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MAVIK®
(trandolapril tablets)
USE IN PREGNANCY
When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, MAVIK should be discontinued as soon as possible. See WARNINGS - Fetal/Neonatal Morbidity and Mortality.
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 C24H34N2O5 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.
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 MAVIK 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. MAVIK 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 MAVIK.
Pharmacokinetics and Metabolism
Special Populations
Pharmacodynamics and Clinical Effects
A single 2-mg dose of MAVIK produces 70 to 85% inhibition of plasma ACE activity at 4 hours with about 10% decline at 24 hours and about half the effect manifest at 8 days. Maximum ACE inhibition is achieved with a plasma trandolaprilat concentration of 2 ng/mL. ACE inhibition is a function of trandolaprilat concentration, not trandolapril concentration. The effect of trandolapril on exogenous angiotensin I was not measured.
Hypertension
Four placebo-controlled dose response studies were conducted using once-daily oral dosing of MAVIK in doses from 0.25 to 16 mg per day in 827 black and non-black patients with mild to moderate hypertension. The minimal effective once-daily dose was 1 mg in non-black patients and 2 mg in black patients. Further decreases in trough supine diastolic blood pressure were obtained in non-black patients with higher doses, and no further response was seen with doses above 4 mg (up to 16 mg). The antihypertensive effect diminished somewhat at the end of the dosing interval, but trough/peak ratios are well above 50% for all effective doses. There was a slightly greater effect on the diastolic pressure, but no difference on systolic pressure with b.i.d. dosing. During chronic therapy, the maximum reduction in blood pressure with any dose is achieved within one week. Following 6 weeks of monotherapy in placebo-controlled trials in patients with mild to moderate hypertension, once-daily doses of 2 to 4 mg lowered supine or standing systolic/diastolic blood pressure 24 hours after dosing by an average 7-10/4-5 mmHg below placebo responses in non-black patients. Once-daily doses of 2 to 4 mg lowered blood pressure 4-6/3-4 mmHg in black patients. Trough to peak ratios for effective doses ranged from 0.5 to 0.9. There were no differences in response between men and women, but responses were somewhat greater in patients under 60 than in patients over 60 years old. Abrupt withdrawal of MAVIK has not been associated with a rapid increase in blood pressure.
Administration of MAVIK to patients with mild to moderate hypertension results in a reduction of supine, sitting and standing blood pressure to about the same extent without compensatory tachycardia.
Symptomatic hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted. (See WARNINGS.) Use of MAVIK in combination with thiazide diuretics gives a blood pressure lowering effect greater than that seen with either agent alone, and the additional effect of trandolapril is similar to the effect of monotherapy.
Heart Failure Post Myocardial Infarction or Left Ventricular Dysfunction Post Myocardial Infarction
The Trandolapril Cardiac Evaluation (TRACE) Trial was a Danish, 27-center, double-blind, placebo controlled, parallel-group study of the effect of trandolapril on all-cause mortality in stable patients with echocardiographic evidence of left ventricular dysfunction 3 to 7 days after a myocardial infarction. Subjects with residual ischemia or overt heart failure were included. Patients tolerant of a test dose of 1 mg trandolapril were randomized to placebo (n=873) or trandolapril (n=876) and followed for 24 months. Among patients randomized to trandolapril, who began treatment on 1 mg, 62% were successfully titrated to a target dose of 4 mg once daily over a period of weeks. The use of trandolapril was associated with a 16% reduction in the risk of all-cause mortality (p=0.042), largely cardiovascular mortality. Trandolapril was also associated with a 20% reduction in the risk of progression of heart failure (p=0.047), defined by a time-to-first-event analysis of death attributed to heart failure, hospitalization for heart failure, or requirement for open-label ACE inhibitor for the treatment of heart failure. There was no significant effect of treatment on other end-points: subsequent hospitalization, incidence of recurrent myocardial infarction, exercise tolerance, ventricular function, ventricular dimensions, or NYHA class.
The population in TRACE was entirely Caucasian and had less usage than would be typical in a U.S. population of other post-infarction interventions: 42% thrombolysis, 16% beta-adrenergic blockade, and 6.7% PTCA or CABG during the entire period of follow-up. Blood pressure control, especially in the placebo group, was poor: 47 to 53% of patients randomized to placebo and 32 to 40% of patients randomized to trandolapril had blood pressures > 140/95 at 90-day follow-up visits.
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).
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.
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 MAVIK, may be subject to a variety of adverse reactions, some of them serious.
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.
PRECAUTIONS
General
INFORMATION FOR PATIENTS
DRUG INTERACTIONS
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
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.
ADVERSE REACTIONS
The safety experience in U.S. placebo-controlled trials included 1067 hypertensive patients, of whom 831 received MAVIK. Nearly 200 hypertensive patients received MAVIK for over one year in open-label trials. In controlled trials, withdrawals for adverse events were 2.1% on placebo and 1.4% on MAVIK. Adverse events considered at least possibly related to treatment occurring in 1% of MAVIK-treated patients and more common on MAVIK than placebo, pooled for all doses, are shown below, together with the frequency of discontinuation of treatment because of these events.
| Occurring at 1% or greater | ||
| MAVIK (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 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.
| 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 | 9.0 | 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 |
| 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 1.0% (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 (the rarer events are in italics) include (uled by body system):
Clinical Laboratory Test Findings
Other
Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors.
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.
DOSAGE AND ADMINISTRATION
Hypertension
The recommended initial dosage of MAVIK 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 MAVIK 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 MAVIK. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning therapy with MAVIK. (See WARNINGS.) Then, if blood pressure is not controlled with MAVIK alone, diuretic therapy should be resumed. If the diuretic cannot be discontinued, an initial dose of 0.5 mg MAVIK 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 MAVIK 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.
HOW SUPPLIED
MAVIK (trandolapril tablets) are supplied as follows:
1 mg tablet - Salmon colored, round shaped, scored, compressed tablets, with Abbott “A” logo on one side and Abbo-Code identification letters FT on the other side. NDC 0074-2278-13 - bottles of 100 NDC 0074-2278-11 - unit dose packs of 100
2 mg tablet - Yellow colored, round shaped, compressed tablets, with Abbott “A” logo on one side and Abbo-Code identification letters FX on the other side. NDC 0074-2279-13 - bottles of 100 NDC 0074-2279-11 - unit dose packs of 100
4 mg tablet - Rose colored, round shaped, compressed tablets, with Abbott “A” logo on one side and Abbo-Code identification letters FZ on the other side. NDC 0074-2280-13 - bottles of 100 NDC 0074-2280-11 - unit dose packs of 100
Dispense in well-closed container with safety closure.
Storage
Store at controlled room temperature: 20-25°C (68-77°F) see USP.
Abbott Laboratories
North Chicago, IL 60064, U.S.A.