Sandbox Trandolapril
Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

# Hypertension
- Dosing Information
- Recommended initial dosage(for non-black patients): 1 mg PO qd
- Recommended initial dosage(for black patients): 2 mg PO qd
- Required dosage for most patients: 4-8 mg PO qd

# Heart Failure Post Myocardial Infarction or Left-Ventricular Dysfunction Post Myocardial Infarction
- Dosing information
- Recommended starting dosage: 1 mg PO qd
- Followed-by: 4 mg PO qd

# Dosage Adjustment in Renal Impairment or Hepatic Cirrhosis
- Dosing information
- 0.5 mg/day and have their dosage titrated to the optimal response.

# Acute ST segment elevation myocardial infarction
- Developed by: (Organization)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)

# Acute ST segment elevation myocardial infarction
- Dosing Information
- 4 mg/day
- Dosing information
- 2-4 mg/day
- 1 mg/day
- 2 mg/day
- Dosing information
- 1 mg PO qd-3 mg PO bid 
- Dosing Information
- Dosing Information
- There is limited information about Off-Label NonGuideline-Supported Use of Sandbox Trandolapril in pediatric patients.
Do not co-administer aliskiren with MAVIK in patients with diabetes
Presumably because angiotensin converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors, including MAVIK, 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 MAVIK. Symptoms suggestive of angioedema or facial edema occurred in 0.13% of MAVIK-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 MAVIK 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.

# 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
MAVIK can cause symptomatic hypotension. Like other ACE inhibitors, MAVIK 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 MAVIK. 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, MAVIK 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 MAVIK or diuretic is increased. 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 MAVIK 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 MAVIK 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 MAVIK, 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 MAVIK for hypotension, oliguria, and hyperkalemia.
Doses of 0.8 mg/kg/day (9.4 mg/m2/day) in rabbits, 1000 mg/kg/day (7000 mg/m2/day) in rats, and 25 mg/kg/day (295 mg/m2/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.

# 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 MAVIK (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.

# Hyperkalemia and Potassium-sparing Diuretics
In clinical trials, hyperkalemia (serum potassium > 6.00 mEq/L) occurred in approximately 0.4% of hypertensive patients receiving MAVIK. 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 MAVIK.

# 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, MAVIK 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.
Headache and fatigue were all seen in more than 1% of MAVIK-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 MAVIK 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.
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 MAVIK (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 MAVIK. 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 failure.

# Clinical Laboratory Test Findings

# Hematology
Thrombocytopenia.

# Serum Electrolytes
Hyponatremia.

# Creatinine and Blood Urea Nitrogen
Increases in creatinine levels occurred in 1.1% of patients receiving MAVIK alone and 7.3% of patients treated with MAVIK, a calcium ion antagonist and a diuretic. Increases in blood urea nitrogen levels occurred in 0.6% of patients receiving MAVIK alone and 1.4% of patients receiving MAVIK, a calcium ion antagonist, and a diuretic. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis.

# Liver Function Tests
Occasional elevation of transaminases at the rate of 3X upper normals occurred in 0.8% of patients and persistent increase in bilirubin occurred in 0.2% of patients. Discontinuation for elevated liver enzymes occurred in 0.2% of patients.

# Other
Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors.