FDA label 3fefdb32-c2b6-5cc2-e054-00144ff88e88

USE IN PREGNANCY When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, Lisinopril tablet should be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality .

WARNINGS Anaphylactoid and Possibly Related Reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Lisinopril tablet) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including Lisinopril tablet. This may occur at any time during treatment. ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients. Lisinopril tablet should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway should be promptly provided (See ADVERSE REACTIONS ). Intestinal angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (See also INDICATIONS AND USAGE and CONTRAINDICATIONS ). Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid Reactions During Membrane Exposure: Sudden and potentially life threatening anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes (e.g., AN69 ®* ) and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped immediately, and aggressive therapy for anaphylactoid reactions must be initiated. Symptoms have not been relieved by antihistamines in these situations. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Hypotension Excessive hypotension is rare in patients with uncomplicated hypertension treated with Lisinopril tablet alone. Patients with heart failure given Lisinopril tablet 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 tablet 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 tablet. Treatment with Lisinopril tablet 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 tablet 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 tablet which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of Lisinopril tablet 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 tablet are insufficient to show that Lisinopril tablet 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/Neonatal Morbidity and Mortality ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible. In a published retrospective epidemiological study, infants whose mothers had taken an ACE inhibitor drug during their first trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants whose mothers had not undergone first trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is small and the findings of this study have not yet been repeated. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure. These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of Lisinopril tablet as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, Lisinopril tablet should be discontinued unless it is considered lifesaving for the mother. Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as 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. 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.

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) Body as a 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 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 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.

