PREGNANCY SECTION.

Pregnancy. Female patients of childbearing age should be told about the consequences of exposure to trandolapril tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. NOTE: As with many other drugs, certain advice to patients being treated with trandolapril tablets are warranted. This information is intended to aid in the safe and effective use of this medication. It is not disclosure of all possible adverse or intended effects.

SPL UNCLASSIFIED SECTION.

When pregnancy is detected, discontinue trandolapril tablets 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) .. When pregnancy is detected, discontinue trandolapril tablets 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).

WARNINGS SECTION.

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 trandolapril tablets, may be subject to variety of adverse reactions, some of them serious.. 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 did not occur when ACE inhibitors were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently readministered. Anaphylactoid Reactions During Membrane Exposure. Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Head and Neck Angioedema. In controlled trials ACE inhibitors (for which adequate data are available) cause higher rate of angioedema in black than in non-black patients. Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors including trandolapril tablets. Symptoms suggestive of angioedema or facial edema occurred in 0.13% of trandolapril tablets-treated patients. Two of the four cases were life-threatening and resolved without treatment or with medication (corticosteroids). Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue or glottis occurs, treatment with trandolapril tablets should be discontinued immediately, the patient treated in accordance with accepted medical care and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, emergency therapy, including but not limited to subcutaneous epinephrine solution 1:1,000 (0.3 to 0.5 mL) should be promptly administered. (See PRECAUTIONS Information for Patients and ADVERSE REACTIONS.) Patients receiving coadministration of an ACE inhibitor with an mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) or neprilysin inhibitor (e.g., sacubitril) may be at increased risk for angioedema.. 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.. Hypotension. Trandolapril can cause symptomatic hypotension. Like other ACE inhibitors, trandolapril tablet 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 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 tablets (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 tablets therapy should be started at the recommended dose under close medical supervision. These patients should be followed closely during the first weeks of treatment and, thereafter, whenever the dosage of trandolapril tablets 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. transient hypotensive response is not contraindication to further doses; however, lower doses of trandolapril tablets 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 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 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 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 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/m2/day) in rabbits, 1000 mg/kg/day (7000 mg/m2/day) in rats, and 25 mg/kg/day (295 mg/m2/day) in cynomolgus monkeys did not produce teratogenic effects. These doses represent 10 and times (rabbits), 1250 and 2564 times (rats), and 312 and 108 times (monkeys) the maximum projected human dose of mg based on body-weight and body-surface-area, respectively assuming 50 kg woman.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Trandolapril tablets USP are supplied as follows:1 mg tablet Pink, round, biconvex, uncoated tablets, debossed with and on either side of the breakline on one side and H01 on the other side. NDC 68180-566-01 bottles of 1002 mg tablet Yellow, round, biconvex, uncoated tablets, debossed with LU on one side and H02 on the other side. NDC 68180-567-01 bottles of 1004 mg tablet Brick red colored, round, biconvex, uncoated tablets, debossed with LU on one side and H03 on the other side. NDC 68180-568-01 bottles of 100Dispense in well-closed container with safety closure.Storage: Store at 20 to 25C (68 to 77F) [See USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Hypertension. Trandolapril tablets are indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive medication such as hydrochlorothiazide.. Heart Failure Post Myocardial Infarction or Left-Ventricular Dysfunction Post Myocardial Infarction. Trandolapril tablets are indicated in stable patients who have evidence of left-ventricular systolic dysfunction (identified by wall motion abnormalities) or who are symptomatic from congestive heart failure within the first few days after sustaining acute myocardial infarction. Administration of trandolapril to Caucasian patients has been shown to decrease the risk of death (principally cardiovascular death) and to decrease the risk of heart failure-related hospitalization (see CLINICAL PHARMACOLOGY -Heart Failure or Left-Ventricular Dysfunction Post Myocardial Infarction for details of the survival trial).

