CONTRAST AGENTS ARE ASSOCIATED WITH RISK AND INCREASED RADIATION
EXPOSURE, AND THE DECISION TO USE ENHANCEMENT SHOULD BE BASED UPON A CAREFUL
EVALUATION OF CLINICAL, OTHER RADIOLOGIC DATA, AND THE RESULTS OF UNENHANCED CT
Patients receiving contrast agents, and especially those
who are medically unstable, must be closely supervised. Diagnostic procedures
which involve the use of iodinated intravascular contrast agents should be
carried out under the direction of personnel skilled and experienced in the particular
procedure to be performed. A fully equipped emergency cart, or equivalent supplies
and equipment, and personnel competent in recognizing and treating adverse
reactions of all types should always be available.
Since severe delayed reactions have been known to occur,
emergency facilities and competent personnel should be available for at least
30 to 60 minutes.
Pediatric patients at higher risk of experiencing an
adverse reaction during and after administration of any contrast agent may include
those with asthma, hypersensitivity to other medication and/or allergens,
cyanotic and acyanotic heart disease, congestive heart failure, or a serum
creatinine greater than 1.5 mg/dL.
Pediatric patients with immature renal function or
dehydration may be at increased risk for adverse events due to prolonged
elimination of iodinated contrast agents.
The injection rates in small vascular beds, and the
relationship of the administered volume or concentration of iodinated contrast
agents in small neonates, infants and small pediatric patients, have not been
established. Caution should be exercised in selecting the volume.
Dehydration, Renal Insufficiency, Congestive Heart
Preparatory dehydration is dangerous and may contribute
to acute renal failure in patients with advanced vascular disease, congestive
heart disease, diabetic patients, and other patients such as those on
medications which alter renal function and the elderly with age-related renal
impairment. Patients should be adequately hydrated prior to and following
intravascular administration of iodinated contrast agent. Dose adjustments in
renal impairment have not been studied.
Iodinated contrast agents may cross the blood-brain
barrier. In patients where the blood-brain barrier is known or suspected to be
disrupted, or in patients with normal blood-brain barrier and associated renal
impairment, CAUTION MUST BE EXERCISED IN THE USE OF AN IODINATED CONTRAST
AGENT. (See Pharmacodynamics.)
Patients with congestive heart failure receiving
concurrent diuretic therapy may have relative intravascular volume depletion,
which may affect the renal response to the contrast agent osmotic load. These
patients should be observed following the procedure to detect delayed hemodynamic
renal function disturbances.
The possibility of a reaction, including serious,
life-threatening, fatal, anaphylactoid or cardiovascular reactions, should
always be considered. Increased risk is associated with a history of a previous
reaction to contrast agent, a known sensitivity to iodine and known allergies
(i.e., bronchial asthma, drug, or food allergies), other hypersensitivities,
and underlying immune disorders, autoimmunity or immunodeficiencies that
predispose to specific or nonspecific mediator release. If during
administration there is evidence of an allergy-like reaction, the injection
should be discontinued and appropriate treatment initiated.
Skin testing cannot be relied upon to predict severe
reactions and may itself be hazardous to the patient. A thorough medical
history with emphasis on allergy and hypersensitivity, immune, autoimmune and
immunodeficiency disorders, and prior receipt of and response to the injection of
any contrast agent may be more accurate than pretesting in predicting potential
Premedication with antihistamines or corticosteroids to
avoid or minimize possible allergic reactions does not prevent serious
life-threatening reactions, but may reduce both their incidence and severity.
Extreme caution should be exercised in considering the use of iodinated
contrast agents in patients with these histories or disorders.
Patients with a history of allergy or drug reaction
should be observed for several hours after drug administration.
General anesthesia may be indicated in the performance of
some procedures in selected patients; however, a higher incidence of adverse reactions
have been reported in these patients. It is not clear if this is due to the
inability of the patient to identify untoward symptoms or to the hypotensive
effect of anesthesia, which can prolong the circulation time and increase the
duration of exposure to a contrast agent.
In angiographic procedures, the possibility of dislodging
plaques, or damaging or perforating the vessel wall with resultant
pseudoaneurysms, hemorrhage at puncture site, dissection of coronary artery,
etc., should be considered during catheter Â anipulations and contrast agent
injection. Angiography may be associated with local and distal organ damage, ischemia,
thrombosis and organ failure (e.g., brachial plexus palsy, chest pain,
myocardial infarction, sinus arrest, hepatorenal function abnormalities, etc.).
