Trandolapril 2 mg Tablet, 90-count — NDC 63629-8003-2 (Billing 63629-8003-02)

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 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 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 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 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 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, wi… [Excerpted — this section continues on DailyMed.]

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 greater TRANDOLAPRIL 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 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

6.8Elevated serum uric acid 15 13 Elevated BUN 9.0

7.6PICA or CABG 7.3

6.1Dyspepsia 6.4

6.0Syncope 5.9

3.3Hyperkalemia 5.3

2.8Bradycardia 4.7

4.4Hypocalcemia 4.7

3.9Myalgia 4.7

3.1Elevated creatinine 4.7

2.4Gastritis 4.2

3.6Cardiogenic shock 3.8 < 2 Intermittent claudication 3.8 < 2 Stroke 3.3

3.2Asthenia 3.3

2.6Clinical 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 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 tablets. 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 Agranulocytos… [Excerpted — this section continues on DailyMed.]

Drug Interactions Trandolapril did not affect the plasma concentration (pre-dose and 2 hours post-dose) of oral digoxin (0.25 mg). Coadministration of trandolapril and cimetidine led to an increase of about 44% in C max 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.

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 tablets and other agents that affect the RAS. Do not co-administer aliskiren with trandolapril tablets in patients with diabetes. Avoid use of aliskiren with trandolapril tablets 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 tablets. The possibility of exacerbation of hypotensive effects with trandolapril tablets may be minimized by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with trandolapril tablets. 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 tablets.

Mammalian Target of Rapamycin (mTOR) I… [Excerpted — this section continues on DailyMed.]

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 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 a 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.