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Hypertension. The recommended initial dosage of trandolapril tablets for patients not receiving diuretic is mg once daily in non-black patients and mg in black patients. Dosage should be adjusted according to the blood pressure response. Generally, dosage adjustments should be made at intervals of at least week. Most patients have required dosages of to mg once daily. There is little clinical experience with doses above mg.Patients inadequately treated with once-daily dosing at mg may be treated with twice-daily dosing. If blood pressure is not adequately controlled with trandolapril tablets monotherapy, diuretic may be added.In patients who are currently being treated with diuretic, symptomatic hypotension occasionally can occur following the initial dose of trandolapril tablets. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning therapy with trandolapril tablets. (see WARNINGS). Then, if blood pressure is not controlled with trandolapril tablets alone, diuretic therapy should be resumed. If the diuretic cannot be discontinued, an initial dose of 0.5 mg trandolapril tablets should be used with careful medical supervision for several hours until blood pressure has stabilized. The dosage should subsequently be titrated (as described above) to the optimal response. (see WARNINGS, PRECAUTIONS, and DRUG INTERACTIONS.) Concomitant administration of trandolapril tablets with potassium supplements, potassium salt substitutes, or potassium sparing diuretics can lead to increases of serum potassium (see PRECAUTIONS.) Heart Failure Post Myocardial Infarction or Left-Ventricular Dysfunction Post Myocardial Infarction. The recommended starting dose is mg, once daily. Following the initial dose, all patients should be titrated (as tolerated) toward target dose of mg, once daily. If 4 mg dose is not tolerated, patients can continue therapy with the greatest tolerated dose.. Dosage Adjustment in Renal Impairment or Hepatic Cirrhosis. For patients with creatinine clearance <30 mL/min. or with hepatic cirrhosis, the recommended starting dose, based on clinical and pharmacokinetic data, is 0.5 mg daily. Patients should subsequently have their dosage titrated (as described above) to the optimal response.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. The safety experience in U.S. placebo-controlled trials included 1069 hypertensive patients, of whom 832 received trandolapril tablets. Nearly 200 hypertensive patients received trandolapril tablets 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 tablets. Adverse events considered at least possibly related to treatment occurring in 1% of trandolapril tablets-treated patients and more common on trandolapril tablets 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 HYPERTENSION TRIALS Occurring at 1% or greaterTRANDOLAPRIL TABLETS(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 tablets-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 tablets occurring at 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 EventTrandolapril N= 876PlaceboN=873Cough 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 tablets (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 FunctionChest pain.CardiovascularAV first degree block, bradycardia, edema, flushing, and palpitations.Central Nervous SystemDrowsiness, insomnia, paresthesia, vertigo.DermatologicPruritus, rash, pemphigus.Eye, Ear, Nose, ThroatEpistaxis, throat inflammation, upper respiratory tract infection.Emotional, Mental, Sexual StatesAnxiety, impotence, decreased libido.GastrointestinalAbdominal distention, abdominal pain/cramps, constipation, dyspepsia, diarrhea, vomiting, nausea.HemopoieticDecreased leukocytes, decreased neutrophils.Metabolism and EndocrineIncreased liver enzymes including SGPT (ALT).Musculoskeletal SystemExtremity pain, muscle cramps, gout.PulmonaryDyspnea.. Postmarketing. The following adverse reactions were identified during post approval use of trandolapril tablets. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 NitrogenIncreases in creatinine levels occurred in 1.1% of patients receiving trandolapril tablets alone and 7.3% of patients treated with trandolapril tablets, calcium ion antagonist and diuretic. Increases in blood urea nitrogen levels occurred in 0.6% of patients receiving trandolapril tablets alone and 1.4% of patients receiving trandolapril tablets, calcium ion antagonist, and 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 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 TestsOccasional 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.

BOXED WARNING SECTION.

WARNING: FETAL TOXICITY. When pregnancy is detected, discontinue trandolapril tablets 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) .. When pregnancy is detected, discontinue trandolapril tablets 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).

