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WARNING: FETAL TOXICITY · When pregnancy is detected, discontinue Trandolapril as soon as possible. · Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (See WARNINGS : Fetal Toxicity ).

Hypotension Trandolapril can cause symptomatic hypotension. Like other ACE inhibitors, trandolapril has only rarely been associated with symptomatic hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been salt-or volume-depleted as a result of prolonged treatment with diuretics, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before initiating treatment with trandolapril (see PRECAUTIONS - Drug Interactions and ADVERSE REACTIONS ). In controlled and uncontrolled studies, hypotension was reported as an adverse event in 0.6% of patients and led to discontinuations in 0.1% of patients. In patients with concomitant congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia, and rarely, with acute renal failure and death. In such patients, trandolapril therapy should be started at the recommended dose under close medical supervision. These patients should be followed closely during the first 2 weeks of treatment and, thereafter, whenever the dosage of trandolapril or diuretic is increased (see DOSAGE AND ADMINISTRATION ). Care in avoiding hypotension should also be taken in patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease. If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, normal saline may be administered intravenously. A transient hypotensive response is not a contraindication to further doses; however, lower doses of trandolapril or reduced concomitant diuretic therapy should be considered.

Neutropenia/Agranulocytosis Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Available data from clinical trials of trandolapril are insufficient to show that trandolapril does not cause agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen-vascular disease and/or renal disease should be considered.

Hepatic Failure ACE inhibitors rarely have been associated with a syndrome of cholestatic jaundice, fulminant hepatic necrosis, and death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice 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 trandolapril 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 trandolapril, 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 trandolapril for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS , Pediatric Use ). Doses of 0.8 mg/kg/day (9.4 mg/m 2 /day) in rabbits, 1000 mg/kg/day (7000 mg/m 2 /day) in rats, and 25 mg/kg/day (295 mg/m 2 /day) in cynomolgus monkeys did not produce teratogenic effects. These doses represent 10 and 3 times (rabbits), 1250 and 2564 times (rats), and 312 and 108 times (monkeys) the maximum projected human dose of 4 mg based on body-weight and body-surface-area, respectively assuming a 50 kg woman.

