Trandolapril

INDICATIONS AND USAGE Hypertension Trandolapril tablets USP are indicated for the treatment of hypertension. They 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 USP 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).

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 a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. Angiotensin II is a 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 a 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, a potent peptide vasodilator; whether increased levels of bradykinin play a 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 a predominantly low-renin group) and non-black patients responded to 2 to 4 mg of trandolapril. Pharmacokinetics and Metabolism Pharmacokinetics Trandolapril’s 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 4 and 10 hours. The elimination half-life of trandolapril is about 6 hours. At steady state, the effective half-life of trandolaprilat is 22.5 hours. Like all ACE inhibitors, trandolaprilat also has a prolonged terminal elimination phase, involving a 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 C max of trandolaprilat or C max 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 (C max and AUC of tra

DOSAGE AND ADMINISTRATION Hypertension The recommended initial dosage of trandolapril tablets for patients not receiving a diuretic is 1 mg once daily in non-black patients and 2 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 1 week. Most patients have required dosages of 2 to 4 mg once daily. There is little clinical experience with doses above 8 mg. Patients inadequately treated with once-daily dosing at 4 mg may be treated with twice-daily dosing. If blood pressure is not adequately controlled with trandolapril tablets monotherapy, a diuretic may be added. In patients who are currently being treated with a 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 1 mg, once daily. Following the initial dose, all patients should be titrated (as tolerated) toward a target dose of 4 mg, once daily. If a 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 a 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 The safety experience in U.S. placebo-controlled trials included 1069 hypertensive patients, of whom 832 received trandolapril. Nearly 200 hypertensive patients received trandolapril 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. Adverse events considered at least possibly related to treatment occurring in 1% of trandolapril-treated patients and more common on trandolapril 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) 0.4 (0) Headache and fatigue were all seen in more than 1% of trandolapril-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 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 6.8 Elevated serum uric acid 15 13 Elevated BUN 9 7.6 PICA or CABG 7.3 6.1 Dyspepsia 6.4 6 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% (except as noted) of the patients treated with trandolapril (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. 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 Agranulocytosis, pancytopenia. Metabolism and Endocrine Increased SGOT (AST). Pulmonary Bronchitis. Renal and Urinary Renal

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

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

OVERDOSAGE No data are available with respect to overdosage in humans. The oral LD 50 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; 0 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 a 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.