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Mechanism of Action. Trandolapril is deesterified to the diacid metabolite, trandolaprilat, which is approximately eight times more active as an inhibitor of ACE activity. ACE is peptidyl dipeptidase that catalyzes the conversion of angiotensin to the vasoconstrictor, angiotensin II. Angiotensin II is potent peripheral vasoconstrictor that also stimulates secretion of aldosterone by the adrenal cortex and provides negative feedback for renin secretion. The effect of trandolapril in hypertension appears to result primarily from the inhibition of circulating and tissue ACE activity thereby reducing angiotensin II formation, decreasing vasoconstriction, decreasing aldosterone secretion, and increasing plasma renin. Decreased aldosterone secretion leads to diuresis, natriuresis, and small increase of serum potassium. In controlled clinical trials, treatment with trandolapril alone resulted in mean increases in potassium of 0.1 mEq/L. (see PRECAUTIONS.) ACE is identical to kininase II, an enzyme that degrades bradykinin, potent peptide vasodilator; whether increased levels of bradykinin play role in the therapeutic effect of trandolapril remains to be elucidated. While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, trandolapril exerts antihypertensive actions even in patients with low-renin hypertension. Trandolapril was an effective antihypertensive in all races studied. Both black patients (usually predominantly low-renin group) and non-black patients responded to to mg of trandolapril.. Pharmacokinetics and Metabolism. Pharmacokinetics. Trandolaprils ACE-inhibiting activity is primarily due to its diacid metabolite, trandolaprilat. Cleavage of the ester group of trandolapril, primarily in the liver, is responsible for conversion. Absolute bioavailability after oral administration of trandolapril is about 10% as trandolapril and 70% as trandolaprilat. After oral trandolapril under fasting conditions, peak trandolapril levels occur at about one hour and peak trandolaprilat levels occur between and 10 hours. The elimination half-life of trandolapril is about hours. At steady state, the effective half-life of trandolaprilat is 22.5 hours. Like all ACE inhibitors, trandolaprilat also has prolonged terminal elimination phase, involving small fraction of administered drug, probably representing binding to plasma and tissue ACE. During multiple dosing of trandolapril, there is no significant accumulation of trandolaprilat. Food slows absorption of trandolapril, but does not affect AUC or Cmax of trandolaprilat or Cmax of trandolapril.. Metabolism and Excretion. After oral administration of trandolapril, about 33% of parent drug and metabolites are recovered in urine, mostly as trandolaprilat, with about 66% in feces. The extent of the absorbed dose which is biliary excreted has not been determined. Plasma concentrations (Cmax and AUC of trandolapril and Cmax of trandolaprilat) are dose proportional over the to mg range, but the AUC of trandolaprilat is somewhat less than dose proportional. In addition to trandolaprilat, at least other metabolites have been found, principally glucuronides or deesterification products.Serum protein binding of trandolapril is about 80%, and is independent of concentration. Binding of trandolaprilat is concentration-dependent, varying from 65% at 1000 ng/mL to 94% at 0.1 ng/mL, indicating saturation of binding with increasing concentration.The volume of distribution of trandolapril is about 18 liters. Total plasma clearances of trandolapril and trandolaprilat after approximately mg IV doses are about 52 liters/hour and liters/hour respectively. Renal clearance of trandolaprilat varies from to liters/hour, depending on dose.. Special Populations. PediatricTrandolapril pharmacokinetics have not been evaluated in patients <18 years of age.Geriatric and GenderTrandolapril pharmacokinetics have been investigated in the elderly (> 65 years) and in both genders. The plasma concentration of trandolapril is increased in elderly hypertensive patients, but the plasma concentration of trandolaprilat and inhibition of ACE activity are similar in elderly and young hypertensive patients. The pharmacokinetics of trandolapril and trandolaprilat and inhibition of ACE activity are similar in male and female elderly hypertensive patients.RacePharmacokinetic differences have not been evaluated in different races. Renal InsufficiencyCompared to normal subjects, the plasma concentrations of trandolapril and trandolaprilat are approximately 2-fold greater and renal clearance is reduced by about 85% in patients with creatinine clearance below 30 mL/min and in patients on hemodialysis. Dosage adjustment is recommended in renally impaired patients. (see DOSAGE AND ADMINISTRATION.) Hepatic InsufficiencyFollowing oral administration in patients with mild to moderate alcoholic cirrhosis, plasma concentrations of trandolapril and trandolaprilat were, respectively, 9-fold and 2-fold greater than in normal subjects, but inhibition of ACE activity was not affected. Lower doses should be considered in patients with hepatic insufficiency (see DOSAGE AND ADMINISTRATION.) Drug Interactions. Trandolapril did not affect the plasma concentration (pre-dose and hours post-dose) of oral digoxin (0.25 mg). Coadministration of trandolapril and cimetidine led to an increase of about 44% in Cmax