ADVERSE REACTIONS The safety experience in U.S. placebo-controlled trials included 1069 hypertensive patients, of whom 832 received trandolapril. Nearly 200 hypertensive patients received trandolapril for over one year in open-label trials. In controlled trials, withdrawals for adverse events were 2.1% on placebo and 1.4% on trandolapril. Adverse events considered at least possibly related to treatment occurring in 1% of trandolapril-treated patients and more common on trandolapril than placebo, pooled for all doses, are shown below, together with the frequency of discontinuation of treatment because of these events. ADVERSE EVENTS IN PLACEBO-CONTROLLED HYPERTENSIO N TRIALS Occurring at 1% or greater TRANDOLAPRIL (N=832) % Incidence (% Discontinuance) PLACEBO (N=237) % Incidence (% Discontinuance) Cough 1.9 (0.1) 0.4 (0.4) Dizziness 1.3 (0.2) 0.4 (0.4) Diarrhea 1.0 (0.0) 0.4 (0.0) Headache and fatigue were all seen in more than 1% of trandolapril-treated patients but were more frequently seen on placebo. Adverse events were not usually persistent or difficult to manage. Left Ventricular Dysfunction Post Myocardial Infarction Adverse reactions related to trandolapril occurring at a rate greater than that observed in placebo-treated patients with left ventricular dysfunction, are shown below. The incidences represent the experiences from the TRACE study. The follow-up time was between 24 and 50 months for this study. Percentage of Patients with Adverse Events Greater Than Placebo Placebo-Controlled (TRACE) Mortality Study Adverse Event Trandolapril N=876 Placebo N=873 Cough 35 22 Dizziness 23 17 Hypotension 11 6.8 Elevated serum uric acid 15 13 Elevated BUN 9.0 7.6 PICA or CABG 7.3 6.1 Dyspepsia 6.4 6.0 Syncope 5.9 3.3 Hyperkalemia 5.3 2.8 Bradycardia 4.7 4.4 Hypocalcemia 4.7 3.9 Myalgia 4.7 3.1 Elevated creatinine 4.7 2.4 Gastritis 4.2 3.6 Cardiogenic shock 3.8 <2 Intermittent claudication 3.8 <2 Stroke 3.3 3.2 Asthenia 3.3 2.6 Clinical adverse experiences possibly or probably related or of uncertain relationship to therapy occurring in 0.3% to 1.0% (except as noted) of the patients treated with trandolapril (with or without concomitant calcium ion antagonist or diuretic) in controlled or uncontrolled trials (N=1134) and less frequent, clinically significant events seen in clinical trials or post-marketing experience include (listed by body system): General Body Function Chest pain. Cardiovascular AV first degree block, bradycardia, edema, flushing, and palpitations. Central Nervous System Drowsiness, insomnia, paresthesia, vertigo. Dermatologic Pruritus, rash, pemphigus. Eye, Ear, Nose, Throat Epistaxis, throat inflammation, upper respiratory tract infection. Emotional, Mental, Sexual States Anxiety, impotence, decreased libido. Gastrointestinal Abdominal distention, abdominal pain/cramps, constipation, dyspepsia, diarrhea, vomiting, nausea. Hemopoietic Decreased leukocytes, decreased neutrophils. Metabolism and Endocrine Increased liver enzymes including SGPT (ALT). Musculoskeletal System Extremity pain, muscle cramps, gout. Pulmonary Dyspnea. Postmarketing The following adverse reactions were identified during post approval use of trandolapril. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General Body Function Malaise, fever. Cardiovascular Myocardial infarction, myocardial ischemia, angina pectoris, cardiac failure, ventricular tachycardia, tachycardia, transient ischemic attack, arrhythmia. Central Nervous System Cerebral hemorrhage. Dermatologic Alopecia, sweating, Stevens-Johnson syndrome and toxic epidermal necrolysis. Emotional, Mental, Sexual States Hallucination, depression. Gastrointestinal Dry mouth, pancreatitis, jaundice and hepatitis. Hemopoietic Agranulocytosis, pancytopenia. Metabolism and Endocrine Increased SGOT (AST). Pulmonary Bronchitis Renal and Urinary Renal failure. Clinical Laboratory Test Findings Hematology Thrombocytopenia. Serum Electrolytes Hyponatremia. Creatinine and Blood Urea Nitrogen Increases in creatinine levels occurred in 1.1% of patients receiving trandolapril alone and 7.3% of patients treated with trandolapril, a calcium ion antagonist and a diuretic. Increases in blood urea nitrogen levels occurred in 0.6% of patients receiving trandolapril alone and 1.4% of patients receiving trandolapril, a calcium ion antagonist, and a diuretic. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis (see PRECAUTIONS and WARNINGS ). Liver Function Tests Occasional elevation of transaminases at the rate of 3X upper normals occurred in 0.8% of patients and persistent increase in bilirubin occurred in 0.2% of patients. Discontinuation for elevated liver enzymes occurred in 0.2% of patients. Other Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors.

Left Ventricular Dysfunction Post Myocardial Infarction Adverse reactions related to trandolapril occurring at a rate greater than that observed in placebo-treated patients with left ventricular dysfunction, are shown below. The incidences represent the experiences from the TRACE study. The follow-up time was between 24 and 50 months for this study. Percentage of Patients with Adverse Events Greater Than Placebo Placebo-Controlled (TRACE) Mortality Study Adverse Event Trandolapril N=876 Placebo N=873 Cough 35 22 Dizziness 23 17 Hypotension 11 6.8 Elevated serum uric acid 15 13 Elevated BUN 9.0 7.6 PICA or CABG 7.3 6.1 Dyspepsia 6.4 6.0 Syncope 5.9 3.3 Hyperkalemia 5.3 2.8 Bradycardia 4.7 4.4 Hypocalcemia 4.7 3.9 Myalgia 4.7 3.1 Elevated creatinine 4.7 2.4 Gastritis 4.2 3.6 Cardiogenic shock 3.8 <2 Intermittent claudication 3.8 <2 Stroke 3.3 3.2 Asthenia 3.3 2.6 Clinical adverse experiences possibly or probably related or of uncertain relationship to therapy occurring in 0.3% to 1.0% (except as noted) of the patients treated with trandolapril (with or without concomitant calcium ion antagonist or diuretic) in controlled or uncontrolled trials (N=1134) and less frequent, clinically significant events seen in clinical trials or post-marketing experience include (listed by body system): General Body Function Chest pain. Cardiovascular AV first degree block, bradycardia, edema, flushing, and palpitations. Central Nervous System Drowsiness, insomnia, paresthesia, vertigo. Dermatologic Pruritus, rash, pemphigus. Eye, Ear, Nose, Throat Epistaxis, throat inflammation, upper respiratory tract infection. Emotional, Mental, Sexual States Anxiety, impotence, decreased libido. Gastrointestinal Abdominal distention, abdominal pain/cramps, constipation, dyspepsia, diarrhea, vomiting, nausea. Hemopoietic Decreased leukocytes, decreased neutrophils. Metabolism and Endocrine Increased liver enzymes including SGPT (ALT). Musculoskeletal System Extremity pain, muscle cramps, gout. Pulmonary Dyspnea. Postmarketing The following adverse reactions were identified during post approval use of trandolapril. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General Body Function Malaise, fever. Cardiovascular Myocardial infarction, myocardial ischemia, angina pectoris, cardiac failure, ventricular tachycardia, tachycardia, transient ischemic attack, arrhythmia. Central Nervous System Cerebral hemorrhage. Dermatologic Alopecia, sweating, Stevens-Johnson syndrome and toxic epidermal necrolysis. Emotional, Mental, Sexual States Hallucination, depression. Gastrointestinal Dry mouth, pancreatitis, jaundice and hepatitis. Hemopoietic Agranulocytosis, pancytopenia. Metabolism and Endocrine Increased SGOT (AST). Pulmonary Bronchitis Renal and Urinary Renal failure. Clinical Laboratory Test Findings Hematology Thrombocytopenia. Serum Electrolytes Hyponatremia. Creatinine and Blood Urea Nitrogen Increases in creatinine levels occurred in 1.1% of patients receiving trandolapril alone and 7.3% of patients treated with trandolapril, a calcium ion antagonist and a diuretic. Increases in blood urea nitrogen levels occurred in 0.6% of patients receiving trandolapril alone and 1.4% of patients receiving trandolapril, a calcium ion antagonist, and a diuretic. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis (see PRECAUTIONS and WARNINGS ). Liver Function Tests Occasional elevation of transaminases at the rate of 3X upper normals occurred in 0.8% of patients and persistent increase in bilirubin occurred in 0.2% of patients. Discontinuation for elevated liver enzymes occurred in 0.2% of patients. Other Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors.

<table width="622px"> <col/> <col/> <col/> <tbody> <tr> <td align="center" valign="top" colspan="3" styleCode=" Botrule Toprule Lrule Rrule "> <content styleCode="bold">ADVERSE EVENTS IN PLACEBO-CONTROLLED </content> <content styleCode="bold"> HYPERTENSIO</content>N<content styleCode="bold"> TRIALS</content> </td> </tr> <tr> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <content styleCode="bold">Occurring at 1% or greater</content> </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> </td> </tr> <tr> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <content styleCode="bold">TRANDOLAPRIL (N=832) % Incidence (% Discontinuance) </content> </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <content styleCode="bold">PLACEBO (N=237) % Incidence (% Discontinuance) </content> </td> </tr> <tr> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Cough</td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> 1.9 (0.1) </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> 0.4 (0.4) </td> </tr> <tr> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Dizziness</td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> 1.3 (0.2) </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> 0.4 (0.4) </td> </tr> <tr> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Diarrhea</td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> 1.0 (0.0) </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> 0.4 (0.0) </td> </tr> </tbody> </table>

<table width="70%"> <col/> <col/> <col/> <tbody> <tr> <td align="center" colspan="3" styleCode=" Botrule Toprule Lrule Rrule "> <content styleCode="bold">Percentage of Patients with Adverse Events Greater Than Placebo</content> </td> </tr> <tr> <td align="center" colspan="3" styleCode=" Botrule Toprule Lrule Rrule "> <content styleCode="bold">Placebo-Controlled (TRACE) Mortality Study</content> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule "> <content styleCode="bold">Adverse Event</content> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Trandolapril</content> </paragraph> <paragraph> <content styleCode="bold"> <content styleCode="bold">N=876</content> </content> </paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> <paragraph> <content styleCode="bold"> <content styleCode="bold"> N=873</content> </content> </paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">Cough</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 35</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 22</td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">Dizziness</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 23</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 17</td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">Hypotension</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 11</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 6.8</td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">Elevated serum uric acid</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 15</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 13</td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">Elevated BUN </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 9.0</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 7.6</td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">PICA or CABG </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 7.3</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 6.1</td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">Dyspepsia </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 6.4</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 6.0</td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">Syncope </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 5.9</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 3.3</td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">Hyperkalemia </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 5.3</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 2.8</td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">Bradycardia </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 4.7</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 4.4</td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">Hypocalcemia </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 4.7</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 3.9</td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">Myalgia </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 4.7</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 3.1</td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">Elevated creatinine </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 4.7</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 2.4</td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">Gastritis </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 4.2</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 3.6</td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">Cardiogenic shock </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 3.8</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> &lt;2</td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">Intermittent claudication </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 3.8</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> &lt;2</td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">Stroke </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 3.3</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 3.2</td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule ">Asthenia</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 3.3</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 2.6</td> </tr> </tbody> </table>