Test injections to ensure proper catheter placement are suggested. During these
procedures, increased thrombosis and activation of the complement system has
also occurred. (See WARNINGS.)
Angiocardiography should be avoided whenever possible in
patients with homocystinuria because of the risk of inducing thrombosis and
embolism. (See Pharmacodynamics.) In an uncontrolled study of 204
patients who received VISIPAQUE Injection and who had cardiovascular disease
associated with either Class II-IV congestive failure, angina, recent myocardial
infarction, left ventricular ejection fraction of < 35% or valvular disease,
the patients were evaluated for the types of interventions needed for treatment
of adverse events. The reported type and frequency of adverse events were
comparable to those in all clinical intraarteriographic studies. Of 204
patients, 63 (31%) of patients had 99 adverse events. Of the 99 events, 68
(68%) required medical intervention of some type. Patients with 17 (17%) of
these adverse events required treatment with cardioversion, multiple
medications, prolonged hospitalization or intensive care. These interventions were
not compared to a control group of similar patients who did not have coronary
Selective coronary arteriography should be performed only
in patients for whom the expected benefits outweigh the procedural risk. Also,
the inherent risks of angiocardiography in patients with chronic pulmonary
emphysema must be weighed against the necessity for performing this procedure.
In addition to the general precautions previously
described, special care is required when venography is performed in patients
with suspected thrombosis, phlebitis, severe ischemic disease, local infection,
venous thrombosis or a totally obstructed venous system. Extreme caution during
injection of a contrast agent is necessary to avoid extravasation. This is especially
important in patients with severe arterial or venous disease.
General Adverse Reactions With Contrast Agents
The following adverse reactions are possible with any
parenterally administered iodinated contrast agent. Severe life-threatening
reactions and fatalities, mostly of cardiovascular origin, have occurred. Most
deaths occur during injection or five to ten minutes later, the main feature being
cardiac arrest, with cardiovascular disease as the main aggravating factor.
Isolated reports of hypotensive collapse and shock are found in the literature.
Based upon clinical literature reported deaths from the administration of other
iodinated contrast agents range from 6.6 per million (0.00066%) to 1 in 10,000
The reported incidence of adverse reactions to contrast
agents in patients with a history of allergy is twice that of the general
population. Patients with a history of a previous reaction to a contrast agent
are three times more susceptible than other patients. However, sensitivity to
contrast media does not appear to increase with repeated examinations.
Thyroid function tests indicative of hypothyroidism or
transient thyroid suppression have been uncommonly reported following iodinated
contrast media administration to adult and pediatric patients, including
infants. Some patients were treated for hypothyroidism.
Adverse reactions to injectable contrast agents fall into
two categories: chemotoxic reactions and idiosyncratic reactions. Chemotoxic
reactions result from the physicochemical properties of the contrast agent, the
dose and the speed of injection. All hemodynamic disturbances and injuries to organs
or vessels perfused by the contrast agent are included in this category.
Idiosyncratic reactions include all other reactions. They
occur more frequently in patients 20 to 40 years old. Idiosyncratic reactions
may or may not be dependent on the dose injected, the speed of injection, the
mode of injection and the radiographic procedure. Idiosyncratic reactions are
subdivided into minor, intermediate, and severe. The minor reactions are
self-limited and of short duration; the severe reactions are life-threatening,
and treatment is urgent and mandatory.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term animal studies have not been performed with
iodixanol to evaluate carcinogenic potential. Iodixanol was not genotoxic in a
series of studies including the Ames test, the CHO/HGPRT assay, a chromosome
aberration assay in CHO cells, and a mouse micronucleus assay. Iodixanol did
not impair the fertility of male or female rats when administered at doses up to
2.0 gI/kg (1.3 times the maximum recommended dose for a 50 kg human, or
approximately 0.2 times the maximum recommended dose for a 50 kg human
following normalization of the data to body surface area estimates).