for trandolapril, but no difference in the pharmacokinetics of trandolaprilat or in ACE inhibition. Coadministration of trandolapril and furosemide led to an increase of about 25% in the renal clearance of trandolaprilat, but no effect was seen on the pharmacokinetics of furosemide or trandolaprilat or on ACE inhibition.. Pharmacodynamics and Clinical Effects. single 2-mg dose of trandolapril produces 70 to 85% inhibition of plasma ACE activity at hours with about 10% decline at 24 hours and about half the effect manifest at days. Maximum ACE inhibition is achieved with plasma trandolaprilat concentration of ng/mL. ACE inhibition is function of trandolaprilat concentration, not trandolapril concentration. The effect of trandolapril on exogenous angiotensin was not measured.. Hypertension. Four placebo-controlled dose response studies were conducted using once-daily oral dosing of trandolapril in doses from 0.25 to 16 mg per day in 827 black and non-black patients with mild to moderate hypertension. The minimal effective once-daily dose was mg in non-black patients and mg in black patients. Further decreases in trough supine diastolic blood pressure were obtained in non-black patients with higher doses, and no further response was seen with doses above mg (up to 16 mg). The antihypertensive effect diminished somewhat at the end of the dosing interval, but trough/peak ratios are well above 50% for all effective doses. There was slightly greater effect on the diastolic pressure, but no difference on systolic pressure with b.i.d. dosing. During chronic therapy, the maximum reduction in blood pressure with any dose is achieved within one week. Following weeks of monotherapy in placebo-controlled trials in patients with mild to moderate hypertension, once-daily doses of to mg lowered supine or standing systolic/diastolic blood pressure 24 hours after dosing by an average to 10/4 to mmHg below placebo responses in non-black patients. Once-daily doses of to mg lowered blood pressure to 6/3 to mmHg in black patients. Trough to peak ratios for effective doses ranged from 0.5 to 0.9. There were no differences in response between men and women, but responses were somewhat greater in patients under 60 than in patients over 60 years old. Abrupt withdrawal of trandolapril has not been associated with rapid increase in blood pressure. Administration of trandolapril to patients with mild to moderate hypertension results in reduction of supine, sitting and standing blood pressure to about the same extent without compensatory tachycardia.Symptomatic hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted (see WARNINGS). Use of trandolapril in combination with thiazide diuretics gives blood pressure lowering effect greater than that seen with either agent alone, and the additional effect of trandolapril is similar to the effect of monotherapy.. Heart Failure Post Myocardial Infarction or Left Ventricular Dysfunction Post Myocardial Infarction. The Trandolapril Cardiac Evaluation (TRACE) Trial was Danish, 27-center, double-blind, placebo controlled, parallel-group study of the effect of trandolapril on all-cause mortality in stable patients with echocardiographic evidence of left ventricular dysfunction to days after myocardial infarction. Subjects with residual ischemia or overt heart failure were included. Patients tolerant of test dose of mg trandolapril were randomized to placebo (n=873) or trandolapril (n=876) and followed for 24 months. Among patients randomized to trandolapril, who began treatment on mg, 62% were successfully titrated to target dose of mg once daily over period of weeks. The use of trandolapril was associated with 16% reduction in the risk of all-cause mortality (p=0.042), largely cardiovascular mortality. Trandolapril was also associated with 20% reduction in the risk of progression of heart failure (p=0.047), defined by time-to-first-event analysis of death attributed to heart failure, hospitalization for heart failure, or requirement for open-label ACE inhibitor for the treatment of heart failure. There was no significant effect of treatment on other end-points: subsequent hospitalization, incidence of recurrent myocardial infarction, exercise tolerance, ventricular function, ventricular dimensions, or NYHA class. The population in TRACE was entirely Caucasian and had less usage than would be typical in U.S. population of other post-infarction interventions: 42% thrombolysis, 16% beta-adrenergic blockade, and 6.7% PTCA or CABG during the entire period of follow-up. Blood pressure control, especially in the placebo group, was poor: 47 to 53% of patients randomized to placebo and 32 to 40% of patients randomized to trandolapril had blood pressures 140/95 at 90-day follow-up visits.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Trandolapril tablets are contraindicated in patients who are hypersensitive to this product, in patients with hereditary/idiopathic angioedema and in patients with history of angioedema related to previous treatment with an ACE inhibitor.Do not co-administer aliskiren with trandolapril tablets in patients with diabetes (see PRECAUTIONS, Drug Interactions). Trandolapril tablets are contraindicated in combination with neprilysin inhibitor (e.g., sacubitril). Do not administer trandolapril tablets within 36 hours of switching to or from sacubitril/valsartan, neprilysin inhibitor (see WARNINGS).

