ADVERSE REACTIONS

Lisinopril tablet 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 tablet, 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 tablet or Lisinopril tablet plus hydrochlorothiazide in controlled clinical trials, and more frequently with Lisinopril tablet and/or Lisinopril tablet plus hydrochlorothiazide than placebo, comparative incidence data are listed in the table below:

PERCENT OF PATIENTS IN CONTROLLED STUDIES

	Lisinopril tablet(n=1349)Incidence (discontinuation)	Lisinopril tablet/ Hydrochlorothiazide (n=629)Incidence (discontinuation)	PLACEBO(n=207) Incidence (discontinuation)
Bodyasa**Whole**
Fatigue****	2.5 (0.3)	4.0 (0.5)	1.0 (0.0)
Asthenia	1.3 (0.5)	2.1 (0.2)	1.0 (0.0)
Orthostatic Effects	1.2 (0.0)	3.5 (0.2)	1.0 (0.0)
Cardiovascular****
Hypotension****	1.2 (0.5)	1.6 (0.5)	0.5 (0.5)
Digestive****
Diarrhea****	2.7 (0.2)	2.7 (0.3)	2.4 (0.0)
Nausea	2.0 (0.4)	2.5 (0.2)	2.4 (0.0)
Vomiting	1.1 (0.2)	1.4 (0.1)	0.5 (0.0)
Dyspepsia	0.9 (0.0)	1.9 (0.0)	0.0 (0.0)
Musculoskeletal
Muscle Cramps****	0.5 (0.0)	2.9 (0.8)	0.5 (0.0)
Nervous**/**Psychiatric
Headache****	5.7 (0.2)	4.5 (0.5)	1.9 (0.0)
Dizziness	5.4 (0.4)	9.2 (1.0)	1.9 (0.0)
Paresthesia	0.8 (0.1)	2.1 (0.2)	0.0 (0.0)
Decreased Libido	0.4 (0.1)	1.3 (0.1)	0.0 (0.0)
Vertigo	0.2 (0.1)	1.1 (0.2)	0.0 (0.0)
Respiratory
Cough****	3.5 (0.7)	4.6 (0.8)	1.0 (0.0)
Upper Respiratory Infection	2.1 (0.1)	2.7 (0.1)	0.0 (0.0)
Common Cold	1.1 (0.1)	1.3 (0.1)	0.0 (0.0)
Nasal Congestion	0.4 (0.1)	1.3 (0.1)	0.0 (0.0)
Influenza	0.3 (0.1)	1.1 (0.1)	0.0 (0.0)
Skin
Rash****	1.3 (0.4)	1.6 (0.2)	0.5 (0.5)
Urogenital
Impotence****	1.0 (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 tablet.

Heart Failure

In patients with heart failure treated with Lisinopril tablet 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 tablet 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 tablet or placebo for up to 12 weeks in controlled clinical trials, and more frequently on Lisinopril tablet than placebo.

	Controlled Trials
	Lisinopril tablet (n=407) Incidence (discontinuation) 12 weeks	Placebo (n=155) Incidence(discontinuation) 12 weeks
Bodyasa****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 tablet but more frequent or as frequent on placebo than Lisinopril tablet 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 tablet.

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 (17-18%) 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	18.9	12.1
Hypotension	10.8	6.7
Creatinine increased	9.9	7.0
Hyperkalemia	6.4	3.5
NPN*****increased	9.2	6.5
Syncope	7.0	5.1

Acute Myocardial Infarction

In the GISSI-3 trial, in patients treated with Lisinopril tablet for six weeks following acute myocardial infarction, discontinuation of therapy occurred in 17.6% of patients.

Patients treated with Lisinopril tablet had a significantly higher incidence of hypotension and renal dysfunction compared with patients not taking Lisinopril tablet.

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 tablet, 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 tablet 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.

**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 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, flushing, diaphoresis, cutaneous pseudolymphoma. 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.

**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 tablet (0.1%) 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 tablet 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 tablet 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).

**Fetal/Neonatal Morbidity and Mortality:**See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

**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 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 tablet 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 tablet 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 tablet 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.

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 tablet, 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 tablet 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 tablet 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 tablet may be required.

Patients with acute myocardial infarction in the GISSI-3 trial treated with Lisinopril tablet 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 tablet 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 tablet (serum creatinine concentration exceeding 3 mg/dL or a doubling from the pre- treatment value) then the physician should consider withdrawal of Lisinopril tablet.

Evaluation of patients with hypertension, heart failure, or myocardial infarction should always include assessment of renal function (SeeDOSAGE 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 tablet should be used cautiously, if at all, with these agents and with frequent monitoring of serum potassium (See 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 tablet 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 tablet. 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 ACE inhibitors during pregnancy. These 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 tablet 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 tablet. The possibility of hypotensive effects with Lisinopril tablet can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Lisinopril tablet. If it is necessary to continue the diuretic, initiate therapy with Lisinopril tablet 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 tablet, 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:**In some patients with comprised renal function who are being treated with non-steroidal anti-inflammatory drugs, the co-administration of lisinopril may result in further deterioration of renal function. These effects are usually reversible. In a study in 36 patients with mild to moderate hypertension where the antihypertensive effects of Lisinopril tablet alone were compared to Lisinopril tablet given concomitantly with indomethacin, the use of indomethacin was associated with a reduced effect, although the difference between the two regimens was not significant.

**Other Agents:**Lisinopril tablet 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 tablet was used concomitantly with propranolol or hydrochlorothiazide. The presence of food in the stomach does not alter the bioavailability of Lisinopril tablet.

**Agents Increasing Serum Potassium:**Lisinopril tablet attenuates potassium loss caused by thiazide-type diuretics. Use of Lisinopril tablet with potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride, eplerenone), 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 tablet.

**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 tablet 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 timesthe 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 timesthe maximum recommended daily human dose). This dose was 6.8 times the maximum human dose based on body surface area in mice.

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

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.

Pregnancy

**Pregnancy Categories C (first trimester) and D (second and third trimesters).**See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

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 tablet, taking into account the importance of the drug to the mother.

Pediatric Use

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

There are no data on the effect of Lisinopril tablet on blood pressure in pediatric patients under the 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 tablet 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 tablet 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 tablet 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).