<table ID="ID62" width="101%"> <caption>PERCENT OF PATIENTS IN CONTROLLED STUDIES</caption> <col width="32%"/> <col width="25%"/> <col width="24%"/> <col width="20%"/> <tbody> <tr> <td align="justify" styleCode=" Botrule Toprule" valign="top"> </td> <td align="center" styleCode=" Botrule Toprule" valign="top">Lisinopril tablet(n=1349)Incidence (discontinuation) </td> <td align="center" styleCode=" Botrule Toprule" valign="top">Lisinopril tablet/ Hydrochlorothiazide (n=629)Incidence (discontinuation) </td> <td align="center" styleCode=" Botrule Toprule" valign="top">PLACEBO(n=207) Incidence (discontinuation) </td> </tr> <tr> <td align="left" styleCode=" Toprule" valign="top"> <content styleCode="bold">Body </content> <content styleCode="bold">as </content> <content styleCode="bold">a </content> <content styleCode="bold">Whole</content> <content styleCode="bold"> </content> </td> <td align="justify" styleCode=" Toprule" valign="top"> </td> <td align="justify" styleCode=" Toprule" valign="top"> </td> <td align="justify" styleCode=" Toprule" valign="top"> </td> </tr> <tr> <td align="left" valign="top">Fatigue <content styleCode="bold"> </content> </td> <td align="center" valign="top">2.5 (0.3) </td> <td align="center" valign="top">4.0 (0.5) </td> <td align="center" valign="top">1.0 (0.0) </td> </tr> <tr> <td align="left" valign="top">Asthenia </td> <td align="center" valign="top">1.3 (0.5) </td> <td align="center" valign="top">2.1 (0.2) </td> <td align="center" valign="top">1.0 (0.0) </td> </tr> <tr> <td align="left" valign="top">Orthostatic Effects </td> <td align="center" valign="top">1.2 (0.0) </td> <td align="center" valign="top">3.5 (0.2) </td> <td align="center" valign="top">1.0 (0.0) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Cardiovascular</content> <content styleCode="bold"> </content> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> </tr> <tr> <td align="left" valign="top">Hypotension <content styleCode="bold"> </content> </td> <td align="center" valign="top">1.2 (0.5) </td> <td align="center" valign="top">1.6 (0.5) </td> <td align="center" valign="top">0.5 (0.5) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Digestive</content> <content styleCode="bold"> </content> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> </tr> <tr> <td align="left" valign="top">Diarrhea <content styleCode="bold"> </content> </td> <td align="center" valign="top">2.7 (0.2) </td> <td align="center" valign="top">2.7 (0.3) </td> <td align="center" valign="top">2.4 (0.0) </td> </tr> <tr> <td align="left" valign="top">Nausea </td> <td align="center" valign="top">2.0 (0.4) </td> <td align="center" valign="top">2.5 (0.2) </td> <td align="center" valign="top">2.4 (0.0) </td> </tr> <tr> <td align="left" valign="top">Vomiting </td> <td align="center" valign="top">1.1 (0.2) </td> <td align="center" valign="top">1.4 (0.1) </td> <td align="center" valign="top">0.5 (0.0) </td> </tr> <tr> <td align="left" valign="top">Dyspepsia </td> <td align="center" valign="top">0.9 (0.0) </td> <td align="center" valign="top">1.9 (0.0) </td> <td align="center" valign="top">0.0 (0.0) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Musculoskeletal</content> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> </tr> <tr> <td align="left" valign="top">Muscle Cramps <content styleCode="bold"> </content> </td> <td align="center" valign="top">0.5 (0.0) </td> <td align="center" valign="top">2.9 (0.8) </td> <td align="center" valign="top">0.5 (0.0) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Nervous</content> <content styleCode="bold">/</content> <content styleCode="bold">Psychiatric</content> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> </tr> <tr> <td align="left" valign="top">Headache <content styleCode="bold"> </content> </td> <td align="center" valign="top">5.7 (0.2) </td> <td align="center" valign="top">4.5 (0.5) </td> <td align="center" valign="top">1.9 (0.0) </td> </tr> <tr> <td align="left" valign="top">Dizziness </td> <td align="center" valign="top">5.4 (0.4) </td> <td align="center" valign="top">9.2 (1.0) </td> <td align="center" valign="top">1.9 (0.0) </td> </tr> <tr> <td align="left" valign="top">Paresthesia </td> <td align="center" valign="top">0.8 (0.1) </td> <td align="center" valign="top">2.1 (0.2) </td> <td align="center" valign="top">0.0 (0.0) </td> </tr> <tr> <td align="left" valign="top">Decreased Libido </td> <td align="center" valign="top">0.4 (0.1) </td> <td align="center" valign="top">1.3 (0.1) </td> <td align="center" valign="top">0.0 (0.0) </td> </tr> <tr> <td align="left" valign="top">Vertigo </td> <td align="center" valign="top">0.2 (0.1) </td> <td align="center" valign="top">1.1 (0.2) </td> <td align="center" valign="top">0.0 (0.0) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Respiratory</content> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> </tr> <tr> <td align="left" valign="top">Cough <content styleCode="bold"> </content> </td> <td align="center" valign="top">3.5 (0.7) </td> <td align="center" valign="top">4.6 (0.8) </td> <td align="center" valign="top">1.0 (0.0) </td> </tr> <tr> <td align="left" valign="top">Upper Respiratory Infection </td> <td align="center" valign="top">2.1 (0.1) </td> <td align="center" valign="top">2.7 (0.1) </td> <td align="center" valign="top">0.0 (0.0) </td> </tr> <tr> <td align="left" valign="top">Common Cold </td> <td align="center" valign="top">1.1 (0.1) </td> <td align="center" valign="top">1.3 (0.1) </td> <td align="center" valign="top">0.0 (0.0) </td> </tr> <tr> <td align="left" valign="top">Nasal Congestion </td> <td align="center" valign="top">0.4 (0.1) </td> <td align="center" valign="top">1.3 (0.1) </td> <td align="center" valign="top">0.0 (0.0) </td> </tr> <tr> <td align="left" valign="top">Influenza </td> <td align="center" valign="top">0.3 (0.1) </td> <td align="center" valign="top">1.1 (0.1) </td> <td align="center" valign="top">0.0 (0.0) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Skin</content> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> </tr> <tr> <td align="left" valign="top">Rash <content styleCode="bold"> </content> </td> <td align="center" valign="top">1.3 (0.4) </td> <td align="center" valign="top">1.6 (0.2) </td> <td align="center" valign="top">0.5 (0.5) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Urogenital</content> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> </tr> <tr> <td align="left" styleCode=" Botrule" valign="top">Impotence <content styleCode="bold"> </content> </td> <td align="center" styleCode=" Botrule" valign="top">1.0 (0.4) </td> <td align="center" styleCode=" Botrule" valign="top">1.6 (0.5) </td> <td align="center" styleCode=" Botrule" valign="top">0.0 (0.0) </td> </tr> </tbody> </table>

