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, 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 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 a 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.

Symptoms suggestive of angioedema or facial edema occurred in 0.13% of trandolapril-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 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 a 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 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.