ADVERSE REACTIONS
The safety experience in U.S. placebo-controlled trials included 1069 hypertensive patients, of whom 832 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 | |
| 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.
Percentage of Patients with Adverse Events Greater Than Placebo 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 include (listed by body system):
General Body Function
Chest pain, malaise, fever.
Cardiovascular
AV first degree block, bradycardia, edema, flushing, hypotension, palpitations.
Central Nervous System
Drowsiness, insomnia, paresthesia, vertigo.
Dermatologic
Pruritus, rash, pemphigus, alopecia, sweating.
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, dry mouth, pancreatitis.
Hemopoietic
Agranulocytosis, decreased leukocytes, decreased neutrophils.
Metabolism and Endocrine
Increased creatinine, increased potassium, increased liver enzymes including SGPT (ALT) and increased SGOT (AST).
Musculoskeletal System
Extremity pain, muscle cramps, gout.
Pulmonary
Dyspnea, bronchitis.
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.
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