<table ID="ID66" width="100%"> <col width="38%"/> <col width="29%"/> <col width="33%"/> <tbody> <tr> <td align="justify" colspan="1" styleCode=" Toprule" valign="top"> </td> <td align="center" colspan="2" styleCode=" Toprule" valign="top">Controlled Trials </td> </tr> <tr> <td align="justify" styleCode=" Botrule" valign="top"> </td> <td align="center" styleCode=" Botrule" valign="top">Lisinopril tablet (n=407) Incidence (discontinuation) 12 weeks </td> <td align="center" styleCode=" Botrule" valign="top">Placebo (n=155) Incidence(discontinuation) 12 weeks </td> </tr> <tr> <td align="justify" styleCode=" Toprule" valign="top"> <content styleCode="bold">Body </content> <content styleCode="bold">as </content> <content styleCode="bold">a </content> <content styleCode="bold">Whole</content> </td> <td align="center" styleCode=" Toprule" valign="top"> </td> <td align="center" styleCode=" Toprule" valign="top"> </td> </tr> <tr> <td align="justify" valign="top">Chest Pain <content styleCode="bold"> </content> </td> <td align="center" valign="top">3.4 (0.2) </td> <td align="center" valign="top">1.3 (0.0) </td> </tr> <tr> <td align="justify" valign="top">Abdominal Pain </td> <td align="center" valign="top">2.2 (0.7) </td> <td align="center" valign="top">1.9 (0.0) </td> </tr> <tr> <td align="justify" valign="top"> <content styleCode="bold">Cardiovascular</content> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> </tr> <tr> <td align="left" valign="top">Hypotension </td> <td align="center" valign="top">4.4 (1.7) </td> <td align="center" valign="top">0.6 (0.6) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Digestive</content> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> </tr> <tr> <td align="left" valign="top">Diarrhea <content styleCode="bold"> </content> </td> <td align="center" valign="top">3.7 (0.5) </td> <td align="center" valign="top">1.9 (0.0) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Nervous</content> <content styleCode="bold">/</content> <content styleCode="bold">Psychiatric</content> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> </tr> <tr> <td align="left" valign="top">Dizziness <content styleCode="bold"> </content> </td> <td align="center" valign="top">11.8 (1.2) </td> <td align="center" valign="top">4.5 (1.3) </td> </tr> <tr> <td align="left" valign="top">Headache </td> <td align="center" valign="top">4.4 (0.2) </td> <td align="center" valign="top">3.9 (0.0) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Respiratory</content> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> </tr> <tr> <td align="left" valign="top">Upper Respiratory Infection <content styleCode="bold"> </content> </td> <td align="center" valign="top">1.5 (0.0) </td> <td align="center" valign="top">1.3 (0.0) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Skin</content> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> </tr> <tr> <td align="left" styleCode=" Botrule" valign="top">Rash </td> <td align="center" styleCode=" Botrule" valign="top">1.7 (0.5) </td> <td align="center" styleCode=" Botrule" valign="top">0.6 (0.6) </td> </tr> </tbody> </table>

<table ID="ID68" width="100%"> <col width="34%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr> <td align="left" colspan="3"> <paragraph styleCode="Footnote"> <content styleCode="bold">*</content>NPN = non-protein nitrogen </paragraph> </td> </tr> </tfoot> <tbody> <tr> <td align="justify" styleCode=" Botrule Toprule" valign="top"> <content styleCode="underline">% </content> <content styleCode="underline">of </content> <content styleCode="underline">patients</content> <content styleCode="underline"> </content> <content styleCode="underline">Events</content> <content styleCode="underline"> </content> </td> <td align="center" styleCode=" Botrule Toprule" valign="top"> <content styleCode="underline">High </content> <content styleCode="underline">Dose</content> <content styleCode="underline"> </content> <content styleCode="underline">(</content> <content styleCode="underline">N</content> <content styleCode="underline">=</content> <content styleCode="underline">1568</content> <content styleCode="underline">)</content> <content styleCode="underline"> </content> </td> <td align="center" styleCode=" Botrule Toprule" valign="top"> <content styleCode="underline">Low </content> <content styleCode="underline">dose </content> <content styleCode="underline"/> <content styleCode="underline">(</content> <content styleCode="underline">N</content> <content styleCode="underline">=</content> <content styleCode="underline">1596</content> <content styleCode="underline">)</content> <content styleCode="underline"> </content> </td> </tr> <tr> <td align="justify" styleCode=" Toprule" valign="top"> </td> <td align="justify" styleCode=" Toprule" valign="top"> </td> <td align="justify" styleCode=" Toprule" valign="top"> </td> </tr> <tr> <td align="justify" valign="top">Dizziness </td> <td align="center" valign="top">18.9 </td> <td align="center" valign="top">12.1 </td> </tr> <tr> <td align="justify" valign="top">Hypotension </td> <td align="center" valign="top">10.8 </td> <td align="center" valign="top">6.7 </td> </tr> <tr> <td align="justify" valign="top">Creatinine increased </td> <td align="center" valign="top">9.9 </td> <td align="center" valign="top">7.0 </td> </tr> <tr> <td align="justify" valign="top">Hyperkalemia </td> <td align="center" valign="top">6.4 </td> <td align="center" valign="top">3.5 </td> </tr> <tr> <td align="justify" valign="top">NPN <content styleCode="bold">* </content>increased </td> <td align="center" valign="top">9.2 </td> <td align="center" valign="top">6.5 </td> </tr> <tr> <td align="justify" styleCode=" Botrule" valign="top">Syncope </td> <td align="center" styleCode=" Botrule" valign="top">7.0 </td> <td align="center" styleCode=" Botrule" valign="top">5.1 </td> </tr> </tbody> </table>