Trandolapril Tablets

FDA Drug Information • Also known as: Trandolapril

Brand Names: Trandolapril
Drug Class: Angiotensin Converting Enzyme Inhibitor [EPC]
Route: ORAL
Dosage Form: TABLET
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue trandolapril as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (See WARNINGS: Fetal Toxicity )

Description

DESCRIPTION Trandolapril is the ethyl ester prodrug of a nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor, trandolaprilat. Trandolapril is chemically described as (2S, 3aR, 7aS)-1-[(S)-N-[(S)-1-Carboxy-3-phenylpropyl]alanyl] hexahydro-2-indolinecarboxylic acid, 1- ethyl ester. Its empirical formula is C 24 H 34 N 2 O 5 and its structural formula is: M.W. = 430.54 Melting Point = 125°C Trandolapril is a white or almost white powder that is soluble (> 100 mg/mL) in chloroform, dichloromethane, and methanol. Trandolapril tablets contain 1 mg, 2 mg, or 4 mg of trandolapril USP for oral administration. Each tablet also contains corn starch, croscarmellose sodium, hypromellose, ferric oxide red, lactose monohydrate, povidone and sodium stearyl fumarate. Structural Formula - Trandolapril

What Is Trandolapril Tablets Used For?

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

Dosage and Administration

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.

Side Effects (Adverse Reactions)

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-CONTROLELD 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-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 Adverse Event Placebo-Controlled (TRACE) Mortality Study Trandolpril N=876 Placebo 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 or 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 Itermittent 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 (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:...

Warnings and Precautions

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...

Drug Interactions

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 trandoladpil 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.

Contraindications

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

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.

How Supplied

HOW SUPPLIED Trandolapril Tablets USP, 1 mg are pink, round biconvex beveled edge tablets, debossed “Є52” on one side and bisected on the other side; available in bottles of 100 and 1000. Trandolapril Tablets USP, 2 mg are pink, round biconvex beveled edge tablets, debossed “Є53” on one side and plain on the other side; available in bottles of 100 and 1000. Trandolapril Tablets USP, 4 mg are pink, round biconvex beveled edge tablets, debossed “Є54” on one side and plain on the other side; available in bottles of 100 and 1000. Storage Store at 20°-25°C (68°-77°F) see USP Controlled Room Temperature. Dispense contents in a tight, light-resistant container as defined in the USP, with a child-resistant closure as required. Manufactured by Epic Pharma, LLC Laurelton, NY 11413 Rev. 11-2017-00 MF052REV11/17 OE1420

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.