Teratogenic Effects - Pregnancy Category B
Reproduction studies performed in rats and rabbits at
doses up to 2.0 gI/kg [1.3 times the maximum recommended dose for a 50 kg
human, or approximately 0.2 (rat) and 0.4 (rabbit) times the maximum
recommended dose for a 50 kg human following normalization of the data to body
surface estimates] have not revealed evidence of impaired fertility or harm to
the fetus due to iodixanol. Adequate and well-controlled studies in pregnant
women have not been conducted. Because animal reproduction studies are not
always predictive of human response, this drug should be used during pregnancy
only if clearly needed.
It is not known whether VISIPAQUE Injection is excreted
in human milk. However, many injectable contrast agents are excreted unchanged
in human milk. Although it has not been established that serious adverse
reactions occur in nursing infants, caution should be exercised when
intravascular contrast agents are administered to nursing women because of the
potential for adverse reactions, and consideration should be given to
temporarily discontinue nursing.
The safety and efficacy of VISIPAQUE has been established
in the pediatric population over 1 year of age for arterial studies and for
intravenous procedures. Use of VISIPAQUE in these age groups is supported by
evidence from adequate and well controlled studies of VISIPAQUE in adults and
additional safety data obtained in pediatric studies. Although VISIPAQUE has
been administered to pediatric patients less than 1 year of age, the relative
safety of the volumes injected, the optimal concentrations, and the potential
need for dose adjustment because of prolonged elimination half-lives have not
been systematically studied. (See CLINICAL PHARMACOLOGY – Special
VISIPAQUE (iodixanol) Injection was administered to 459
pediatric patients. There were 26 patients administered VISIPAQUE Injection in
the birth to < 29 day age range, 148 from 29 days to 2 years, 263 from 2 to
< 12 years, and 22 from 12 to 18 years. The mean age was 4.4 years (range
< 1 day to 17.4 years). Of the 459 patients, 252 (55%) were male and 207
(45%) were female. The racial distribution was: Caucasian-81%, Black-14%,
Oriental-2%, and other or unknown-4%. The demographic information for the pool
of patients who received a comparison contrast agent was similar.
In pediatric patients who received intravenous injection
for computerized tomography or excretory urography, a concentration of 270
mgI/mL was used in 144 patients, and a concentration of 320 mgI/mL in 154
patients. All patients received one intravenous injection of 1-2 mL/kg.
In pediatric patients who received intra-arterial and
intracardiac studies, a concentration of 320 mgI/mL was used in 161 patients.
Of the 161 patients in the intra-arterial studies, the mean age was 2.6 years.
Twenty-two patients were < 29 days of age; 78 were 29 days to 2 years of
age; and 61 were over 2 years. Most of these pediatric patients received
initial volumes of 1-2 mL/kg and most patients had a maximum of 3 injections.
Optimal volumes, concentrations or injection rates of
VISIPAQUE have not been established because different injection volumes,
concentrations, and injection rates were not studied. The relationship of the
volume of injection with respect to the size of the target vascular bed has not
been established. The potential need for dose adjustment to maximize efficacy
of computerized tomography, or to minimize the toxicity to other immature body
tissues, has not been studied in neonates or infants with immature renal
In the above patients, adverse events were associated
with decreasing age and intra-arterial procedures. In general the type of
adverse events reported are similar to those of adults. Although the frequency
of events appears to be comparable, the percentages cannot be confirmed because
of the different ability of pediatric and adult patients to report adverse
ADVERSE EVENTS REPORTED IN PEDIATRIC PATIENTS WHO RECEIVED
VISIPAQUE (BY AGE, ROUTE OF ADMINISTRATION, AND CONCENTRATION OF IODINE)
||Number of Patients with Adverse Events
| < 29 days
||P < 0.05 between the < 29 day and 1-2 year patient groups.
| > 29 days - 6 months
| > 6 months - 12 months
|1 year - 2 year
| > 2 years
||P < 0.05
||P < 0.05
(For additional information see the CLINICAL
PHARMACOLOGY – Special Populations, and DOSAGE AND ADMINISTRATION
Of the total number of patients in clinical studies of
VISIPAQUE in the U.S., 254/757 (34%) were 65 and over. No overall differences
in safety or effectiveness were observed between these patients and younger
patients, and other reported clinical experience has not identified differences
in response between the elderly and younger patients, but greater sensitivity
of some older individuals cannot be ruled out. In general, dose selection for
an elderly patient should be cautious usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal or
cardiac function, and of concomitant disease or other drug therapy. This drug
is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care
should be taken in dose selection, and it may be useful to monitor renal