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.

ADVERSE EVENTS IN PLACEBO-CONTROLLED HYPERTENSION TRIALS Occurring at 1% or greater

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.

Percentage of Patients with Adverse Events Greater Than Placebo Placebo-Controlled (TRACE) Mortality 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 (the rarer events are in italics) include (listed by body system):

General Body Function: chest pain.

Cardiovascular: AV first degree block, bradycardia, edema, flushing, hypotension, 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, pancreatitis.

Hemopoietic: decreased leukocytes, decreased neutrophils.

Metabolism and Endocrine: increased creatinine, increased potassium, increased SGPT (ALT).

Musculoskeletal System: extremity pain, muscle cramps, gout.

Pulmonary: dyspnea.

Angioedema: Angioedema has been reported in 4 (0.13%) patients receiving MAVIK in U.S. and foreign studies. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis, and/or larynx occurs, treatment with MAVIK should be discontinued and appropriate therapy instituted immediately. (See WARNINGS.)

Hypotension: In hypertensive patients, symptomatic hypotension occurred in 0.6% and near syncope occurred in 0.2%. Hypotension or syncope was a cause for discontinuation of therapy in 0.1% of hypertensive patients.

Fetal/Neonatal Morbidity and Mortality: (See WARNINGS, Fetal Neonatal Morbidity and Mortality.)

Cough: (See PRECAUTIONS, Cough.) Clinical Laboratory Test Findings

Hematology: (See WARNINGS.) Low white blood cells, low neutrophils, low lymphocytes, thrombocytopenia.

Serum Electrolytes: Hyperkalemia (See PRECAUTIONS, ) 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. (See PRECAUTIONS and WARNINGS.)

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.

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 hypoten-sive 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 interaction has been found between trandolaprilat and food, cimetidine, digoxin, or furosemide. The anticoagulant effect of warfarin was not significantly changed by trandolapril.

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