FDA label 19d489f2-c12c-4d59-bda3-9895de2787fe

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, Trandolapril Tablets 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 Trandolapril Tablets, may be subject to a 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 temporaaarily withheld, but they reappeared when the ACE inhibitors were inadvertently readministered. Amaphylactoid 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 liporprotein apheresis with dextran sulfate absorption. Head and Neck Angioedema 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 Tablet-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 andioedema 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 disppears. In instances where swelling is confiined 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 .) 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 Tablets can cause symptomatic hypotension. Like other ACE inhibitors, Trandolapril Tablets 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 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 2 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. A transient hypotensive response is not a 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 uncomlicated 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 syndrome of cholestatic jaundice, fulminant heptatic 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/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. 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. The 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 trandolapril as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, trandolapril should be discontinued unless it is considered life saving for the mother. Contraction stress testing (CST), a non-stress 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 transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. 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, respectively assuming a 50 kg woman.

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 a 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 temporaaarily withheld, but they reappeared when the ACE inhibitors were inadvertently readministered. Amaphylactoid 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 liporprotein apheresis with dextran sulfate absorption.

Head and Neck Angioedema 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 Tablet-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 andioedema 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 disppears. In instances where swelling is confiined 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 .)

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.

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 Tablet-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 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 Tablet-treated patients but were more frequently seen on placebo. Adverse events were not usually persistent or difficult to manage. Left Ventricular Dysfunction Post Mycardial Infarction Adverse reactions related toTrandolapril Tablets 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 Trandolapril Placebo Adverse Event N=876 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 and 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 Funtion: chest pain, malaise, fever. Cardiovascular: AV first degree block, bradycardia, edema, flushing, hypotension, palpitations. Central Nervous System: drowsiness, insomnia, paresthesia, vertigo Dermatologic: pruritus, rash, pemphigus, alopecia, sweating. 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, dry mouth, pancreatitis. Hemopoietic: agranulocytosis, decreased leukocytes, decreased neutrophils. Metabolism and Endocrine: increased creatinine, increased potassium, increased liver enzymes including SGPT (ALT) and increased SGOT (AST). Musculoskeletal System: extremity pain, muscle cramps, gout. Pulmonary: dyspnea, bronchitis. Angioedema: Angioedema has been reported in 4 (0.13%) patients receiving Trandolapril Tablets in U.S. and foreign studies. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis, and/or larynx occurs, treatment with Trandolapril Tablets should be discontinued and appropriate therapy instituted immediately. (See WARNINGS .) Hypotension: In hypertensive patients, symptomatic hypotension occurred in 0.6% and near syncope occurred in 0.2%. Hypotension or syncope was a cause for discontinuation of therapy in 0.1% of hypertensive patients. Fetal/Neonatal Morbidity and Mortality: (See Warnings, Fetal Neonatal Morbidity and Mortality .) Cough: (See PRECAUTIONS, Cough .) Clinical Laboratory Test Findings Hematology: (See WARNINGS .) Low white blood cells, low neutrophils, low lymphocytes, thrombocytopenia. Serum Electrolytes: Hyperkalemia (See PRECAUTIONS .) hyponatremia. Creatinine and Blood Urea Nitrogen: Increases in creatinine levels occurred in 1.1% of patients receiving Trandolapril Tablets alone and 7.3% of patients treated with Trandolapril Tablets, a calcium ion antagonist and a 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, 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 Mycardial Infarction Adverse reactions related toTrandolapril Tablets 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 Trandolapril Placebo Adverse Event N=876 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 and 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 Funtion: chest pain, malaise, fever.

Cardiovascular: AV first degree block, bradycardia, edema, flushing, hypotension, palpitations.