PRECAUTIONS General Impaired Renal Function As a 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 a 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. 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. (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 a relationship to dose. Surgery/Anesthesia In patients undergoing major surgery or during anesthesia with agents that produce hypotension, trandolapril 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. Information for Patients Angioedema Angioedema, including laryngeal edema, may occur at any time during treatment with ACE inhibitors, including trandolapril. 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 therapy, and should be reported to a 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 a 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 a sign of neutropenia. Pregnancy Female patients of childbearing age should be told about the consequences of exposure to trandolapril 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 is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. Drug Interactions Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on trandolapril and other agents that affect the RAS. Do not co-administer aliskiren with trandolapril in patients with diabetes. Avoid use of aliskiren with trandolapril in patients with renal impairment (GFR <60 mL/min). Concomitant Diuretic Therapy As with other ACE inhibitors, patients on diuretics, especially those on recently instituted diuretic therapy, may experience an excessive reduction of blood pressure after initiation of therapy with trandolapril. The possibility of exacerbation of hypotensive effects with trandolapril may be minimized by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with trandolapril. If it is not possible to discontinue the diuretic, the starting dose of trandolapril should be reduced. (See DOSAGE AND ADMINISTRATION .) Agents Increasing Serum Potassium Trandolapril can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. Use of potassium-sparing diuretics (spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes concomitantly with ACE inhibitors can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be used with caution and with appropriate monitoring of serum potassium. (See PRECAUTIONS .) Antidiabetic Agents Concomitant use of ACE inhibitors and antidiabetic medicines (insulin or oral hypoglycemic agents) may cause an increased blood glucose lowering effect with greater risk of hypoglycemia. Lithium Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including trandolapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving trandolapril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including trandolapril may be attenuated by NSAIDs. Gold Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including trandolapril. Mammalian Target of Rapamycin (mTOR) Inhibitors Patients taking concomitant mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see Warnings – Head and Neck Angioedema). Neprilysin Inhibitor Patients taking concomitant neprilysin inhibitors (e.g., sacubitril) may be at increased risk for angioedema (see WARNINGS ). Other No clinically significant pharmacokinetic interaction has been found between trandolaprilat and food, cimetidine, digoxin, or furosemide. The anticoagulant effect of warfarin was not significantly changed by trandolapril. The hypotensive effect of certain inhalation anesthetics may be enhanced by ACE inhibitors including trandolapril. (See PRECAUTIONS-Surgery/Anesthesia .) Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies were conducted with oral trandolapril administered by gavage to mice (78 weeks) and rats (104 and 106 weeks). No evidence of carcinogenic potential was seen in mice dosed up to 25 mg/kg/day (85 mg/m2/day) or rats dosed up to 8 mg/kg/day (60 mg/m2/day). These doses are 313 and 32 times (mice), and 100 and 23 times (rats) the maximum recommended human daily dose (MRHDD) of 4 mg based on body-weight and body-surface-area, respectively assuming a 50 kg individual. The genotoxic potential of trandolapril was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, and the micronucleus test in mice. There was no evidence of mutagenic or clastogenic potential in these in vitro and in vivo assays. Reproduction studies in rats did not show any impairment of fertility at doses up to 100 mg/kg/day (710 mg/m2/day) of trandolapril, or 1250 and 260 times the MRHDD on the basis of body-weight and body-surface-area, respectively. Nursing Mothers Radiolabeled trandolapril or its metabolites are secreted in rat milk. Trandolapril should not be administered to nursing mothers. Geriatric Use In placebo-controlled studies of trandolapril, 31.1% of patients were 60 years and older, 20.1% were 65 years and older, and 2.3% were 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients. (Greater sensitivity of some older individual patients cannot be ruled out.) Pediatric Use Neonates with a history of in utero exposure to trandolapril If oliguria or hypotension occurs, direct attention 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. The safety and effectiveness of trandolapril in pediatric patients have not been established.