1 (0.2)0 (0)Decreased libido0.4 (0.1)1.3 (0.1)0 (0)Vertigo0.2 (0.1)1.1 (0.2)0 (0) Respiratory Cough3.5 (0.7)4.6 (0.8)1 (0)Upper respiratoryinfection2.1 (0.1)2.7 (0.1)0 (0)Common cold1.1 (0.1)1.3 (0.1)0 (0)Nasal congestion0.4 (0.1)1.3 (0.1)0 (0)Influenza0.3 (0.1)1.1 (0.1)0 (0) Skin Rash1.3 (0.4)1.6 (0.2)0.5 (0.5) Urogenital Impotence1 (0.4)1.6 (0.5)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% 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 pain3.4 (0.2)1.3 (0)Abdominal pain2.2 (0.7)1.9 (0) Cardiovascular Hypotension4.4 (1.7)0.6 (0.6) Digestive Diarrhea3.7 (0.5)1.9 (0) Nervous/Psychiatric Dizziness11.8 (1.2)4.5 (1.3)Headache4.4 (0.2)3.9 (0) Respiratory Upper respiratoryInfection1.5 (0)1.3 (0) Skin Rash1.7 (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 Hypotension Creatinine increased Hyperkalemia NPN* *increased Syncope18.9 10.8 9.9 6.4 9.2 712.1 6.7 7 3.5 6.5 5.1 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%), 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% 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 embolsim and infarction, arrhythmias (including ventricular tachycardia, atrial tachycardia, atrial fibillation, 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 antidiurectic 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 postmarketing 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 and mood alterations (including depressive symptoms). 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, flusing, diaphoresis, cutaneous pseudolymphoma, psoriasis. Other severe skin reactions have been reported rarely, including toxic epidermal necrolysis and Stevens-Johnson syndrome; causual 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 PRECAUTIONSand 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 postmarketing 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 pressure100 mmHg) resulted in discontinuation of therapy in 9.7% of the patients (see WARNINGS). Cough 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 p> Creatinine, Blood Urea Nitrogen Minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 2% 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) occured 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 casual 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% 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 faulure trials, 3.4% of patiens discontinued therapy due to laboratory adverse experience; 1.8% due to elevations in blood ura nitrogen and/or creatinine and 0.6 due to elevations in serum potassium. In the myocardial infarction trial, 2% of patients receiving lisinopril discontinued thereapy 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% of patients discontinued therapy due to other laboratory adverse experiences: 0.1% with hyperkalemia and less than 0.1% with hepatic enzyme alterations.
Contraindications
CONTRAINDICATIONS Lisinopril tablets are contraindicated in patients who are hypersensitive to 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.
Overdose
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, AnaphylactoidReactions During Membrane Exposure).