Mavik 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)-N-[(S)-1-Ethoxycarbonyl)-3-phenylpropyl)alanyl]hexahydro-2-indolinecarboxylic acid. Its empirical formula is C24 H34 N2 O5 and its structural formula is:

M.W. = 430.54

Melting Point = 125°C

Trandolapril is a white, crystalline powder that is soluble (> 100 mg/mL) in chloroform, dichloromethane, and methanol. MAVIK tablets contain 1 mg, 2 mg, or 4 mg of trandolapril for oral administration. Each tablet also contains corn starch, croscarmellose sodium, hypromellose, iron oxide, lactose monohydrate, povidone, sodium stearyl fumarate.

Mavik Indications And Usage

Hypertension

MAVIK is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive medication such as hydrochlorothiazide.

In considering the use of MAVIK, it should be noted that in controlled trials ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients. (See WARNINGS? Angioedema .)

When using MAVIK, consideration should be given to the fact that ACE inhibitors, including trandolapril have caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. (See WARNINGS .)

Heart Failure Post Myocardial Infarction Or Left-ventricular Dysfunction Post Myocardial Infarction

MAVIK is 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).

Mavik Contraindications

MAVIK is contraindicated in patients who are hypersensitive to this product and in patients with a history of angioedema related to previous treatment with an ACE inhibitor.

Mavik Side Effects

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 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

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 . (See PRECAUTIONS - Information for Patients and ADVERSE REACTIONS .)

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. (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, 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. (See DOSAGE AND ADMINISTRATION .) 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

As with other ACE inhibitors, trandolapril, 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. Therefore, 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/Neonatal Morbidity and Mortality

ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure.

These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of trandolapril as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, trandolapril should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy.

Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed 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.

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.

Mavik 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. (See DOSAGE AND ADMINISTRATION .)

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. (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, 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.

Information For Patients

Angioedema

Angioedema, including laryngeal edema, may occur at any time during treatment with ACE inhibitors, including MAVIK. 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 MAVIK 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 second- and third-trimester exposure to ACE inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. These 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 MAVIK 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

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 MAVIK. The possibility of exacerbation of hypotensive effects with MAVIK may be minimized by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with MAVIK. 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 .)

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.

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.

As with all antihypertensives, NSAIDs may reduce the antihypertensive effects of trandolapril. Blood pressure monitoring should be increased when any NSAID is added or discontinued in a patient treated with trandolapril.

The hypotensive effect of certain inhalation anesthetics may be enhanced by ACE inhibitors including trandolapril.

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.

Pregnancy

Pregnancy Categories C (First Trimester) and D (Second And Third Trimesters)

(See WARNINGS - Fetal/Neonatal Morbidity and Mortality.)

Nursing Mothers

Radiolabeled trandolapril or its metabolites are secreted in rat milk. MAVIK should not be administered to nursing mothers.

Geriatric Use

In placebo-controlled studies of MAVIK, 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

The safety and effectiveness of MAVIK in pediatric patients have not been established.

Mavik Overdosage

No data are available with respect to overdosage in humans. The oral LD50 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.

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.

Mavik Information For Patients

Angioedema

Angioedema, including laryngeal edema, may occur at any time during treatment with ACE inhibitors, including MAVIK. 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 MAVIK 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 second- and third-trimester exposure to ACE inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. These 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 MAVIK 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.