DESCRIPTION SECTION.

DESCRIPTION. Trandolapril is the ethyl ester prodrug of nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor, trandolaprilat. Trandolapril is chemically described as (2S,3aR,7aS)-1-[(S)-N-[(S)-1-Carboxy-3-phenylpropyl] alanyl] hexahydro-2-indolinecarboxylic acid, 1-ethyl ester. Its empirical formula is C24H34N2O5 and its structural formula isImageM.W.=430.54Melting Point=125CTrandolapril is white or almost white powder that is soluble (>100 mg/mL) in chloroform, dichloromethane, and methanol. Trandolapril tablets USP contain mg, mg, or mg of trandolapril for oral administration. Each tablet also contains croscarmellose sodium, hypromellose, lactose monohydrate, povidone, starch (corn starch), sodium stearyl fumarate, red iron oxide or yellow iron oxide.. image.

DRUG INTERACTIONS SECTION.

Drug Interactions. Trandolapril did not affect the plasma concentration (pre-dose and hours post-dose) of oral digoxin (0.25 mg). Coadministration of trandolapril and cimetidine led to an increase of about 44% in Cmax for trandolapril, but no difference in the pharmacokinetics of trandolaprilat or in ACE inhibition. Coadministration of trandolapril and furosemide led to an increase of about 25% in the renal clearance of trandolaprilat, but no effect was seen on the pharmacokinetics of furosemide or trandolaprilat or on ACE inhibition.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. Angioedema. Angioedema, including laryngeal edema, may occur at any time during treatment with ACE inhibitors, including trandolapril tablets. 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 stop taking the drug until they have consulted with their physician (see WARNINGS and ADVERSE REACTIONS.) Symptomatic Hypotension. Patients should be cautioned that light-headedness can occur, especially during the first days of trandolapril tablets therapy, and should be reported to physician. If actual syncope occurs, patients should be told to stop taking the drug until they have consulted with their physician (see WARNINGS.) All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting, resulting in reduced fluid volume, may precipitate an excessive fall in blood pressure with the same consequences of light-headedness and possible syncope.Patients planning to undergo any surgery and/or anesthesia should be told to inform their physician that they are taking an ACE inhibitor that has long duration of action.. Hyperkalemia. Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting their physician (see PRECAUTIONS.) Neutropenia. Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which could be sign of neutropenia.. Pregnancy. Female patients of childbearing age should be told about the consequences of exposure to trandolapril tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. NOTE: As with many other drugs, certain advice to patients being treated with trandolapril tablets are warranted. This information is intended to aid in the safe and effective use of this medication. It is not disclosure of all possible adverse or intended effects.

MECHANISM OF ACTION SECTION.

Mechanism of Action. Trandolapril is deesterified to the diacid metabolite, trandolaprilat, which is approximately eight times more active as an inhibitor of ACE activity. ACE is peptidyl dipeptidase that catalyzes the conversion of angiotensin to the vasoconstrictor, angiotensin II. Angiotensin II is potent peripheral vasoconstrictor that also stimulates secretion of aldosterone by the adrenal cortex and provides negative feedback for renin secretion. The effect of trandolapril in hypertension appears to result primarily from the inhibition of circulating and tissue ACE activity thereby reducing angiotensin II formation, decreasing vasoconstriction, decreasing aldosterone secretion, and increasing plasma renin. Decreased aldosterone secretion leads to diuresis, natriuresis, and small increase of serum potassium. In controlled clinical trials, treatment with trandolapril alone resulted in mean increases in potassium of 0.1 mEq/L. (see PRECAUTIONS.) ACE is identical to kininase II, an enzyme that degrades bradykinin, potent peptide vasodilator; whether increased levels of bradykinin play role in the therapeutic effect of trandolapril remains to be elucidated. While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, trandolapril exerts antihypertensive actions even in patients with low-renin hypertension. Trandolapril was an effective antihypertensive in all races studied. Both black patients (usually predominantly low-renin group) and non-black patients responded to to mg of trandolapril.

OVERDOSAGE SECTION.

OVERDOSAGE. No data are available with respect to overdosage in humans. The oral LD50 of trandolapril in mice was 4875 mg/Kg in males and 3990 mg/Kg in females. In rats, an oral dose of 5000 mg/Kg caused low mortality (1 male out of 5; females). In dogs, an oral dose of 1000 mg/Kg did not cause mortality and abnormal clinical signs were not observed. In humans, the most likely clinical manifestation would be symptoms attributable to severe hypotension. Symptoms also expected with ACE inhibitors are hypotension, hyperkalemia, and renal failure.Laboratory determinations of serum levels of trandolapril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of trandolapril overdose. No data are available to suggest that physiological maneuvers (e.g., maneuvers to change the pH of the urine) might accelerate elimination of trandolapril and its metabolites. Trandolaprilat is removed by hemodialysis. Angiotensin II could presumably serve as specific antagonist antidote in the setting of trandolapril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of trandolapril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat trandolapril overdose by infusion of normal saline solution.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. Trandolapril Tablets USPRx Only1 mgNDC 68180-566-01Bottle Label 100 TabletsTrandolapril Tablets USPRx Only2 mgNDC 68180-567-01Bottle Label 100 TabletsTrandolapril Tablets USPRx Only4 mgNDC 68180-568-01Bottle Label 100 Tablets. image1. image2. image3.

PHARMACOKINETICS SECTION.

Pharmacokinetics. Trandolaprils ACE-inhibiting activity is primarily due to its diacid metabolite, trandolaprilat. Cleavage of the ester group of trandolapril, primarily in the liver, is responsible for conversion. Absolute bioavailability after oral administration of trandolapril is about 10% as trandolapril and 70% as trandolaprilat. After oral trandolapril under fasting conditions, peak trandolapril levels occur at about one hour and peak trandolaprilat levels occur between and 10 hours. The elimination half-life of trandolapril is about hours. At steady state, the effective half-life of trandolaprilat is 22.5 hours. Like all ACE inhibitors, trandolaprilat also has prolonged terminal elimination phase, involving small fraction of administered drug, probably representing binding to plasma and tissue ACE. During multiple dosing of trandolapril, there is no significant accumulation of trandolaprilat. Food slows absorption of trandolapril, but does not affect AUC or Cmax of trandolaprilat or Cmax of trandolapril.

PRECAUTIONS SECTION.

PRECAUTIONS. General. Impaired Renal Function. As consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including trandolapril, 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 have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when ACE inhibitors have been given concomitantly with diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction and/or discontinuation of any diuretic and/or the ACE inhibitor may be required. Evaluation of hypertensive patients should always include assessment of renal function (see DOSAGE AND ADMINISTRATION.) Hyperkalemia and Potassium-sparing Diuretics. In clinical trials, hyperkalemia (serum potassium 6 mEq/L) occurred in approximately 0.4% of hypertensive patients receiving trandolapril tablets. In most cases, elevated serum potassium levels were isolated values, which resolved despite continued therapy. None of these patients were discontinued from the trials because of hyperkalemia. 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, which should be used cautiously, if at all, with trandolapril tablets (see PRECAUTIONS Drug Interactions.) Cough. Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor induced cough should be considered in the differential diagnosis of cough. In controlled trials of trandolapril, cough was present in 2% of trandolapril patients and 0% of patients given placebo. There was no evidence of relationship to dose.. Surgery/Anesthesia. In patients undergoing major surgery or during anesthesia with agents that produce hypotension, trandolapril tablets will 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.